INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84291, 2009, 'plos', 'The logic of EGFR/ErbB signaling: theoretical properties and analysis of high-throughput data', 'Samaga, Regina|Saez-Rodriguez, Julio|Alexopoulos, Leonidas G|Sorger, Peter K|Klamt, Steffen', 'Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.|Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.|Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.|Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.|Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.', 'Germany|Germany|Germany|Germany|Germany', 139, 'Algorithms|Cell Line, Tumor|Computational Biology|Computer Simulation|Databases, Factual|ErbB Receptors|Feedback, Physiological|Hepatocytes|Humans|Liver Neoplasms|Models, Biological|Protein Interaction Mapping|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000438', '19662154', 'The epidermal growth factor receptor (EGFR) signaling pathway is probably the best-studied receptor system in mammalian cells, and it also has become a popular example for employing mathematical modeling to cellular signaling networks. Dynamic models have the highest explanatory and predictive potential, however, the lack of kinetic information restricts current models of EGFR signaling to smaller sub-networks. This work aims to provide a large-scale qualitative model that comprises the main and also the side routes of EGFR/ErbB signaling and that still enables one to derive important functional properties and predictions. Using a recently introduced logical modeling framework, we first examined general topological properties and the qualitative stimulus-response behavior of the network. With species equivalence classes, we introduce a new technique for logical networks that reveals sets of nodes strongly coupled in their behavior. We also analyzed a model variant which explicitly accounts for uncertainties regarding the logical combination of signals in the model. The predictive power of this model is still high, indicating highly redundant sub-structures in the network. Finally, one key advance of this work is the introduction of new techniques for assessing high-throughput data with logical models (and their underlying interaction graph). By employing these techniques for phospho-proteomic data from primary hepatocytes and the HepG2 cell line, we demonstrate that our approach enables one to uncover inconsistencies between experimental results and our current qualitative knowledge and to generate new hypotheses and conclusions. Our results strongly suggest that the Rac/Cdc42 induced p38 and JNK cascades are independent of PI3K in both primary hepatocytes and HepG2. Furthermore, we detected that the activation of JNK in response to neuregulin follows a PI3K-dependent signaling pathway.'),
(84292, 2009, 'plos', 'A kinetic model of trp-cage folding from multiple biased molecular dynamics simulations', 'Marinelli, Fabrizio|Pietrucci, Fabio|Laio, Alessandro|Piana, Stefano', 'International School for Advanced Studies (SISSA-ISAS) and DEMOCRITOS, Trieste, Italy.|International School for Advanced Studies (SISSA-ISAS) and DEMOCRITOS, Trieste, Italy.|International School for Advanced Studies (SISSA-ISAS) and DEMOCRITOS, Trieste, Italy.|International School for Advanced Studies (SISSA-ISAS) and DEMOCRITOS, Trieste, Italy.', 'Italy|Italy|Italy|Italy', 0, 'Algorithms|Cluster Analysis|Computational Biology|Computer Simulation|Kinetics|Models, Chemical|Models, Molecular|Nuclear Magnetic Resonance, Biomolecular|Oligopeptides|Peptides|Protein Folding|Reproducibility of Results|Temperature|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000452', '19662155', 'Trp-cage is a designed 20-residue polypeptide that, in spite of its size, shares several features with larger globular proteins.Although the system has been intensively investigated experimentally and theoretically, its folding mechanism is not yet fully understood. Indeed, some experiments suggest a two-state behavior, while others point to the presence of intermediates. In this work we show that the results of a bias-exchange metadynamics simulation can be used for constructing a detailed thermodynamic and kinetic model of the system. The model, although constructed from a biased simulation, has a quality similar to those extracted from the analysis of long unbiased molecular dynamics trajectories. This is demonstrated by a careful benchmark of the approach on a smaller system, the solvated Ace-Ala3-Nme peptide. For theTrp-cage folding, the model predicts that the relaxation time of 3100 ns observed experimentally is due to the presence of a compact molten globule-like conformation. This state has an occupancy of only 3% at 300 K, but acts as a kinetic trap.Instead, non-compact structures relax to the folded state on the sub-microsecond timescale. The model also predicts the presence of a state at Calpha-RMSD of 4.4 A from the NMR structure in which the Trp strongly interacts with Pro12. This state can explain the abnormal temperature dependence of the Pro12-delta3 and Gly11-alpha3 chemical shifts. The structures of the two most stable misfolded intermediates are in agreement with NMR experiments on the unfolded protein. Our work shows that, using biased molecular dynamics trajectories, it is possible to construct a model describing in detail the Trp-cage folding kinetics and thermodynamics in agreement with experimental data.'),
(84293, 2009, 'plos', 'A generalized framework for quantifying the dynamics of EEG event-related desynchronization', 'Lemm, Steven|Müller, Klaus-Robert|Curio, Gabriel', 'Intelligent Data Analysis Group, Fraunhofer Institute FIRST, Berlin, Germany. steven.lemm@first.fraunhofer.de|Intelligent Data Analysis Group, Fraunhofer Institute FIRST, Berlin, Germany. steven.lemm@first.fraunhofer.de|Intelligent Data Analysis Group, Fraunhofer Institute FIRST, Berlin, Germany. steven.lemm@first.fraunhofer.de', 'Germany|Germany|Germany', 16, 'Algorithms|Computational Biology|Computer Simulation|Cortical Synchronization|Evoked Potentials, Somatosensory|Humans|Statistics, Nonparametric', 'Journal Article', '10.1371/journal.pcbi.1000453', '19662156', 'Brains were built by evolution to react swiftly to environmental challenges. Thus, sensory stimuli must be processed ad hoc, i.e., independent--to a large extent--from the momentary brain state incidentally prevailing during stimulus occurrence. Accordingly, computational neuroscience strives to model the robust processing of stimuli in the presence of dynamical cortical states. A pivotal feature of ongoing brain activity is the regional predominance of EEG eigenrhythms, such as the occipital alpha or the pericentral mu rhythm, both peaking spectrally at 10 Hz. Here, we establish a novel generalized concept to measure event-related desynchronization (ERD), which allows one to model neural oscillatory dynamics also in the presence of dynamical cortical states. Specifically, we demonstrate that a somatosensory stimulus causes a stereotypic sequence of first an ERD and then an ensuing amplitude overshoot (event-related synchronization), which at a dynamical cortical state becomes evident only if the natural relaxation dynamics of unperturbed EEG rhythms is utilized as reference dynamics. Moreover, this computational approach also encompasses the more general notion of a conditional ERD, through which candidate explanatory variables can be scrutinized with regard to their possible impact on a particular oscillatory dynamics under study. Thus, the generalized ERD represents a powerful novel analysis tool for extending our understanding of inter-trial variability of evoked responses and therefore the robust processing of environmental stimuli.'),
(84294, 2009, 'plos', 'Geometric de-noising of protein-protein interaction networks', 'Kuchaiev, Oleksii|Rasajski, Marija|Higham, Desmond J|Przulj, Natasa', 'Department of Computer Science, University of California, Irvine, California, USA.|Department of Computer Science, University of California, Irvine, California, USA.|Department of Computer Science, University of California, Irvine, California, USA.|Department of Computer Science, University of California, Irvine, California, USA.', 'United States|United States|United States|United States', 0, 'Algorithms|Computational Biology|Databases, Protein|Humans|Models, Biological|Protein Interaction Mapping|Proteins|ROC Curve|Reproducibility of Results|Sensitivity and Specificity|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000454', '19662157', 'Understanding complex networks of protein-protein interactions (PPIs) is one of the foremost challenges of the post-genomic era. Due to the recent advances in experimental bio-technology, including yeast-2-hybrid (Y2H), tandem affinity purification (TAP) and other high-throughput methods for protein-protein interaction (PPI) detection, huge amounts of PPI network data are becoming available. Of major concern, however, are the levels of noise and incompleteness. For example, for Y2H screens, it is thought that the false positive rate could be as high as 64%, and the false negative rate may range from 43% to 71%. TAP experiments are believed to have comparable levels of noise.We present a novel technique to assess the confidence levels of interactions in PPI networks obtained from experimental studies. We use it for predicting new interactions and thus for guiding future biological experiments. This technique is the first to utilize currently the best fitting network model for PPI networks, geometric graphs. Our approach achieves specificity of 85% and sensitivity of 90%. We use it to assign confidence scores to physical protein-protein interactions in the human PPI network downloaded from BioGRID. Using our approach, we predict 251 interactions in the human PPI network, a statistically significant fraction of which correspond to protein pairs sharing common GO terms. Moreover, we validate a statistically significant portion of our predicted interactions in the HPRD database and the newer release of BioGRID. The data and Matlab code implementing the methods are freely available from the web site: http://www.kuchaev.com/Denoising.'),
(84295, 2009, 'plos', 'Identifying currents in the gene pool for bacterial populations using an integrative approach', 'Tang, Jing|Hanage, William P|Fraser, Christophe|Corander, Jukka', 'Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland. jing.tang@helsinki.fi|Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland. jing.tang@helsinki.fi|Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland. jing.tang@helsinki.fi|Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland. jing.tang@helsinki.fi', 'Finland|Finland|Finland|Finland', 74, 'Algorithms|Bacteria|Bayes Theorem|Computational Biology|Computer Simulation|Gene Flow|Gene Pool|Genes, Bacterial|Models, Genetic|Neisseria lactamica|Neisseria meningitidis|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1000455', '19662158', 'The evolution of bacterial populations has recently become considerably better understood due to large-scale sequencing of population samples. It has become clear that DNA sequences from a multitude of genes, as well as a broad sample coverage of a target population, are needed to obtain a relatively unbiased view of its genetic structure and the patterns of ancestry connected to the strains. However, the traditional statistical methods for evolutionary inference, such as phylogenetic analysis, are associated with several difficulties under such an extensive sampling scenario, in particular when a considerable amount of recombination is anticipated to have taken place. To meet the needs of large-scale analyses of population structure for bacteria, we introduce here several statistical tools for the detection and representation of recombination between populations. Also, we introduce a model-based description of the shape of a population in sequence space, in terms of its molecular variability and affinity towards other populations. Extensive real data from the genus Neisseria are utilized to demonstrate the potential of an approach where these population genetic tools are combined with an phylogenetic analysis. The statistical tools introduced here are freely available in BAPS 5.2 software, which can be downloaded from http://web.abo.fi/fak/mnf/mate/jc/software/baps.html.'),
(84296, 2009, 'plos', 'Towards reproducible descriptions of neuronal network models', 'Nordlie, Eilen|Gewaltig, Marc-Oliver|Plesser, Hans Ekkehard', 'Department of Mathematical Sciences and Technology, Norwegian University of Life Sciences, Aas, Norway.|Department of Mathematical Sciences and Technology, Norwegian University of Life Sciences, Aas, Norway.|Department of Mathematical Sciences and Technology, Norwegian University of Life Sciences, Aas, Norway.', 'Norway|Norway|Norway', 0, 'Animals|Brain|Computational Biology|Humans|Membrane Potentials|Models, Neurological|Nerve Net|Neurons|Neurosciences|Reproducibility of Results|Synapses', 'Journal Article', '10.1371/journal.pcbi.1000456', '19662159', 'Progress in science depends on the effective exchange of ideas among scientists. New ideas can be assessed and criticized in a meaningful manner only if they are formulated precisely. This applies to simulation studies as well as to experiments and theories. But after more than 50 years of neuronal network simulations, we still lack a clear and common understanding of the role of computational models in neuroscience as well as established practices for describing network models in publications. This hinders the critical evaluation of network models as well as their re-use. We analyze here 14 research papers proposing neuronal network models of different complexity and find widely varying approaches to model descriptions, with regard to both the means of description and the ordering and placement of material. We further observe great variation in the graphical representation of networks and the notation used in equations. Based on our observations, we propose a good model description practice, composed of guidelines for the organization of publications, a checklist for model descriptions, templates for tables presenting model structure, and guidelines for diagrams of networks. The main purpose of this good practice is to trigger a debate about the communication of neuronal network models in a manner comprehensible to humans, as opposed to machine-readable model description languages. We believe that the good model description practice proposed here, together with a number of other recent initiatives on data-, model-, and software-sharing, may lead to a deeper and more fruitful exchange of ideas among computational neuroscientists in years to come. We further hope that work on standardized ways of describing--and thinking about--complex neuronal networks will lead the scientific community to a clearer understanding of high-level concepts in network dynamics, and will thus lead to deeper insights into the function of the brain.'),
(84297, 2009, 'plos', 'Ten simple rules for choosing between industry and academia', 'Searls, David B', 'Department of Mathematical Sciences and Technology, Norwegian University of Life Sciences, Aas, Norway.', 'Norway', 7, 'Biotechnology|Career Choice|Computational Biology|Humans|Industry|Personal Satisfaction|Universities|Workforce', 'Editorial', '10.1371/journal.pcbi.1000388', '19668326', '-'),
(84298, 2009, 'plos', 'How thioredoxin dissociates its mixed disulfide', 'Roos, Goedele|Foloppe, Nicolas|Van Laer, Koen|Wyns, Lode|Nilsson, Lennart|Geerlings, Paul|Messens, Joris', 'Department of Molecular and Cellular Interactions, Vlaams Interuniversitair Instituut voor Biotechnologie, Brussels, Belgium. groos@vub.ac.be|Department of Molecular and Cellular Interactions, Vlaams Interuniversitair Instituut voor Biotechnologie, Brussels, Belgium. groos@vub.ac.be|Department of Molecular and Cellular Interactions, Vlaams Interuniversitair Instituut voor Biotechnologie, Brussels, Belgium. groos@vub.ac.be|Department of Molecular and Cellular Interactions, Vlaams Interuniversitair Instituut voor Biotechnologie, Brussels, Belgium. groos@vub.ac.be|Department of Molecular and Cellular Interactions, Vlaams Interuniversitair Instituut voor Biotechnologie, Brussels, Belgium. groos@vub.ac.be|Department of Molecular and Cellular Interactions, Vlaams Interuniversitair Instituut voor Biotechnologie, Brussels, Belgium. groos@vub.ac.be|Department of Molecular and Cellular Interactions, Vlaams Interuniversitair Instituut voor Biotechnologie, Brussels, Belgium. groos@vub.ac.be', 'Belgium|Belgium|Belgium|Belgium|Belgium|Belgium|Belgium', 0, 'Arsenate Reductases|Computer Simulation|Cysteine|Disulfides|Kinetics|Linear Models|Models, Chemical|Models, Molecular|Oxidation-Reduction|Protein Conformation|Sulfhydryl Compounds|Thioredoxins', 'Journal Article', '10.1371/journal.pcbi.1000461', '19675666', 'The dissociation mechanism of the thioredoxin (Trx) mixed disulfide complexes is unknown and has been debated for more than twenty years. Specifically, opposing arguments for the activation of the nucleophilic cysteine as a thiolate during the dissociation of the complex have been put forward. As a key model, the complex between Trx and its endogenous substrate, arsenate reductase (ArsC), was used. In this structure, a Cys29(Trx)-Cys89(ArsC) intermediate disulfide is formed by the nucleophilic attack of Cys29(Trx) on the exposed Cys82(ArsC)-Cys89(ArsC) in oxidized ArsC. With theoretical reactivity analysis, molecular dynamics simulations, and biochemical complex formation experiments with Cys-mutants, Trx mixed disulfide dissociation was studied. We observed that the conformational changes around the intermediate disulfide bring Cys32(Trx) in contact with Cys29(Trx). Cys32(Trx) is activated for its nucleophilic attack by hydrogen bonds, and Cys32(Trx) is found to be more reactive than Cys82(ArsC). Additionally, Cys32(Trx) directs its nucleophilic attack on the more susceptible Cys29(Trx) and not on Cys89(ArsC). This multidisciplinary approach provides fresh insights into a universal thiol/disulfide exchange reaction mechanism that results in reduced substrate and oxidized Trx.'),
(84299, 2009, 'plos', 'Qualia: the geometry of integrated information', 'Balduzzi, David|Tononi, Giulio', 'Department of Psychiatry, University of Wisconsin, Madison, WI, USA.|Department of Psychiatry, University of Wisconsin, Madison, WI, USA.', 'United States|United States', 0, 'Algorithms|Artificial Intelligence|Computational Biology|Consciousness|Databases, Factual|Information Theory|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1000462', '19680424', 'According to the integrated information theory, the quantity of consciousness is the amount of integrated information generated by a complex of elements, and the quality of experience is specified by the informational relationships it generates. This paper outlines a framework for characterizing the informational relationships generated by such systems. Qualia space (Q) is a space having an axis for each possible state (activity pattern) of a complex. Within Q, each submechanism specifies a point corresponding to a repertoire of system states. Arrows between repertoires in Q define informational relationships. Together, these arrows specify a quale -- a shape that completely and univocally characterizes the quality of a conscious experience. Phi -- the height of this shape -- is the quantity of consciousness associated with the experience. Entanglement measures how irreducible informational relationships are to their component relationships, specifying concepts and modes. Several corollaries follow from these premises. The quale is determined by both the mechanism and state of the system. Thus, two different systems having identical activity patterns may generate different qualia. Conversely, the same quale may be generated by two systems that differ in both activity and connectivity. Both active and inactive elements specify a quale, but elements that are inactivated do not. Also, the activation of an element affects experience by changing the shape of the quale. The subdivision of experience into modalities and submodalities corresponds to subshapes in Q. In principle, different aspects of experience may be classified as different shapes in Q, and the similarity between experiences reduces to similarities between shapes. Finally, specific qualities, such as the redness of red, while generated by a local mechanism, cannot be reduced to it, but require considering the entire quale. Ultimately, the present framework may offer a principled way for translating qualitative properties of experience into mathematics.'),
(84300, 2009, 'plos', 'Temporal controls of the asymmetric cell division cycle in Caulobacter crescentus', 'Li, Shenghua|Brazhnik, Paul|Sobral, Bruno|Tyson, John J', 'Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.|Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.|Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.|Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.', 'United States|United States|United States|United States', 19, 'Bacterial Proteins|Caulobacter crescentus|Cell Cycle Proteins|Cell Division|Computational Biology|Computer Simulation|Gene Expression|Internet|Models, Biological|Mutation|Phenotype|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1000463', '19680425', 'The asymmetric cell division cycle of Caulobacter crescentus is orchestrated by an elaborate gene-protein regulatory network, centered on three major control proteins, DnaA, GcrA and CtrA. The regulatory network is cast into a quantitative computational model to investigate in a systematic fashion how these three proteins control the relevant genetic, biochemical and physiological properties of proliferating bacteria. Different controls for both swarmer and stalked cell cycles are represented in the mathematical scheme. The model is validated against observed phenotypes of wild-type cells and relevant mutants, and it predicts the phenotypes of novel mutants and of known mutants under novel experimental conditions. Because the cell cycle control proteins of Caulobacter are conserved across many species of alpha-proteobacteria, the model we are proposing here may be applicable to other genera of importance to agriculture and medicine (e.g., Rhizobium, Brucella).'),
(84301, 2009, 'plos', 'Nash equilibria in multi-agent motor interactions', 'Braun, Daniel A|Ortega, Pedro A|Wolpert, Daniel M', 'Computational and Biological Learning Laboratory, Department of Engineering, University of Cambridge, Cambridge, UK. dab54@cam.ac.uk|Computational and Biological Learning Laboratory, Department of Engineering, University of Cambridge, Cambridge, UK. dab54@cam.ac.uk|Computational and Biological Learning Laboratory, Department of Engineering, University of Cambridge, Cambridge, UK. dab54@cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 41, 'Game Theory|Genetics, Population|Humans|Models, Theoretical|Motor Activity', 'Journal Article', '10.1371/journal.pcbi.1000468', '19680426', 'Social interactions in classic cognitive games like the ultimatum game or the prisoners dilemma typically lead to Nash equilibria when multiple competitive decision makers with perfect knowledge select optimal strategies. However, in evolutionary game theory it has been shown that Nash equilibria can also arise as attractors in dynamical systems that can describe, for example, the population dynamics of microorganisms. Similar to such evolutionary dynamics, we find that Nash equilibria arise naturally in motor interactions in which players vie for control and try to minimize effort. When confronted with sensorimotor interaction tasks that correspond to the classical prisoners dilemma and the rope-pulling game, two-player motor interactions led predominantly to Nash solutions. In contrast, when a single player took both roles, playing the sensorimotor game bimanually, cooperative solutions were found. Our methodology opens up a new avenue for the study of human motor interactions within a game theoretic framework, suggesting that the coupling of motor systems can lead to game theoretic solutions.'),
(84302, 2009, 'plos', 'A parsimony approach to biological pathway reconstruction/inference for genomes and metagenomes', 'Ye, Yuzhen|Doak, Thomas G', 'School of Informatics, Indiana University, Bloomington, IN, USA. yye@indiana.edu|School of Informatics, Indiana University, Bloomington, IN, USA. yye@indiana.edu', 'India|India', 0, 'Algorithms|Databases, Genetic|Escherichia coli|Gene Regulatory Networks|Genome, Bacterial|Genome, Human|Genomics|Humans|Metabolic Networks and Pathways|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000465', '19680427', 'A common biological pathway reconstruction approach -- as implemented by many automatic biological pathway services (such as the KAAS and RAST servers) and the functional annotation of metagenomic sequences -- starts with the identification of protein functions or families (e.g., KO families for the KEGG database and the FIG families for the SEED database) in the query sequences, followed by a direct mapping of the identified protein families onto pathways. Given a predicted patchwork of individual biochemical steps, some metric must be applied in deciding what pathways actually exist in the genome or metagenome represented by the sequences. Commonly, and straightforwardly, a complete biological pathway can be identified in a dataset if at least one of the steps associated with the pathway is found. We report, however, that this naïve mapping approach leads to an inflated estimate of biological pathways, and thus overestimates the functional diversity of the sample from which the DNA sequences are derived. We developed a parsimony approach, called MinPath (Minimal set of Pathways), for biological pathway reconstructions using protein family predictions, which yields a more conservative, yet more faithful, estimation of the biological pathways for a query dataset. MinPath identified far fewer pathways for the genomes collected in the KEGG database -- as compared to the naïve mapping approach -- eliminating some obviously spurious pathway annotations. Results from applying MinPath to several metagenomes indicate that the common methods used for metagenome annotation may significantly overestimate the biological pathways encoded by microbial communities.'),
(84303, 2009, 'plos', 'Recognizing sequences of sequences', 'Kiebel, Stefan J|von Kriegstein, Katharina|Daunizeau, Jean|Friston, Karl J', 'Wellcome Trust Centre for Neuroimaging, London, UK. skiebel@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, London, UK. skiebel@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, London, UK. skiebel@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, London, UK. skiebel@fil.ion.ucl.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 80, 'Bayes Theorem|Computer Simulation|Models, Theoretical|Nerve Net|Neural Networks (Computer)|Pattern Recognition, Physiological|Speech Recognition Software|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000464', '19680429', 'The brains decoding of fast sensory streams is currently impossible to emulate, even approximately, with artificial agents. For example, robust speech recognition is relatively easy for humans but exceptionally difficult for artificial speech recognition systems. In this paper, we propose that recognition can be simplified with an internal model of how sensory input is generated, when formulated in a Bayesian framework. We show that a plausible candidate for an internal or generative model is a hierarchy of stable heteroclinic channels. This model describes continuous dynamics in the environment as a hierarchy of sequences, where slower sequences cause faster sequences. Under this model, online recognition corresponds to the dynamic decoding of causal sequences, giving a representation of the environment with predictive power on several timescales. We illustrate the ensuing decoding or recognition scheme using synthetic sequences of syllables, where syllables are sequences of phonemes and phonemes are sequences of sound-wave modulations. By presenting anomalous stimuli, we find that the resulting recognition dynamics disclose inference at multiple time scales and are reminiscent of neuronal dynamics seen in the real brain.'),
(84304, 2009, 'plos', 'A condensation-ordering mechanism in nanoparticle-catalyzed peptide aggregation', 'Auer, Stefan|Trovato, Antonio|Vendruscolo, Michele', 'Centre for Self Organising Molecular Systems, University of Leeds, Leeds, UK. s.auer@leeds.ac.uk|Centre for Self Organising Molecular Systems, University of Leeds, Leeds, UK. s.auer@leeds.ac.uk|Centre for Self Organising Molecular Systems, University of Leeds, Leeds, UK. s.auer@leeds.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 66, 'Cluster Analysis|Computational Biology|Computer Simulation|Hydrogen Bonding|Hydrophobic and Hydrophilic Interactions|Models, Chemical|Molecular Conformation|Nanoparticles|Particle Size|Peptides|Polymers|Protein Conformation|Protein Multimerization|Protein Structure, Secondary', 'Journal Article', '10.1371/journal.pcbi.1000458', '19680431', 'Nanoparticles introduced in living cells are capable of strongly promoting the aggregation of peptides and proteins. We use here molecular dynamics simulations to characterise in detail the process by which nanoparticle surfaces catalyse the self-assembly of peptides into fibrillar structures. The simulation of a system of hundreds of peptides over the millisecond timescale enables us to show that the mechanism of aggregation involves a first phase in which small structurally disordered oligomers assemble onto the nanoparticle and a second phase in which they evolve into highly ordered as their size increases.'),
(84305, 2009, 'plos', 'Red Queen dynamics with non-standard fitness interactions', 'Engelstädter, Jan|Bonhoeffer, Sebastian', 'Institute of Integrative Biology, ETH Zurich, Switzerland. jan.engelstaedter@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Switzerland. jan.engelstaedter@env.ethz.ch', 'Switzerland|Switzerland', 0, 'Computational Biology|Computer Simulation|Evolution, Molecular|Genetics, Population|Genotype|Host-Parasite Interactions|Linkage Disequilibrium|Models, Genetic|Polymorphism, Genetic|Recombination, Genetic|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000469', '19680432', 'Antagonistic coevolution between hosts and parasites can involve rapid fluctuations of genotype frequencies that are known as Red Queen dynamics. Under such dynamics, recombination in the hosts may be advantageous because genetic shuffling can quickly produce disproportionately fit offspring (the Red Queen hypothesis). Previous models investigating these dynamics have assumed rather simple models of genetic interactions between hosts and parasites. Here, we assess the robustness of earlier theoretical predictions about the Red Queen with respect to the underlying host-parasite interactions. To this end, we created large numbers of random interaction matrices, analysed the resulting dynamics through simulation, and ascertained whether recombination was favoured or disfavoured. We observed Red Queen dynamics in many of our simulations provided the interaction matrices exhibited sufficient antagonicity. In agreement with previous studies, strong selection on either hosts or parasites favours selection for increased recombination. However, fast changes in the sign of linkage disequilibrium or epistasis were only infrequently observed and do not appear to be a necessary condition for the Red Queen hypothesis to work. Indeed, recombination was often favoured even though the linkage disequilibrium remained of constant sign throughout the simulations. We conclude that Red Queen-type dynamics involving persistent fluctuations in host and parasite genotype frequencies appear to not be an artefact of specific assumptions about host-parasite fitness interactions, but emerge readily with the general interactions studied here. Our results also indicate that although recombination is often favoured, some of the factors previously thought to be important in this process such as linkage disequilibrium fluctuations need to be reassessed when fitness interactions between hosts and parasites are complex.'),
(84306, 2009, 'plos', 'Accelerated immunodeficiency by anti-CCR5 treatment in HIV infection', 'Weinberger, Ariel D|Perelson, Alan S|Ribeiro, Ruy M|Weinberger, Leor S', 'Biophysics Graduate Group, University of California, Berkeley, CA, USA. arielw@berkeley.edu|Biophysics Graduate Group, University of California, Berkeley, CA, USA. arielw@berkeley.edu|Biophysics Graduate Group, University of California, Berkeley, CA, USA. arielw@berkeley.edu|Biophysics Graduate Group, University of California, Berkeley, CA, USA. arielw@berkeley.edu', 'United States|United States|United States|United States', 0, 'Acquired Immunodeficiency Syndrome|Anti-HIV Agents|CCR5 Receptor Antagonists|HIV-1|Humans|Models, Biological|Receptors, CCR5|Receptors, CXCR4|Virulence', 'Journal Article', '10.1371/journal.pcbi.1000467', '19680436', 'In 50% of progressing HIV-1 patients, CXCR4-tropic (X4) virus emerges late in infection, often overtaking CCR5-tropic (R5) virus as the dominant viral strain. This phenotypic switch is strongly associated with rapidly declining CD4(+) T cell counts and AIDS onset, yet its causes remain unknown. Here, we analyze a mathematical model for the mechanism of X4 emergence in late-stage HIV infection and use this analysis to evaluate the utility of a promising new class of antiretroviral drugs -- CCR5 inhibitors -- in dual R5, X4 infection. The model shows that the R5-to-X4 switch occurs as CD4(+) T cell activation levels increase above a threshold and as CD4(+) T cell counts decrease below a threshold during late-stage HIV infection. Importantly, the model also shows that highly active antiretroviral therapy (HAART) can inhibit X4 emergence but that monotherapy with CCR5 blockers can accelerate X4 onset and immunodeficiency if X4 infection of memory CD4(+) T cells occurs at a high rate. Fortunately, when CXCR4 blockers or HAART are used in conjunction with CCR5 blockers, this risk of accelerated immunodeficiency is eliminated. The results suggest that CCR5 blockers will be more effective when used in combination with CXCR4 blockers and caution against CCR5 blockers in the absence of an effective HAART regimen or during HAART failure.'),
(84307, 2009, 'plos', 'Four distances between pairs of amino acids provide a precise description of their interaction', 'Cohen, Mati|Potapov, Vladimir|Schreiber, Gideon', 'Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel|Israel', 21, 'Amino Acid Sequence|Amino Acids|Crystallography, X-Ray|Databases, Protein|Models, Molecular|Protein Conformation|Proteins|Proteomics', 'Journal Article', '10.1371/journal.pcbi.1000470', '19680437', 'The three-dimensional structures of proteins are stabilized by the interactions between amino acid residues. Here we report a method where four distances are calculated between any two side chains to provide an exact spatial definition of their bonds. The data were binned into a four-dimensional grid and compared to a random model, from which the preference for specific four-distances was calculated. A clear relation between the quality of the experimental data and the tightness of the distance distribution was observed, with crystal structure data providing far tighter distance distributions than NMR data. Since the four-distance data have higher information content than classical bond descriptions, we were able to identify many unique inter-residue features not found previously in proteins. For example, we found that the side chains of Arg, Glu, Val and Leu are not symmetrical in respect to the interactions of their head groups. The described method may be developed into a function, which computationally models accurately protein structures.'),
(84308, 2009, 'plos', 'Model-based deconvolution of cell cycle time-series data reveals gene expression details at high resolution', 'Siegal-Gaskins, Dan|Ash, Joshua N|Crosson, Sean', 'Mathematical Biosciences Institute, Ohio State University, Columbus, OH, USA. dsg@mbi.osu.edu|Mathematical Biosciences Institute, Ohio State University, Columbus, OH, USA. dsg@mbi.osu.edu|Mathematical Biosciences Institute, Ohio State University, Columbus, OH, USA. dsg@mbi.osu.edu', 'United States|United States|United States', 0, 'Algorithms|Bacterial Proteins|Caulobacter crescentus|Cell Cycle|Cell Cycle Proteins|Computational Biology|Databases, Genetic|Gene Expression|Gene Expression Profiling|Models, Biological|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000460', '19680537', 'In both prokaryotic and eukaryotic cells, gene expression is regulated across the cell cycle to ensure just-in-time assembly of select cellular structures and molecular machines. However, present in all time-series gene expression measurements is variability that arises from both systematic error in the cell synchrony process and variance in the timing of cell division at the level of the single cell. Thus, gene or protein expression data collected from a population of synchronized cells is an inaccurate measure of what occurs in the average single-cell across a cell cycle. Here, we present a general computational method to extract single-cell-like information from population-level time-series expression data. This method removes the effects of 1) variance in growth rate and 2) variance in the physiological and developmental state of the cell. Moreover, this method represents an advance in the deconvolution of molecular expression data in its flexibility, minimal assumptions, and the use of a cross-validation analysis to determine the appropriate level of regularization. Applying our deconvolution algorithm to cell cycle gene expression data from the dimorphic bacterium Caulobacter crescentus, we recovered critical features of cell cycle regulation in essential genes, including ctrA and ftsZ, that were obscured in population-based measurements. In doing so, we highlight the problem with using population data alone to decipher cellular regulatory mechanisms and demonstrate how our deconvolution algorithm can be applied to produce a more realistic picture of temporal regulation in a cell.'),
(84309, 2009, 'plos', 'Investigating CTL mediated killing with a 3D cellular automaton', 'Graw, Frederik|Regoes, Roland R', 'Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. frederik.graw@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. frederik.graw@env.ethz.ch', 'Switzerland|Switzerland', 29, 'Algorithms|Animals|Cell Movement|Computer Simulation|Imaging, Three-Dimensional|Mice|Models, Immunological|Spleen|T-Lymphocytes, Cytotoxic', 'Journal Article', '10.1371/journal.pcbi.1000466', '19696876', 'Cytotoxic T lymphocytes (CTLs) are important immune effectors against intra-cellular pathogens. These cells search for infected cells and kill them. Recently developed experimental methods in combination with mathematical models allow for the quantification of the efficacy of CTL killing in vivo and, hence, for the estimation of parameters that characterize the effect of CTL killing on the target cell populations. It is not known how these population-level parameters relate to single-cell properties. To address this question, we developed a three-dimensional cellular automaton model of the region of the spleen where CTL killing takes place. The cellular automaton model describes the movement of different cell populations and their interactions. Cell movement patterns in our cellular automaton model agree with observations from two-photon microscopy. We find that, despite the strong spatial nature of the kinetics in our cellular automaton model, the killing of target cells by CTLs can be described by a term which is linear in the target cell frequency and saturates with respect to the CTL levels. Further, we find that the parameters describing CTL killing on the population level are most strongly impacted by the time a CTL needs to kill a target cell. This suggests that the killing of target cells, rather than their localization, is the limiting step in CTL killing dynamics given reasonable frequencies of CTL. Our analysis identifies additional experimental directions which are of particular importance to interpret estimates of killing rates and could advance our quantitative understanding of CTL killing.'),
(84310, 2009, 'plos', 'On the accessibility of adaptive phenotypes of a bacterial metabolic network', 'Ndifon, Wilfred|Plotkin, Joshua B|Dushoff, Jonathan', 'Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, USA. ndifon@gmail.com|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, USA. ndifon@gmail.com|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, USA. ndifon@gmail.com', 'Jersey|Jersey|Jersey', 10, 'Adaptation, Biological|Algorithms|Computer Simulation|Escherichia coli|Evolution, Molecular|Genotype|Metabolic Networks and Pathways|Models, Genetic|Phenotype', 'Journal Article', '10.1371/journal.pcbi.1000472', '19696877', 'The mechanisms by which adaptive phenotypes spread within an evolving population after their emergence are understood fairly well. Much less is known about the factors that influence the evolutionary accessibility of such phenotypes, a pre-requisite for their emergence in a population. Here, we investigate the influence of environmental quality on the accessibility of adaptive phenotypes of Escherichia colis central metabolic network. We used an established flux-balance model of metabolism as the basis for a genotype-phenotype map (GPM). We quantified the effects of seven qualitatively different environments (corresponding to both carbohydrate and gluconeogenic metabolic substrates) on the structure of this GPM. We found that the GPM has a more rugged structure in qualitatively poorer environments, suggesting that adaptive phenotypes could be intrinsically less accessible in such environments. Nevertheless, on average approximately 74% of the genotype can be altered by neutral drift, in the environment where the GPM is most rugged, this could allow evolving populations to circumvent such ruggedness. Furthermore, we found that the normalized mutual information (NMI) of genotype differences relative to phenotype differences, which measures the GPMs capacity to transmit information about phenotype differences, is positively correlated with (simulation-based) estimates of the accessibility of adaptive phenotypes in different environments. These results are consistent with the predictions of a simple analytic theory that makes explicit the relationship between the NMI and the speed of adaptation. The results suggest an intuitive information-theoretic principle for evolutionary adaptation, adaptation could be faster in environments where the GPM has a greater capacity to transmit information about phenotype differences. More generally, our results provide insight into fundamental environment-specific differences in the accessibility of adaptive phenotypes, and they suggest opportunities for research at the interface between information theory and evolutionary biology.'),
(84311, 2009, 'plos', 'Accurate prediction of DnaK-peptide binding via homology modelling and experimental data', 'Van Durme, Joost|Maurer-Stroh, Sebastian|Gallardo, Rodrigo|Wilkinson, Hannah|Rousseau, Frederic|Schymkowitz, Joost', 'VIB Switch Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.|VIB Switch Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.|VIB Switch Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.|VIB Switch Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.|VIB Switch Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.|VIB Switch Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.', 'Belgium|Belgium|Belgium|Belgium|Belgium|Belgium', 0, 'Algorithms|Binding Sites|Computational Biology|Escherichia coli Proteins|HSP70 Heat-Shock Proteins|Immobilized Proteins|Models, Molecular|Pattern Recognition, Automated|Peptides|Protein Binding|ROC Curve|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1000475', '19696878', 'Molecular chaperones are essential elements of the protein quality control machinery that governs translocation and folding of nascent polypeptides, refolding and degradation of misfolded proteins, and activation of a wide range of client proteins. The prokaryotic heat-shock protein DnaK is the E. coli representative of the ubiquitous Hsp70 family, which specializes in the binding of exposed hydrophobic regions in unfolded polypeptides. Accurate prediction of DnaK binding sites in E. coli proteins is an essential prerequisite to understand the precise function of this chaperone and the properties of its substrate proteins. In order to map DnaK binding sites in protein sequences, we have developed an algorithm that combines sequence information from peptide binding experiments and structural parameters from homology modelling. We show that this combination significantly outperforms either single approach. The final predictor had a Matthews correlation coefficient (MCC) of 0.819 when assessed over the 144 tested peptide sequences to detect true positives and true negatives. To test the robustness of the learning set, we have conducted a simulated cross-validation, where we omit sequences from the learning sets and calculate the rate of repredicting them. This resulted in a surprisingly good MCC of 0.703. The algorithm was also able to perform equally well on a blind test set of binders and non-binders, of which there was no prior knowledge in the learning sets. The algorithm is freely available at http://limbo.vib.be.'),
(84312, 2009, 'plos', 'Temporal variability and social heterogeneity in disease transmission: the case of SARS in Hong Kong', 'Cori, Anne|Boëlle, Pierre-Yves|Thomas, Guy|Leung, Gabriel M|Valleron, Alain-Jacques', 'INSERM, Paris, France. cori@u707.jussieu.fr|INSERM, Paris, France. cori@u707.jussieu.fr|INSERM, Paris, France. cori@u707.jussieu.fr|INSERM, Paris, France. cori@u707.jussieu.fr|INSERM, Paris, France. cori@u707.jussieu.fr', 'France|France|France|France|France', 17, 'Algorithms|Community-Acquired Infections|Cross Infection|Disease Outbreaks|Health Personnel|Hong Kong|Humans|Infectious Disease Transmission, Patient-to-Professional|Infectious Disease Transmission, Professional-to-Patient|Markov Chains|Models, Statistical|Monte Carlo Method|SARS Virus|Severe Acute Respiratory Syndrome|Stochastic Processes|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1000471', '19696879', 'The extent to which self-adopted or intervention-related changes in behaviors affect the course of epidemics remains a key issue for outbreak control. This study attempted to quantify the effect of such changes on the risk of infection in different settings, i.e., the community and hospitals. The 2002-2003 severe acute respiratory syndrome (SARS) outbreak in Hong Kong, where 27% of cases were healthcare workers, was used as an example. A stochastic compartmental SEIR (susceptible-exposed-infectious-removed) model was used: the population was split into healthcare workers, hospitalized people and general population. Super spreading events (SSEs) were taken into account in the model. The temporal evolutions of the daily effective contact rates in the community and hospitals were modeled with smooth functions. Data augmentation techniques and Markov chain Monte Carlo (MCMC) methods were applied to estimate SARS epidemiological parameters. In particular, estimates of daily reproduction numbers were provided for each subpopulation. The average duration of the SARS infectious period was estimated to be 9.3 days (+/-0.3 days). The model was able to disentangle the impact of the two SSEs from background transmission rates. The effective contact rates, which were estimated on a daily basis, decreased with time, reaching zero inside hospitals. This observation suggests that public health measures and possible changes in individual behaviors effectively reduced transmission, especially in hospitals. The temporal patterns of reproduction numbers were similar for healthcare workers and the general population, indicating that on average, an infectious healthcare worker did not infect more people than any other infectious person. We provide a general method to estimate time dependence of parameters in structured epidemic models, which enables investigation of the impact of control measures and behavioral changes in different settings.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84313, 2009, 'plos', 'Can molecular motors drive distance measurements in injured neurons?', 'Kam, Naaman|Pilpel, Yitzhak|Fainzilber, Mike', 'Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel|Israel', 27, 'Computer Simulation|Data Interpretation, Statistical|Databases, Factual|Dyneins|Models, Neurological|Neurons|Peripheral Nerve Injuries|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000477', '19696880', 'Injury to nerve axons induces diverse responses in neuronal cell bodies, some of which are influenced by the distance from the site of injury. This suggests that neurons have the capacity to estimate the distance of the injury site from their cell body. Recent work has shown that the molecular motor dynein transports importin-mediated retrograde signaling complexes from axonal lesion sites to cell bodies, raising the question whether dynein-based mechanisms enable axonal distance estimations in injured neurons? We used computer simulations to examine mechanisms that may provide nerve cells with dynein-dependent distance assessment capabilities. A multiple-signals model was postulated based on the time delay between the arrival of two or more signals produced at the site of injury-a rapid signal carried by action potentials or similar mechanisms and slower signals carried by dynein. The time delay between the arrivals of these two types of signals should reflect the distance traversed, and simulations of this model show that it can indeed provide a basis for distance measurements in the context of nerve injuries. The analyses indicate that the suggested mechanism can allow nerve cells to discriminate between distances differing by 10% or more of their total axon length, and suggest that dynein-based retrograde signaling in neurons can be utilized for this purpose over different scales of nerves and organisms. Moreover, such a mechanism might also function in synapse to nucleus signaling in uninjured neurons. This could potentially allow a neuron to dynamically sense the relative lengths of its processes on an ongoing basis, enabling appropriate metabolic output from cell body to processes.'),
(84314, 2009, 'plos', 'Microarray comparative genomic hybridisation analysis incorporating genomic organisation, and application to enterobacterial plant pathogens', 'Pritchard, Leighton|Liu, Hui|Booth, Clare|Douglas, Emma|François, Patrice|Schrenzel, Jacques|Hedley, Peter E|Birch, Paul R J|Toth, Ian K', 'Plant Pathology Programme, SCRI, Dundee, Scotland, United Kingdom. lpritc@scri.ac.uk|Plant Pathology Programme, SCRI, Dundee, Scotland, United Kingdom. lpritc@scri.ac.uk|Plant Pathology Programme, SCRI, Dundee, Scotland, United Kingdom. lpritc@scri.ac.uk|Plant Pathology Programme, SCRI, Dundee, Scotland, United Kingdom. lpritc@scri.ac.uk|Plant Pathology Programme, SCRI, Dundee, Scotland, United Kingdom. lpritc@scri.ac.uk|Plant Pathology Programme, SCRI, Dundee, Scotland, United Kingdom. lpritc@scri.ac.uk|Plant Pathology Programme, SCRI, Dundee, Scotland, United Kingdom. lpritc@scri.ac.uk|Plant Pathology Programme, SCRI, Dundee, Scotland, United Kingdom. lpritc@scri.ac.uk|Plant Pathology Programme, SCRI, Dundee, Scotland, United Kingdom. lpritc@scri.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Cluster Analysis|Comparative Genomic Hybridization|Computer Simulation|Enterobacteriaceae|Gene Transfer, Horizontal|Genetic Variation|Genome, Bacterial|Genomic Islands|Markov Chains|Models, Statistical|Normal Distribution|Oligonucleotide Array Sequence Analysis|Plant Diseases|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000473', '19696881', 'Microarray comparative genomic hybridisation (aCGH) provides an estimate of the relative abundance of genomic DNA (gDNA) taken from comparator and reference organisms by hybridisation to a microarray containing probes that represent sequences from the reference organism. The experimental method is used in a number of biological applications, including the detection of human chromosomal aberrations, and in comparative genomic analysis of bacterial strains, but optimisation of the analysis is desirable in each problem domain.We present a method for analysis of bacterial aCGH data that encodes spatial information from the reference genome in a hidden Markov model. This technique is the first such method to be validated in comparisons of sequenced bacteria that diverge at the strain and at the genus level: Pectobacterium atrosepticum SCRI1043 (Pba1043) and Dickeya dadantii 3937 (Dda3937), and Lactococcus lactis subsp. lactis IL1403 and L. lactis subsp. cremoris MG1363. In all cases our method is found to outperform common and widely used aCGH analysis methods that do not incorporate spatial information. This analysis is applied to comparisons between commercially important plant pathogenic soft-rotting enterobacteria (SRE) Pba1043, P. atrosepticum SCRI1039, P. carotovorum 193, and Dda3937.Our analysis indicates that it should not be assumed that hybridisation strength is a reliable proxy for sequence identity in aCGH experiments, and robustly extends the applicability of aCGH to bacterial comparisons at the genus level. Our results in the SRE further provide evidence for a dynamic, plastic accessory genome, revealing major genomic islands encoding gene products that provide insight into, and may play a direct role in determining, variation amongst the SRE in terms of their environmental survival, host range and aetiology, such as phytotoxin synthesis, multidrug resistance, and nitrogen fixation.'),
(84315, 2009, 'plos', 'Amyloidogenic regions and interaction surfaces overlap in globular proteins related to conformational diseases', 'Castillo, Virginia|Ventura, Salvador', 'Departament de Bioquímica i Biologia Molecular and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Barcelona, Spain.|Departament de Bioquímica i Biologia Molecular and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Barcelona, Spain.', 'Spain|Spain', 55, 'Alzheimer Disease|Amyloid|Amyloid beta-Peptides|Humans|Immunoglobulins|Models, Molecular|Muramidase|Parkinson Disease|Prealbumin|Protein Folding|Protein Interaction Domains and Motifs|Protein Multimerization|Superoxide Dismutase|beta 2-Microglobulin', 'Journal Article', '10.1371/journal.pcbi.1000476', '19696882', 'Protein aggregation underlies a wide range of human disorders. The polypeptides involved in these pathologies might be intrinsically unstructured or display a defined 3D-structure. Little is known about how globular proteins aggregate into toxic assemblies under physiological conditions, where they display an initially folded conformation. Protein aggregation is, however, always initiated by the establishment of anomalous protein-protein interactions. Therefore, in the present work, we have explored the extent to which protein interaction surfaces and aggregation-prone regions overlap in globular proteins associated with conformational diseases. Computational analysis of the native complexes formed by these proteins shows that aggregation-prone regions do frequently overlap with protein interfaces. The spatial coincidence of interaction sites and aggregating regions suggests that the formation of functional complexes and the aggregation of their individual subunits might compete in the cell. Accordingly, single mutations affecting complex interface or stability usually result in the formation of toxic aggregates. It is suggested that the stabilization of existing interfaces in multimeric proteins or the formation of new complexes in monomeric polypeptides might become effective strategies to prevent disease-linked aggregation of globular proteins.'),
(84316, 2009, 'plos', 'A self-organizing algorithm for modeling protein loops', 'Liu, Pu|Zhu, Fangqiang|Rassokhin, Dmitrii N|Agrafiotis, Dimitris K', 'Johnson & Johnson Pharmaceutical Research and Development, Exton, Pennsylvania, USA. pliu24@its.jnj.com|Johnson & Johnson Pharmaceutical Research and Development, Exton, Pennsylvania, USA. pliu24@its.jnj.com|Johnson & Johnson Pharmaceutical Research and Development, Exton, Pennsylvania, USA. pliu24@its.jnj.com|Johnson & Johnson Pharmaceutical Research and Development, Exton, Pennsylvania, USA. pliu24@its.jnj.com', 'United States|United States|United States|United States', 26, 'Algorithms|Computational Biology|Crystallography, X-Ray|Databases, Protein|Models, Chemical|Models, Molecular|Protein Conformation|Proteins', 'Journal Article', '10.1371/journal.pcbi.1000478', '19696883', 'Protein loops, the flexible short segments connecting two stable secondary structural units in proteins, play a critical role in protein structure and function. Constructing chemically sensible conformations of protein loops that seamlessly bridge the gap between the anchor points without introducing any steric collisions remains an open challenge. A variety of algorithms have been developed to tackle the loop closure problem, ranging from inverse kinematics to knowledge-based approaches that utilize pre-existing fragments extracted from known protein structures. However, many of these approaches focus on the generation of conformations that mainly satisfy the fixed end point condition, leaving the steric constraints to be resolved in subsequent post-processing steps. In the present work, we describe a simple solution that simultaneously satisfies not only the end point and steric conditions, but also chirality and planarity constraints. Starting from random initial atomic coordinates, each individual conformation is generated independently by using a simple alternating scheme of pairwise distance adjustments of randomly chosen atoms, followed by fast geometric matching of the conformationally rigid components of the constituent amino acids. The method is conceptually simple, numerically stable and computationally efficient. Very importantly, additional constraints, such as those derived from NMR experiments, hydrogen bonds or salt bridges, can be incorporated into the algorithm in a straightforward and inexpensive way, making the method ideal for solving more complex multi-loop problems. The remarkable performance and robustness of the algorithm are demonstrated on a set of protein loops of length 4, 8, and 12 that have been used in previous studies.'),
(84317, 2009, 'plos', 'A mapping of drug space from the viewpoint of small molecule metabolism', 'Adams, James Corey|Keiser, Michael J|Basuino, Li|Chambers, Henry F|Lee, Deok-Sun|Wiest, Olaf G|Babbitt, Patricia C', 'Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, California, USA.|Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, California, USA.|Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, California, USA.|Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, California, USA.|Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, California, USA.|Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, California, USA.|Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, California, USA.', 'United States|United States|United States|United States|United States|United States|United States', 0, 'Animals|Computational Biology|Databases, Factual|Drug Delivery Systems|Drug Discovery|Enzymes|Humans|Metabolic Networks and Pathways|Methicillin-Resistant Staphylococcus aureus|Pharmaceutical Preparations', 'Journal Article', '10.1371/journal.pcbi.1000474', '19701464', 'Small molecule drugs target many core metabolic enzymes in humans and pathogens, often mimicking endogenous ligands. The effects may be therapeutic or toxic, but are frequently unexpected. A large-scale mapping of the intersection between drugs and metabolism is needed to better guide drug discovery. To map the intersection between drugs and metabolism, we have grouped drugs and metabolites by their associated targets and enzymes using ligand-based set signatures created to quantify their degree of similarity in chemical space. The results reveal the chemical space that has been explored for metabolic targets, where successful drugs have been found, and what novel territory remains. To aid other researchers in their drug discovery efforts, we have created an online resource of interactive maps linking drugs to metabolism. These maps predict the effect space comprising likely target enzymes for each of the 246 MDDR drug classes in humans. The online resource also provides species-specific interactive drug-metabolism maps for each of the 385 model organisms and pathogens in the BioCyc database collection. Chemical similarity links between drugs and metabolites predict potential toxicity, suggest routes of metabolism, and reveal drug polypharmacology. The metabolic maps enable interactive navigation of the vast biological data on potential metabolic drug targets and the drug chemistry currently available to prosecute those targets. Thus, this work provides a large-scale approach to ligand-based prediction of drug action in small molecule metabolism.'),
(84318, 2009, 'plos', 'Computation of conformational coupling in allosteric proteins', 'Kidd, Brian A|Baker, David|Thomas, Wendy E', 'Department of Bioengineering, University of Washington, Seattle, Washington, United States of America.|Department of Bioengineering, University of Washington, Seattle, Washington, United States of America.|Department of Bioengineering, University of Washington, Seattle, Washington, United States of America.', 'United States|United States|United States', 41, 'Algorithms|Allosteric Site|Binding Sites|Catalytic Domain|Computational Biology|Databases, Protein|Ligands|Models, Statistical|Models, Theoretical|Molecular Conformation|Protein Conformation|Proteins|Software', 'Journal Article', '10.1371/journal.pcbi.1000484', '19714199', 'In allosteric regulation, an effector molecule binding a protein at one site induces conformational changes, which alter structure and function at a distant active site. Two key challenges in the computational modeling of allostery are the prediction of the structure of one allosteric state starting from the structure of the other, and elucidating the mechanisms underlying the conformational coupling of the effector and active sites. Here we approach these two challenges using the Rosetta high-resolution structure prediction methodology. We find that the method can recapitulate the relaxation of effector-bound forms of single domain allosteric proteins into the corresponding ligand-free states, particularly when sampling is focused on regions known to change conformation most significantly. Analysis of the coupling between contacting pairs of residues in large ensembles of conformations spread throughout the landscape between and around the two allosteric states suggests that the transitions are built up from blocks of tightly coupled interacting sets of residues that are more loosely coupled to one another.'),
(84319, 2009, 'plos', 'Stable, precise, and reproducible patterning of bicoid and hunchback molecules in the early Drosophila embryo', 'Okabe-Oho, Yurie|Murakami, Hiroki|Oho, Suguru|Sasai, Masaki', 'Department of Computational Science and Engineering, Nagoya University, Nagoya, Japan.|Department of Computational Science and Engineering, Nagoya University, Nagoya, Japan.|Department of Computational Science and Engineering, Nagoya University, Nagoya, Japan.|Department of Computational Science and Engineering, Nagoya University, Nagoya, Japan.', 'Japan|Japan|Japan|Japan', 0, 'Animals|Body Patterning|Computational Biology|Computer Simulation|DNA-Binding Proteins|Databases, Protein|Drosophila|Drosophila Proteins|Gene Expression Profiling|Gene Expression Regulation, Developmental|Homeodomain Proteins|Mitosis|Models, Biological|Models, Genetic|Models, Statistical|Reproducibility of Results|Trans-Activators|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000486', '19714200', 'Precise patterning of morphogen molecules and their accurate reading out are of key importance in embryonic development. Recent experiments have visualized distributions of proteins in developing embryos and shown that the gradient of concentration of Bicoid morphogen in Drosophila embryos is established rapidly after fertilization and remains stable through syncytial mitoses. This stable Bicoid gradient is read out in a precise way to distribute Hunchback with small fluctuations in each embryo and in a reproducible way, with small embryo-to-embryo fluctuation. The mechanisms of such stable, precise, and reproducible patterning through noisy cellular processes, however, still remain mysterious. To address these issues, here we develop the one- and three-dimensional stochastic models of the early Drosophila embryo. The simulated results show that the fluctuation in expression of the hunchback gene is dominated by the random arrival of Bicoid at the hunchback enhancer. Slow diffusion of Hunchback protein, however, averages out this intense fluctuation, leading to the precise patterning of distribution of Hunchback without loss of sharpness of the boundary of its distribution. The coordinated rates of diffusion and transport of input Bicoid and output Hunchback play decisive roles in suppressing fluctuations arising from the dynamical structure change in embryos and those arising from the random diffusion of molecules, and give rise to the stable, precise, and reproducible patterning of Bicoid and Hunchback distributions.'),
(84320, 2009, 'plos', 'FLORA: a novel method to predict protein function from structure in diverse superfamilies', 'Redfern, Oliver C|Dessailly, Benoît H|Dallman, Timothy J|Sillitoe, Ian|Orengo, Christine A', 'Research Department of Structural and Molecular Biology, University College London, London, United Kingdom.|Research Department of Structural and Molecular Biology, University College London, London, United Kingdom.|Research Department of Structural and Molecular Biology, University College London, London, United Kingdom.|Research Department of Structural and Molecular Biology, University College London, London, United Kingdom.|Research Department of Structural and Molecular Biology, University College London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 32, 'Algorithms|Amino Acid Motifs|Area Under Curve|Computational Biology|Data Interpretation, Statistical|Databases, Protein|Genomics|Multigene Family|Protein Conformation|Protein Structure, Tertiary|Proteins|Proteomics|ROC Curve|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000485', '19714201', 'Predicting protein function from structure remains an active area of interest, particularly for the structural genomics initiatives where a substantial number of structures are initially solved with little or no functional characterisation. Although global structure comparison methods can be used to transfer functional annotations, the relationship between fold and function is complex, particularly in functionally diverse superfamilies that have evolved through different secondary structure embellishments to a common structural core. The majority of prediction algorithms employ local templates built on known or predicted functional residues. Here, we present a novel method (FLORA) that automatically generates structural motifs associated with different functional sub-families (FSGs) within functionally diverse domain superfamilies. Templates are created purely on the basis of their specificity for a given FSG, and the method makes no prior prediction of functional sites, nor assumes specific physico-chemical properties of residues. FLORA is able to accurately discriminate between homologous domains with different functions and substantially outperforms (a 2-3 fold increase in coverage at low error rates) popular structure comparison methods and a leading function prediction method. We benchmark FLORA on a large data set of enzyme superfamilies from all three major protein classes (alpha, beta, alphabeta) and demonstrate the functional relevance of the motifs it identifies. We also provide novel predictions of enzymatic activity for a large number of structures solved by the Protein Structure Initiative. Overall, we show that FLORA is able to effectively detect functionally similar protein domain structures by purely using patterns of structural conservation of all residues.'),
(84321, 2009, 'plos', 'Detection of functional modes in protein dynamics', 'Hub, Jochen S|de Groot, Bert L', 'Computational Biomolecular Dynamics Group, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.|Computational Biomolecular Dynamics Group, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.', 'Germany|Germany', 0, 'Algorithms|Bacteriophage T4|Binding Sites|Computational Biology|Computer Simulation|Escherichia coli Proteins|Models, Statistical|Molecular Conformation|Muramidase|Peptides|Periplasmic Binding Proteins|Proteins|Solvents|Static Electricity|Tryptophan', 'Journal Article', '10.1371/journal.pcbi.1000480', '19714202', 'Proteins frequently accomplish their biological function by collective atomic motions. Yet the identification of collective motions related to a specific protein function from, e.g., a molecular dynamics trajectory is often non-trivial. Here, we propose a novel technique termed functional mode analysis that aims to detect the collective motion that is directly related to a particular protein function. Based on an ensemble of structures, together with an arbitrary functional quantity that quantifies the functional state of the protein, the technique detects the collective motion that is maximally correlated to the functional quantity. The functional quantity could, e.g., correspond to a geometric, electrostatic, or chemical observable, or any other variable that is relevant to the function of the protein. In addition, the motion that displays the largest likelihood to induce a substantial change in the functional quantity is estimated from the given protein ensemble. Two different correlation measures are applied: first, the Pearson correlation coefficient that measures linear correlation only, and second, the mutual information that can assess any kind of interdependence. Detecting the maximally correlated motion allows one to derive a model for the functional state in terms of a single collective coordinate. The new approach is illustrated using a number of biomolecules, including a polyalanine-helix, T4 lysozyme, Trp-cage, and leucine-binding protein.'),
(84322, 2009, 'plos', 'Hierarchical modeling of activation mechanisms in the ABL and EGFR kinase domains: thermodynamic and mechanistic catalysts of kinase activation by cancer mutations', 'Dixit, Anshuman|Verkhivker, Gennady M', 'Graduate Program in Bioinformatics and Center for Bioinformatics, The University of Kansas, Lawrence, Kansas, United States of America.|Graduate Program in Bioinformatics and Center for Bioinformatics, The University of Kansas, Lawrence, Kansas, United States of America.', 'United States|United States', 0, 'Catalysis|Cell Line, Tumor|Computational Biology|Computer Simulation|Crystallography, X-Ray|ErbB Receptors|Gene Expression Regulation, Neoplastic|Humans|Molecular Conformation|Mutation|Neoplasms|Protein Conformation|Protein Structure, Tertiary|Proto-Oncogene Proteins c-abl|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000487', '19714203', 'Structural and functional studies of the ABL and EGFR kinase domains have recently suggested a common mechanism of activation by cancer-causing mutations. However, dynamics and mechanistic aspects of kinase activation by cancer mutations that stimulate conformational transitions and thermodynamic stabilization of the constitutively active kinase form remain elusive. We present a large-scale computational investigation of activation mechanisms in the ABL and EGFR kinase domains by a panel of clinically important cancer mutants ABL-T315I, ABL-L387M, EGFR-T790M, and EGFR-L858R. We have also simulated the activating effect of the gatekeeper mutation on conformational dynamics and allosteric interactions in functional states of the ABL-SH2-SH3 regulatory complexes. A comprehensive analysis was conducted using a hierarchy of computational approaches that included homology modeling, molecular dynamics simulations, protein stability analysis, targeted molecular dynamics, and molecular docking. Collectively, the results of this study have revealed thermodynamic and mechanistic catalysts of kinase activation by major cancer-causing mutations in the ABL and EGFR kinase domains. By using multiple crystallographic states of ABL and EGFR, computer simulations have allowed one to map dynamics of conformational fluctuations and transitions in the normal (wild-type) and oncogenic kinase forms. A proposed multi-stage mechanistic model of activation involves a series of cooperative transitions between different conformational states, including assembly of the hydrophobic spine, the formation of the Src-like intermediate structure, and a cooperative breakage and formation of characteristic salt bridges, which signify transition to the active kinase form. We suggest that molecular mechanisms of activation by cancer mutations could mimic the activation process of the normal kinase, yet exploiting conserved structural catalysts to accelerate a conformational transition and the enhanced stabilization of the active kinase form. The results of this study reconcile current experimental data with insights from theoretical approaches, pointing to general mechanistic aspects of activating transitions in protein kinases.'),
(84323, 2009, 'plos', 'Autocatalytic loop, amplification and diffusion: a mathematical and computational model of cell polarization in neural chemotaxis', 'Causin, Paola|Facchetti, Giuseppe', 'Department of Mathematics F Enriques, Università degli Studi di Milano, Milano, Italy. Paola.Causin@unimi.it|Department of Mathematics F Enriques, Università degli Studi di Milano, Milano, Italy. Paola.Causin@unimi.it', 'Italy|Italy', 7, 'Animals|Catalysis|Cell Polarity|Chemotaxis|Computational Biology|Cytoskeleton|Diffusion|Feedback|Humans|Models, Biological|Models, Theoretical|Neurons|Signal Transduction|Software', 'Journal Article', '10.1371/journal.pcbi.1000479', '19714204', 'The chemotactic response of cells to graded fields of chemical cues is a complex process that requires the coordination of several intracellular activities. Fundamental steps to obtain a front vs. back differentiation in the cell are the localized distribution of internal molecules and the amplification of the external signal. The goal of this work is to develop a mathematical and computational model for the quantitative study of such phenomena in the context of axon chemotactic pathfinding in neural development. In order to perform turning decisions, axons develop front-back polarization in their distal structure, the growth cone. Starting from the recent experimental findings of the biased redistribution of receptors on the growth cone membrane, driven by the interaction with the cytoskeleton, we propose a model to investigate the significance of this process. Our main contribution is to quantitatively demonstrate that the autocatalytic loop involving receptors, cytoplasmic species and cytoskeleton is adequate to give rise to the chemotactic behavior of neural cells. We assess the fact that spatial bias in receptors is a precursory key event for chemotactic response, establishing the necessity of a tight link between upstream gradient sensing and downstream cytoskeleton dynamics. We analyze further crosslinked effects and, among others, the contribution to polarization of internal enzymatic reactions, which entail the production of molecules with a one-to-more factor. The model shows that the enzymatic efficiency of such reactions must overcome a threshold in order to give rise to a sufficient amplification, another fundamental precursory step for obtaining polarization. Eventually, we address the characteristic behavior of the attraction/repulsion of axons subjected to the same cue, providing a quantitative indicator of the parameters which more critically determine this nontrivial chemotactic response.'),
(84324, 2009, 'plos', 'The origins of lactase persistence in Europe', 'Itan, Yuval|Powell, Adam|Beaumont, Mark A|Burger, Joachim|Thomas, Mark G', 'Research Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.|Research Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.|Research Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.|Research Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.|Research Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Alleles|Bayes Theorem|Computational Biology|Computer Simulation|Diet|Europe|Evolution, Molecular|Gene Frequency|Genetic Markers|Geography|Haplotypes|Humans|Lactase|Lactose|Polymorphism, Genetic|Vitamin D', 'Journal Article', '10.1371/journal.pcbi.1000491', '19714206', 'Lactase persistence (LP) is common among people of European ancestry, but with the exception of some African, Middle Eastern and southern Asian groups, is rare or absent elsewhere in the world. Lactase gene haplotype conservation around a polymorphism strongly associated with LP in Europeans (-13,910 C/T) indicates that the derived allele is recent in origin and has been subject to strong positive selection. Furthermore, ancient DNA work has shown that the--13,910*T (derived) allele was very rare or absent in early Neolithic central Europeans. It is unlikely that LP would provide a selective advantage without a supply of fresh milk, and this has lead to a gene-culture coevolutionary model where lactase persistence is only favoured in cultures practicing dairying, and dairying is more favoured in lactase persistent populations. We have developed a flexible demic computer simulation model to explore the spread of lactase persistence, dairying, other subsistence practices and unlinked genetic markers in Europe and western Asias geographic space. Using data on--13,910*T allele frequency and farming arrival dates across Europe, and approximate Bayesian computation to estimate parameters of interest, we infer that the--13,910*T allele first underwent selection among dairying farmers around 7,500 years ago in a region between the central Balkans and central Europe, possibly in association with the dissemination of the Neolithic Linearbandkeramik culture over Central Europe. Furthermore, our results suggest that natural selection favouring a lactase persistence allele was not higher in northern latitudes through an increased requirement for dietary vitamin D. Our results provide a coherent and spatially explicit picture of the coevolution of lactase persistence and dairying in Europe.'),
(84325, 2009, 'plos', 'Pushing structural information into the yeast interactome by high-throughput protein docking experiments', 'Mosca, Roberto|Pons, Carles|Fernández-Recio, Juan|Aloy, Patrick', 'Institute for Research in Biomedicine, Barcelona, Spain.|Institute for Research in Biomedicine, Barcelona, Spain.|Institute for Research in Biomedicine, Barcelona, Spain.|Institute for Research in Biomedicine, Barcelona, Spain.', 'Spain|Spain|Spain|Spain', 60, 'Anthranilate Synthase|Computational Biology|Computer Simulation|Databases, Factual|Databases, Protein|Genome, Fungal|Models, Biological|Protein Binding|Protein Interaction Mapping|Proteins|Proteomics|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Software', 'Journal Article', '10.1371/journal.pcbi.1000490', '19714207', 'The last several years have seen the consolidation of high-throughput proteomics initiatives to identify and characterize protein interactions and macromolecular complexes in model organisms. In particular, more that 10,000 high-confidence protein-protein interactions have been described between the roughly 6,000 proteins encoded in the budding yeast genome (Saccharomyces cerevisiae). However, unfortunately, high-resolution three-dimensional structures are only available for less than one hundred of these interacting pairs. Here, we expand this structural information on yeast protein interactions by running the first-ever high-throughput docking experiment with some of the best state-of-the-art methodologies, according to our benchmarks. To increase the coverage of the interaction space, we also explore the possibility of using homology models of varying quality in the docking experiments, instead of experimental structures, and assess how it would affect the global performance of the methods. In total, we have applied the docking procedure to 217 experimental structures and 1,023 homology models, providing putative structural models for over 3,000 protein-protein interactions in the yeast interactome. Finally, we analyze in detail the structural models obtained for the interaction between SAM1-anthranilate synthase complex and the MET30-RNA polymerase III to illustrate how our predictions can be straightforwardly used by the scientific community. The results of our experiment will be integrated into the general 3D-Repertoire pipeline, a European initiative to solve the structures of as many as possible protein complexes in yeast at the best possible resolution. All docking results are available at http://gatealoy.pcb.ub.es/HT_docking/.'),
(84326, 2009, 'plos', 'Bioinformatics in Malaysia: hope, initiative, effort, reality, and challenges', 'Zeti, Azura M H|Shamsir, Mohd S|Tajul-Arifin, Khairina|Merican, Amir F|Mohamed, Rahmah|Nathan, Sheila|Mahadi, Nor Muhammad|Napis, Suhaimi|Tan, Tin W', 'Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia. zeti@ukm.my|Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia. zeti@ukm.my|Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia. zeti@ukm.my|Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia. zeti@ukm.my|Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia. zeti@ukm.my|Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia. zeti@ukm.my|Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia. zeti@ukm.my|Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia. zeti@ukm.my|Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia. zeti@ukm.my', 'Malaysia|Malaysia|Malaysia|Malaysia|Malaysia|Malaysia|Malaysia|Malaysia|Malaysia', 10, 'Biodiversity|Computational Biology|Genomics|Humans|Industry|Malaysia|Research|Technology|Workforce', 'Journal Article', '10.1371/journal.pcbi.1000457', '19714208', '-'),
(84327, 2009, 'plos', 'Strong inference for systems biology', 'Beard, Daniel A|Kushmerick, Martin J', 'Department of Physiology, Medical College of Wisconsin, Biotechnology and Bioengineering Center, Milwaukee, Wisconsin, United States of America.dbeard@mcw.edu|Department of Physiology, Medical College of Wisconsin, Biotechnology and Bioengineering Center, Milwaukee, Wisconsin, United States of America.dbeard@mcw.edu', 'United States|United States', 45, 'Adenosine Triphosphate|Animals|Computational Biology|Computer Simulation|Energy Metabolism|Heart|Humans|Hydrolysis|Kinetics|Research|Science|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000459', '19714210', '-'),
(84328, 2009, 'plos', 'A quick guide to teaching R programming to computational biology students', 'Eglen, Stephen J', 'Department of Applied Mathematics and Theoretical Physics,Cambridge Computational Biology Institute, University of Cambridge, Cambridge, United Kingdom. S.J.Eglen@damtp.cam.ac.uk', 'United Kingdom', 0, 'Algorithms|Computational Biology|Computers|Computing Methodologies|Curriculum|Genomics|Information Science|Internet|Programming Languages|Software|Teaching', 'Journal Article', '10.1371/journal.pcbi.1000482', '19714211', '-'),
(84329, 2009, 'plos', 'Evolutionary triplet models of structured RNA', 'Bradley, Robert K|Holmes, Ian', 'Biophysics Graduate Group, University of California, Berkeley, California, United States of America.|Biophysics Graduate Group, University of California, Berkeley, California, United States of America.', 'United States|United States', 5, 'Algorithms|Base Sequence|Computational Biology|Computer Simulation|Evolution, Molecular|Likelihood Functions|Markov Chains|Models, Statistical|Phylogeny|RNA|Sequence Analysis, RNA|Software', 'Journal Article', '10.1371/journal.pcbi.1000483', '19714212', 'The reconstruction and synthesis of ancestral RNAs is a feasible goal for paleogenetics. This will require new bioinformatics methods, including a robust statistical framework for reconstructing histories of substitutions, indels and structural changes. We describe a transducer composition algorithm for extending pairwise probabilistic models of RNA structural evolution to models of multiple sequences related by a phylogenetic tree. This algorithm draws on formal models of computational linguistics as well as the 1985 protosequence algorithm of David Sankoff. The output of the composition algorithm is a multiple-sequence stochastic context-free grammar. We describe dynamic programming algorithms, which are robust to null cycles and empty bifurcations, for parsing this grammar. Example applications include structural alignment of non-coding RNAs, propagation of structural information from an experimentally-characterized sequence to its homologs, and inference of the ancestral structure of a set of diverged RNAs. We implemented the above algorithms for a simple model of pairwise RNA structural evolution, in particular, the algorithms for maximum likelihood (ML) alignment of three known RNA structures and a known phylogeny and inference of the common ancestral structure. We compared this ML algorithm to a variety of related, but simpler, techniques, including ML alignment algorithms for simpler models that omitted various aspects of the full model and also a posterior-decoding alignment algorithm for one of the simpler models. In our tests, incorporation of basepair structure was the most important factor for accurate alignment inference, appropriate use of posterior-decoding was next, and fine details of the model were least important. Posterior-decoding heuristics can be substantially faster than exact phylogenetic inference, so this motivates the use of sum-over-pairs heuristics where possible (and approximate sum-over-pairs). For more exact probabilistic inference, we discuss the use of transducer composition for ML (or MCMC) inference on phylogenies, including possible ways to make the core operations tractable.'),
(84330, 2009, 'plos', 'Interpreting expression data with metabolic flux models: predicting Mycobacterium tuberculosis mycolic acid production', 'Colijn, Caroline|Brandes, Aaron|Zucker, Jeremy|Lun, Desmond S|Weiner, Brian|Farhat, Maha R|Cheng, Tan-Yun|Moody, D Branch|Murray, Megan|Galagan, James E', 'Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. C.Colijn@bristol.ac.uk|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. C.Colijn@bristol.ac.uk|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. C.Colijn@bristol.ac.uk|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. C.Colijn@bristol.ac.uk|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. C.Colijn@bristol.ac.uk|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. C.Colijn@bristol.ac.uk|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. C.Colijn@bristol.ac.uk|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. C.Colijn@bristol.ac.uk|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. C.Colijn@bristol.ac.uk|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. C.Colijn@bristol.ac.uk', 'United States|United States|United States|United States|United States|United States|United States|Un', 231, 'Algorithms|Cluster Analysis|Computational Biology|Fatty Acids|Gene Expression Profiling|Gene Expression Regulation|Gene Expression Regulation, Bacterial|Genome, Bacterial|Metabolic Networks and Pathways|Models, Biological|Models, Statistical|Mycobacterium tuberculosis|Mycolic Acids|Reproducibility of Results|Software', 'Journal Article', '10.1371/journal.pcbi.1000489', '19714220', 'Metabolism is central to cell physiology, and metabolic disturbances play a role in numerous disease states. Despite its importance, the ability to study metabolism at a global scale using genomic technologies is limited. In principle, complete genome sequences describe the range of metabolic reactions that are possible for an organism, but cannot quantitatively describe the behaviour of these reactions. We present a novel method for modeling metabolic states using whole cell measurements of gene expression. Our method, which we call E-Flux (as a combination of flux and expression), extends the technique of Flux Balance Analysis by modeling maximum flux constraints as a function of measured gene expression. In contrast to previous methods for metabolically interpreting gene expression data, E-Flux utilizes a model of the underlying metabolic network to directly predict changes in metabolic flux capacity. We applied E-Flux to Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB). Key components of mycobacterial cell walls are mycolic acids which are targets for several first-line TB drugs. We used E-Flux to predict the impact of 75 different drugs, drug combinations, and nutrient conditions on mycolic acid biosynthesis capacity in M. tuberculosis, using a public compendium of over 400 expression arrays. We tested our method using a model of mycolic acid biosynthesis as well as on a genome-scale model of M. tuberculosis metabolism. Our method correctly predicts seven of the eight known fatty acid inhibitors in this compendium and makes accurate predictions regarding the specificity of these compounds for fatty acid biosynthesis. Our method also predicts a number of additional potential modulators of TB mycolic acid biosynthesis. E-Flux thus provides a promising new approach for algorithmically predicting metabolic state from gene expression data.'),
(84331, 2009, 'plos', 'A combinatorial approach to detect coevolved amino acid networks in protein families of variable divergence', 'Baussand, Julie|Carbone, Alessandra', 'Génomique Analytique, Université Pierre et Marie Curie, Paris, France.|Génomique Analytique, Université Pierre et Marie Curie, Paris, France.', 'France|France', 20, 'Algorithms|Amino Acid Sequence|Amino Acids|Binding Sites|Cluster Analysis|Combinatorial Chemistry Techniques|Conserved Sequence|Hemoglobins|Leucine Dehydrogenase|Models, Molecular|Molecular Sequence Data|PDZ Domains|Protein Interaction Mapping|Proteins|Sequence Alignment|Serine Proteases|Substrate Specificity', 'Journal Article', '10.1371/journal.pcbi.1000488', '19730672', 'Communication between distant sites often defines the biological role of a protein: amino acid long-range interactions are as important in binding specificity, allosteric regulation and conformational change as residues directly contacting the substrate. The maintaining of functional and structural coupling of long-range interacting residues requires coevolution of these residues. Networks of interaction between coevolved residues can be reconstructed, and from the networks, one can possibly derive insights into functional mechanisms for the protein family. We propose a combinatorial method for mapping conserved networks of amino acid interactions in a protein which is based on the analysis of a set of aligned sequences, the associated distance tree and the combinatorics of its subtrees. The degree of coevolution of all pairs of coevolved residues is identified numerically, and networks are reconstructed with a dedicated clustering algorithm. The method drops the constraints on high sequence divergence limiting the range of applicability of the statistical approaches previously proposed. We apply the method to four protein families where we show an accurate detection of functional networks and the possibility to treat sets of protein sequences of variable divergence.'),
(84332, 2009, 'plos', 'Thermodynamic selection of steric zipper patterns in the amyloid cross-beta spine', 'Park, Jiyong|Kahng, Byungnam|Hwang, Wonmuk', 'Department of Physics and Astronomy, Seoul National University, Seoul, Korea.|Department of Physics and Astronomy, Seoul National University, Seoul, Korea.|Department of Physics and Astronomy, Seoul National University, Seoul, Korea.', '-|-|-', 0, 'Algorithms|Amyloid|Computer Simulation|Crystallography, X-Ray|Models, Molecular|Peptides|Protein Folding|Protein Multimerization|Protein Stability|Protein Structure, Secondary|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000492', '19730673', 'At the core of amyloid fibrils is the cross-beta spine, a long tape of beta-sheets formed by the constituent proteins. Recent high-resolution x-ray studies show that the unit of this filamentous structure is a beta-sheet bilayer with side chains within the bilayer forming a tightly interdigitating steric zipper interface. However, for a given peptide, different bilayer patterns are possible, and no quantitative explanation exists regarding which pattern is selected or under what condition there can be more than one pattern observed, exhibiting molecular polymorphism. We address the structural selection mechanism by performing molecular dynamics simulations to calculate the free energy of incorporating a peptide monomer into a beta-sheet bilayer. We test filaments formed by several types of peptides including GNNQQNY, NNQQ, VEALYL, KLVFFAE and STVIIE, and find that the patterns with the lowest binding free energy correspond to available atomistic structures with high accuracy. Molecular polymorphism, as exhibited by NNQQ, is likely because there are more than one most stable structures whose binding free energies differ by less than the thermal energy. Detailed analysis of individual energy terms reveals that these short peptides are not strained nor do they lose much conformational entropy upon incorporating into a beta-sheet bilayer. The selection of a bilayer pattern is determined mainly by the van der Waals and hydrophobic forces as a quantitative measure of shape complementarity among side chains between the beta-sheets. The requirement for self-complementary steric zipper formation supports that amyloid fibrils form more easily among similar or same sequences, and it also makes parallel beta-sheets generally preferred over anti-parallel ones. But the presence of charged side chains appears to kinetically drive anti-parallel beta-sheets to form at early stages of assembly, after which the bilayer formation is likely driven by energetics.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84333, 2009, 'plos', 'Global motions of the nuclear pore complex: insights from elastic network models', 'Lezon, Timothy R|Sali, Andrej|Bahar, Ivet', 'Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.', 'United States|United States|United States', 0, 'Active Transport, Cell Nucleus|Computational Biology|Elasticity|Fungal Proteins|Models, Biological|Nuclear Pore|Nuclear Pore Complex Proteins|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1000496', '19730674', 'The nuclear pore complex (NPC) is the gate to the nucleus. Recent determination of the configuration of proteins in the yeast NPC at approximately 5 nm resolution permits us to study the NPC global dynamics using coarse-grained structural models. We investigate these large-scale motions by using an extended elastic network model (ENM) formalism applied to several coarse-grained representations of the NPC. Two types of collective motions (global modes) are predicted by the ENMs to be intrinsically favored by the NPC architecture: global bending and extension/contraction from circular to elliptical shapes. These motions are shown to be robust against tested variations in the representation of the NPC, and are largely captured by a simple model of a toroid with axially varying mass density. We demonstrate that spoke multiplicity significantly affects the accessible number of symmetric low-energy modes of motion, the NPC-like toroidal structures composed of 8 spokes have access to highly cooperative symmetric motions that are inaccessible to toroids composed of 7 or 9 spokes. The analysis reveals modes of motion that may facilitate macromolecular transport through the NPC, consistent with previous experimental observations.'),
(84334, 2009, 'plos', 'Interrogating and predicting tolerated sequence diversity in protein folds: application to E elaterium trypsin inhibitor-II cystine-knot miniprotein', 'Lahti, Jennifer L|Silverman, Adam P|Cochran, Jennifer R', 'Department of Bioengineering, Cancer Center, Bio-X Program, Stanford University, Stanford, California, United States of America.|Department of Bioengineering, Cancer Center, Bio-X Program, Stanford University, Stanford, California, United States of America.|Department of Bioengineering, Cancer Center, Bio-X Program, Stanford University, Stanford, California, United States of America.', 'United States|United States|United States', 23, 'Amino Acid Sequence|Cloning, Molecular|Cucurbitaceae|Models, Molecular|Molecular Sequence Data|Peptide Library|Plant Proteins|Protein Conformation|Protein Folding|Protein Interaction Domains and Motifs|Sequence Analysis, Protein|Trypsin|Trypsin Inhibitors|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1000499', '19730675', 'Cystine-knot miniproteins (knottins) are promising molecular scaffolds for protein engineering applications. Members of the knottin family have multiple loops capable of displaying conformationally constrained polypeptides for molecular recognition. While previous studies have illustrated the potential of engineering knottins with modified loop sequences, a thorough exploration into the tolerated loop lengths and sequence space of a knottin scaffold has not been performed. In this work, we used the Ecballium elaterium trypsin inhibitor II (EETI) as a model member of the knottin family and constructed libraries of EETI loop-substituted variants with diversity in both amino acid sequence and loop length. Using yeast surface display, we isolated properly folded EETI loop-substituted clones and applied sequence analysis tools to assess the tolerated diversity of both amino acid sequence and loop length. In addition, we used covariance analysis to study the relationships between individual positions in the substituted loops, based on the expectation that correlated amino acid substitutions will occur between interacting residue pairs. We then used the results of our sequence and covariance analyses to successfully predict loop sequences that facilitated proper folding of the knottin when substituted into EETI loop 3. The sequence trends we observed in properly folded EETI loop-substituted clones will be useful for guiding future protein engineering efforts with this knottin scaffold. Furthermore, our findings demonstrate that the combination of directed evolution with sequence and covariance analyses can be a powerful tool for rational protein engineering.'),
(84335, 2009, 'plos', 'Googling food webs: can an eigenvector measure species importance for coextinctions?', 'Allesina, Stefano|Pascual, Mercedes', 'National Center for Ecological Analysis and Synthesis, Santa Barbara, California, United States of America. allesina@nceas.ucsb.edu|National Center for Ecological Analysis and Synthesis, Santa Barbara, California, United States of America. allesina@nceas.ucsb.edu', 'United States|United States', 0, 'Algorithms|Animals|Biodiversity|Computer Simulation|Ecosystem|Extinction, Biological|Food Chain|Models, Biological|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000494', '19730676', 'A major challenge in ecology is forecasting the effects of species extinctions, a pressing problem given current human impacts on the planet. Consequences of species losses such as secondary extinctions are difficult to forecast because species are not isolated, but interact instead in a complex network of ecological relationships. Because of their mutual dependence, the loss of a single species can cascade in multiple coextinctions. Here we show that an algorithm adapted from the one Google uses to rank web-pages can order species according to their importance for coextinctions, providing the sequence of losses that results in the fastest collapse of the network. Moreover, we use the algorithm to bridge the gap between qualitative (who eats whom) and quantitative (at what rate) descriptions of food webs. We show that our simple algorithm finds the best possible solution for the problem of assigning importance from the perspective of secondary extinctions in all analyzed networks. Our approach relies on network structure, but applies regardless of the specific dynamical model of species interactions, because it identifies the subset of coextinctions common to all possible models, those that will happen with certainty given the complete loss of prey of a given predator. Results show that previous measures of importance based on the concept of hubs or number of connections, as well as centrality measures, do not identify the most effective extinction sequence. The proposed algorithm provides a basis for further developments in the analysis of extinction risk in ecosystems.'),
(84336, 2009, 'plos', 'The role of ongoing dendritic oscillations in single-neuron dynamics', 'Remme, Michiel W H|Lengyel, Máté|Gutkin, Boris S', 'Group for Neural Theory, Département dEtudes Cognitives, Ecole Normale Supérieure, Paris, France. michiel.remme@nyu.edu|Group for Neural Theory, Département dEtudes Cognitives, Ecole Normale Supérieure, Paris, France. michiel.remme@nyu.edu|Group for Neural Theory, Département dEtudes Cognitives, Ecole Normale Supérieure, Paris, France. michiel.remme@nyu.edu', 'France|France|France', 42, 'Action Potentials|Algorithms|Dendrites|Models, Neurological|Neurons|Synapses|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000493', '19730677', 'The dendritic tree contributes significantly to the elementary computations a neuron performs while converting its synaptic inputs into action potential output. Traditionally, these computations have been characterized as both temporally and spatially localized. Under this localist account, neurons compute near-instantaneous mappings from their current input to their current output, brought about by somatic summation of dendritic contributions that are generated in functionally segregated compartments. However, recent evidence about the presence of oscillations in dendrites suggests a qualitatively different mode of operation: the instantaneous phase of such oscillations can depend on a long history of inputs, and under appropriate conditions, even dendritic oscillators that are remote may interact through synchronization. Here, we develop a mathematical framework to analyze the interactions of local dendritic oscillations and the way these interactions influence single cell computations. Combining weakly coupled oscillator methods with cable theoretic arguments, we derive phase-locking states for multiple oscillating dendritic compartments. We characterize how the phase-locking properties depend on key parameters of the oscillating dendrite: the electrotonic properties of the (active) dendritic segment, and the intrinsic properties of the dendritic oscillators. As a direct consequence, we show how input to the dendrites can modulate phase-locking behavior and hence global dendritic coherence. In turn, dendritic coherence is able to gate the integration and propagation of synaptic signals to the soma, ultimately leading to an effective control of somatic spike generation. Our results suggest that dendritic oscillations enable the dendritic tree to operate on more global temporal and spatial scales than previously thought, notably that local dendritic activity may be a mechanism for generating on-going whole-cell voltage oscillations.'),
(84337, 2009, 'plos', 'A structured model of video reproduces primary visual cortical organisation', 'Berkes, Pietro|Turner, Richard E|Sahani, Maneesh', 'Gatsby Computational Neuroscience Unit, London, United Kingdom. berkes@brandeis.edu|Gatsby Computational Neuroscience Unit, London, United Kingdom. berkes@brandeis.edu|Gatsby Computational Neuroscience Unit, London, United Kingdom. berkes@brandeis.edu', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Algorithms|Animals|Artificial Intelligence|Bayes Theorem|Cats|Models, Neurological|Models, Statistical|Video Recording|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1000495', '19730679', 'The visual system must learn to infer the presence of objects and features in the world from the images it encounters, and as such it must, either implicitly or explicitly, model the way these elements interact to create the image. Do the response properties of cells in the mammalian visual system reflect this constraint? To address this question, we constructed a probabilistic model in which the identity and attributes of simple visual elements were represented explicitly and learnt the parameters of this model from unparsed, natural video sequences. After learning, the behaviour and grouping of variables in the probabilistic model corresponded closely to functional and anatomical properties of simple and complex cells in the primary visual cortex (V1). In particular, feature identity variables were activated in a way that resembled the activity of complex cells, while feature attribute variables responded much like simple cells. Furthermore, the grouping of the attributes within the model closely parallelled the reported anatomical grouping of simple cells in cat V1. Thus, this generative model makes explicit an interpretation of complex and simple cells as elements in the segmentation of a visual scene into basic independent features, along with a parametrisation of their moment-by-moment appearances. We speculate that such a segmentation may form the initial stage of a hierarchical system that progressively separates the identity and appearance of more articulated visual elements, culminating in view-invariant object recognition.'),
(84338, 2009, 'plos', 'Influence of sequence changes and environment on intrinsically disordered proteins', 'Mohan, Amrita|Uversky, Vladimir N|Radivojac, Predrag', 'School of Informatics and Computing, Indiana University, Bloomington, Indiana, United States of America.|School of Informatics and Computing, Indiana University, Bloomington, Indiana, United States of America.|School of Informatics and Computing, Indiana University, Bloomington, Indiana, United States of America.', 'India|India|India', 31, 'Algorithms|Amino Acid Sequence|Crystallography, X-Ray|Cyclophilins|Databases, Protein|Hydrogen-Ion Concentration|Models, Molecular|Protein Conformation|Protein Folding|Proteins|Structure-Activity Relationship|Temperature|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000497', '19730682', 'Many large-scale studies on intrinsically disordered proteins are implicitly based on the structural models deposited in the Protein Data Bank. Yet, the static nature of deposited models supplies little insight into variation of protein structure and function under diverse cellular and environmental conditions. While the computational predictability of disordered regions provides practical evidence that disorder is an intrinsic property of proteins, the robustness of disordered regions to changes in sequence or environmental conditions has not been systematically studied. We analyzed intrinsically disordered regions in the same or similar proteins crystallized independently and studied their sensitivity to changes in protein sequence and parameters of crystallographic experiments. The observed changes in the existence, position, and length of disordered regions indicate that their appearance in X-ray structures dramatically depends on changes in amino acid sequence and peculiarities of the crystallographic experiment. Our study also raises general questions regarding protein evolution and the regulation of protein structure, dynamics, and function via variations in cellular and environmental conditions.'),
(84339, 2009, 'plos', 'Species tree inference by minimizing deep coalescences', 'Than, Cuong|Nakhleh, Luay', 'Department of Computer Science, Rice University, Houston, Texas, United States of America.|Department of Computer Science, Rice University, Houston, Texas, United States of America.', 'United States|United States', 132, 'Animals|Apicomplexa|Cluster Analysis|Computational Biology|Databases, Genetic|Genetic Speciation|Models, Genetic|Phylogeny|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1000501', '19749978', 'In a 1997 seminal paper, W. Maddison proposed minimizing deep coalescences, or MDC, as an optimization criterion for inferring the species tree from a set of incongruent gene trees, assuming the incongruence is exclusively due to lineage sorting. In a subsequent paper, Maddison and Knowles provided and implemented a search heuristic for optimizing the MDC criterion, given a set of gene trees. However, the heuristic is not guaranteed to compute optimal solutions, and its hill-climbing search makes it slow in practice. In this paper, we provide two exact solutions to the problem of inferring the species tree from a set of gene trees under the MDC criterion. In other words, our solutions are guaranteed to find the tree that minimizes the total number of deep coalescences from a set of gene trees. One solution is based on a novel integer linear programming (ILP) formulation, and another is based on a simple dynamic programming (DP) approach. Powerful ILP solvers, such as CPLEX, make the first solution appealing, particularly for very large-scale instances of the problem, whereas the DP-based solution eliminates dependence on proprietary tools, and its simplicity makes it easy to integrate with other genomic events that may cause gene tree incongruence. Using the exact solutions, we analyze a data set of 106 loci from eight yeast species, a data set of 268 loci from eight Apicomplexan species, and several simulated data sets. We show that the MDC criterion provides very accurate estimates of the species tree topologies, and that our solutions are very fast, thus allowing for the accurate analysis of genome-scale data sets. Further, the efficiency of the solutions allow for quick exploration of sub-optimal solutions, which is important for a parsimony-based criterion such as MDC, as we show. We show that searching for the species tree in the compatibility graph of the clusters induced by the gene trees may be sufficient in practice, a finding that helps ameliorate the computational requirements of optimization solutions. Further, we study the statistical consistency and convergence rate of the MDC criterion, as well as its optimality in inferring the species tree. Finally, we show how our solutions can be used to identify potential horizontal gene transfer events that may have caused some of the incongruence in the data, thus augmenting Maddisons original framework. We have implemented our solutions in the PhyloNet software package, which is freely available at: http://bioinfo.cs.rice.edu/phylonet.'),
(84340, 2009, 'plos', 'Eradication of chronic myeloid leukemia stem cells: a novel mathematical model predicts no therapeutic benefit of adding G-CSF to imatinib', 'Foo, Jasmine|Drummond, Mark W|Clarkson, Bayard|Holyoake, Tessa|Michor, Franziska', 'Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.|Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.|Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.|Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.|Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.', 'United States|United States|United States|United States|United States', 47, 'Antineoplastic Combined Chemotherapy Protocols|Benzamides|Cell Differentiation|Computer Simulation|Drug Synergism|Granulocyte Colony-Stimulating Factor|Humans|Imatinib Mesylate|Leukemia, Myelogenous, Chronic, BCR-ABL Positive|Models, Biological|Neoplastic Stem Cells|Piperazines|Pyrimidines', 'Journal Article', '10.1371/journal.pcbi.1000503', '19749982', 'Imatinib mesylate induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML), yet many patients have detectable BCR-ABL transcripts in peripheral blood even after prolonged therapy. Bone marrow studies have shown that this residual disease resides within the stem cell compartment. Quiescence of leukemic stem cells has been suggested as a mechanism conferring insensitivity to imatinib, and exposure to the Granulocyte-Colony Stimulating Factor (G-CSF), together with imatinib, has led to a significant reduction in leukemic stem cells in vitro. In this paper, we design a novel mathematical model of stem cell quiescence to investigate the treatment response to imatinib and G-CSF. We find that the addition of G-CSF to an imatinib treatment protocol leads to observable effects only if the majority of leukemic stem cells are quiescent, otherwise it does not modulate the leukemic cell burden. The latter scenario is in agreement with clinical findings in a pilot study administering imatinib continuously or intermittently, with or without G-CSF (GIMI trial). Furthermore, our model predicts that the addition of G-CSF leads to a higher risk of resistance since it increases the production of cycling leukemic stem cells. Although the pilot study did not include enough patients to draw any conclusion with statistical significance, there were more cases of progression in the experimental arms as compared to continuous imatinib. Our results suggest that the additional use of G-CSF may be detrimental to patients in the clinic.'),
(84341, 2009, 'plos', 'Evaluation of objective uncertainty in the visual system', 'Barthelmé, Simon|Mamassian, Pascal', 'Laboratoire Psychologie de la Perception, CNRS, Université Paris Descartes, Paris, France. simon.barthelme@parisdescartes.fr|Laboratoire Psychologie de la Perception, CNRS, Université Paris Descartes, Paris, France. simon.barthelme@parisdescartes.fr', 'France|France', 0, 'Bayes Theorem|Decision Making|Humans|Models, Biological|Psychometrics|Uncertainty|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1000504', '19750003', 'The role of sensory systems is to provide an organism with information about its environment. Because sensory information is noisy and insufficient to uniquely determine the environment, natural perceptual systems have to cope with systematic uncertainty. The extent of that uncertainty is often crucial to the organism: for instance, in judging the potential threat in a stimulus. Inducing uncertainty by using visual noise, we had human observers perform a task where they could improve their performance by choosing the less uncertain among pairs of visual stimuli. Results show that observers had access to a reliable measure of visual uncertainty in their decision-making, showing that subjective uncertainty in this case is connected to objective uncertainty. Based on a Bayesian model of the task, we discuss plausible computational schemes for that ability.'),
(84342, 2009, 'plos', 'Parallel computational subunits in dentate granule cells generate multiple place fields', 'Ujfalussy, Balázs|Kiss, Tamás|Erdi, Péter', 'Department of Biophysics, KFKI Research Institute for Particle and Nuclear Physics of the Hungarian Academy of Sciences, Budapest, Hungary. ubi@rmki.kfki.hu|Department of Biophysics, KFKI Research Institute for Particle and Nuclear Physics of the Hungarian Academy of Sciences, Budapest, Hungary. ubi@rmki.kfki.hu|Department of Biophysics, KFKI Research Institute for Particle and Nuclear Physics of the Hungarian Academy of Sciences, Budapest, Hungary. ubi@rmki.kfki.hu', 'Hungary|Hungary|Hungary', 17, 'Algorithms|Computational Biology|Computer Simulation|Dendrites|Dentate Gyrus|Models, Neurological|Neuronal Plasticity|Neurons|Synapses', 'Journal Article', '10.1371/journal.pcbi.1000500', '19750211', 'A fundamental question in understanding neuronal computations is how dendritic events influence the output of the neuron. Different forms of integration of neighbouring and distributed synaptic inputs, isolated dendritic spikes and local regulation of synaptic efficacy suggest that individual dendritic branches may function as independent computational subunits. In the present paper, we study how these local computations influence the output of the neuron. Using a simple cascade model, we demonstrate that triggering somatic firing by a relatively small dendritic branch requires the amplification of local events by dendritic spiking and synaptic plasticity. The moderately branching dendritic tree of granule cells seems optimal for this computation since larger dendritic trees favor local plasticity by isolating dendritic compartments, while reliable detection of individual dendritic spikes in the soma requires a low branch number. Finally, we demonstrate that these parallel dendritic computations could contribute to the generation of multiple independent place fields of hippocampal granule cells.'),
(84343, 2009, 'plos', 'Fast mapping of short sequences with mismatches, insertions and deletions using index structures', 'Hoffmann, Steve|Otto, Christian|Kurtz, Stefan|Sharma, Cynthia M|Khaitovich, Philipp|Vogel, Jörg|Stadler, Peter F|Hackermüller, Jörg', 'Bioinformatics Group, Department of Computer Science, University of Leipzig, Leipzig, Germany.|Bioinformatics Group, Department of Computer Science, University of Leipzig, Leipzig, Germany.|Bioinformatics Group, Department of Computer Science, University of Leipzig, Leipzig, Germany.|Bioinformatics Group, Department of Computer Science, University of Leipzig, Leipzig, Germany.|Bioinformatics Group, Department of Computer Science, University of Leipzig, Leipzig, Germany.|Bioinformatics Group, Department of Computer Science, University of Leipzig, Leipzig, Germany.|Bioinformatics Group, Department of Computer Science, University of Leipzig, Leipzig, Germany.|Bioinformatics Group, Department of Computer Science, University of Leipzig, Leipzig, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany', 0, 'Algorithms|Base Sequence|Computational Biology|DNA Mutational Analysis|Mutation|Sequence Alignment', 'Journal Article', '10.1371/journal.pcbi.1000502', '19750212', 'With few exceptions, current methods for short read mapping make use of simple seed heuristics to speed up the search. Most of the underlying matching models neglect the necessity to allow not only mismatches, but also insertions and deletions. Current evaluations indicate, however, that very different error models apply to the novel high-throughput sequencing methods. While the most frequent error-type in Illumina reads are mismatches, reads produced by 454s GS FLX predominantly contain insertions and deletions (indels). Even though 454 sequencers are able to produce longer reads, the method is frequently applied to small RNA (miRNA and siRNA) sequencing. Fast and accurate matching in particular of short reads with diverse errors is therefore a pressing practical problem. We introduce a matching model for short reads that can, besides mismatches, also cope with indels. It addresses different error models. For example, it can handle the problem of leading and trailing contaminations caused by primers and poly-A tails in transcriptomics or the length-dependent increase of error rates. In these contexts, it thus simplifies the tedious and error-prone trimming step. For efficient searches, our method utilizes index structures in the form of enhanced suffix arrays. In a comparison with current methods for short read mapping, the presented approach shows significantly increased performance not only for 454 reads, but also for Illumina reads. Our approach is implemented in the software segemehl available at http://www.bioinf.uni-leipzig.de/Software/segemehl/.'),
(84344, 2009, 'plos', 'Predicting positive p53 cancer rescue regions using Most Informative Positive (MIP) active learning', 'Danziger, Samuel A|Baronio, Roberta|Ho, Lydia|Hall, Linda|Salmon, Kirsty|Hatfield, G Wesley|Kaiser, Peter|Lathrop, Richard H', 'Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, California, United States of America.|Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, California, United States of America.|Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, California, United States of America.|Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, California, United States of America.|Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, California, United States of America.|Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, California, United States of America.|Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, California, United States of America.|Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, California, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Algorithms|Artificial Intelligence|Computational Biology|Computer Simulation|DNA Mutational Analysis|Fungal Proteins|Humans|Models, Genetic|Models, Molecular|Mutation|Protein Engineering|Reproducibility of Results|Tumor Suppressor Protein p53|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1000498', '19756158', 'Many protein engineering problems involve finding mutations that produce proteins with a particular function. Computational active learning is an attractive approach to discover desired biological activities. Traditional active learning techniques have been optimized to iteratively improve classifier accuracy, not to quickly discover biologically significant results. We report here a novel active learning technique, Most Informative Positive (MIP), which is tailored to biological problems because it seeks novel and informative positive results. MIP active learning differs from traditional active learning methods in two ways: (1) it preferentially seeks Positive (functionally active) examples, and (2) it may be effectively extended to select gene regions suitable for high throughput combinatorial mutagenesis. We applied MIP to discover mutations in the tumor suppressor protein p53 that reactivate mutated p53 found in human cancers. This is an important biomedical goal because p53 mutants have been implicated in half of all human cancers, and restoring active p53 in tumors leads to tumor regression. MIP found Positive (cancer rescue) p53 mutants in silico using 33% fewer experiments than traditional non-MIP active learning, with only a minor decrease in classifier accuracy. Applying MIP to in vivo experimentation yielded immediate Positive results. Ten different p53 mutations found in human cancers were paired in silico with all possible single amino acid rescue mutations, from which MIP was used to select a Positive Region predicted to be enriched for p53 cancer rescue mutants. In vivo assays showed that the predicted Positive Region: (1) had significantly more (p<0.01) new strong cancer rescue mutants than control regions (Negative, and non-MIP active learning), (2) had slightly more new strong cancer rescue mutants than an Expert region selected for purely biological considerations, and (3) rescued for the first time the previously unrescuable p53 cancer mutant P152L.'),
(84345, 2009, 'plos', 'Human miRNA precursors with box H/ACA snoRNA features', 'Scott, Michelle S|Avolio, Fabio|Ono, Motoharu|Lamond, Angus I|Barton, Geoffrey J', 'Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, United Kingdom. michelle@compbio.dundee.ac.uk|Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, United Kingdom. michelle@compbio.dundee.ac.uk|Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, United Kingdom. michelle@compbio.dundee.ac.uk|Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, United Kingdom. michelle@compbio.dundee.ac.uk|Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, United Kingdom. michelle@compbio.dundee.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 135, 'Base Sequence|Cell Cycle Proteins|Conserved Sequence|Evolution, Molecular|HeLa Cells|Humans|MicroRNAs|Molecular Sequence Data|Nuclear Proteins|Nucleic Acid Conformation|RNA Precursors|RNA, Small Nucleolar|Repetitive Sequences, Nucleic Acid|Subcellular Fractions', 'Journal Article', '10.1371/journal.pcbi.1000507', '19763159', 'MicroRNAs (miRNAs) and small nucleolar RNAs (snoRNAs) are two classes of small non-coding regulatory RNAs, which have been much investigated in recent years. While their respective functions in the cell are distinct, they share interesting genomic similarities, and recent sequencing projects have identified processed forms of snoRNAs that resemble miRNAs. Here, we investigate a possible evolutionary relationship between miRNAs and box H/ACA snoRNAs. A comparison of the genomic locations of reported miRNAs and snoRNAs reveals an overlap of specific members of these classes. To test the hypothesis that some miRNAs might have evolved from snoRNA encoding genomic regions, reported miRNA-encoding regions were scanned for the presence of box H/ACA snoRNA features. Twenty miRNA precursors show significant similarity to H/ACA snoRNAs as predicted by snoGPS. These include molecules predicted to target known ribosomal RNA pseudouridylation sites in vivo for which no guide snoRNA has yet been reported. The predicted folded structures of these twenty H/ACA snoRNA-like miRNA precursors reveal molecules which resemble the structures of known box H/ACA snoRNAs. The genomic regions surrounding these predicted snoRNA-like miRNAs are often similar to regions around snoRNA retroposons, including the presence of transposable elements, target site duplications and poly (A) tails. We further show that the precursors of five H/ACA snoRNA-like miRNAs (miR-151, miR-605, mir-664, miR-215 and miR-140) bind to dyskerin, a specific protein component of functional box H/ACA small nucleolar ribonucleoprotein complexes suggesting that these molecules have retained some H/ACA snoRNA functionality. The detection of small RNA molecules that share features of miRNAs and snoRNAs suggest that these classes of RNA may have an evolutionary relationship.'),
(84346, 2009, 'plos', 'Noise management by molecular networks', 'Bruggeman, Frank J|Blüthgen, Nils|Westerhoff, Hans V', 'Regulatory Networks Group, Netherlands Institute for Systems Biology, Amsterdam, The Netherlands. frank.bruggeman@sysbio.nl|Regulatory Networks Group, Netherlands Institute for Systems Biology, Amsterdam, The Netherlands. frank.bruggeman@sysbio.nl|Regulatory Networks Group, Netherlands Institute for Systems Biology, Amsterdam, The Netherlands. frank.bruggeman@sysbio.nl', 'Netherlands|Netherlands|Netherlands', 56, 'Algorithms|Computer Simulation|Feedback|Gene Regulatory Networks|Models, Biological|Signal Transduction|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000506', '19763166', 'Fluctuations in the copy number of key regulatory macromolecules (noise) may cause physiological heterogeneity in populations of (isogenic) cells. The kinetics of processes and their wiring in molecular networks can modulate this molecular noise. Here we present a theoretical framework to study the principles of noise management by the molecular networks in living cells. The theory makes use of the natural, hierarchical organization of those networks and makes their noise management more understandable in terms of network structure. Principles governing noise management by ultrasensitive systems, signaling cascades, gene networks and feedback circuitry are discovered using this approach. For a few frequently occurring network motifs we show how they manage noise. We derive simple and intuitive equations for noise in molecule copy numbers as a determinant of physiological heterogeneity. We show how noise levels and signal sensitivity can be set independently in molecular networks, but often changes in signal sensitivity affect noise propagation. Using theory and simulations, we show that negative feedback can both enhance and reduce noise. We identify a trade-off, noise reduction in one molecular intermediate by negative feedback is at the expense of increased noise in the levels of other molecules along the feedback loop. The reactants of the processes that are strongly (cooperatively) regulated, so as to allow for negative feedback with a high strength, will display enhanced noise.'),
(84347, 2009, 'plos', 'Estimating the continuous-time dynamics of energy and fat metabolism in mice', 'Guo, Juen|Hall, Kevin D', 'Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA.|Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA.', 'United States|United States', 43, 'Adipose Tissue|Algorithms|Animals|Body Composition|Body Weight|Eating|Energy Metabolism|Lipid Metabolism|Male|Markov Chains|Mice|Mice, Inbred C57BL|Models, Biological|Monte Carlo Method|Obesity', 'Journal Article', '10.1371/journal.pcbi.1000511', '19763167', 'The mouse has become the most popular organism for investigating molecular mechanisms of body weight regulation. But understanding the physiological context by which a molecule exerts its effect on body weight requires knowledge of energy intake, energy expenditure, and fuel selection. Furthermore, measurements of these variables made at an isolated time point cannot explain why body weight has its present value since body weight is determined by the past history of energy and macronutrient imbalance. While food intake and body weight changes can be frequently measured over several weeks (the relevant time scale for mice), correspondingly frequent measurements of energy expenditure and fuel selection are not currently feasible. To address this issue, we developed a mathematical method based on the law of energy conservation that uses the measured time course of body weight and food intake to estimate the underlying continuous-time dynamics of energy output and net fat oxidation. We applied our methodology to male C57BL/6 mice consuming various ad libitum diets during weight gain and loss over several weeks and present the first continuous-time estimates of energy output and net fat oxidation rates underlying the observed body composition changes. We show that transient energy and fat imbalances in the first several days following a diet switch can account for a significant fraction of the total body weight change. We also discovered a time-invariant curve relating body fat and fat-free masses in male C57BL/6 mice, and the shape of this curve determines how diet, fuel selection, and body composition are interrelated.'),
(84348, 2009, 'plos', 'Predicting the evolution of sex on complex fitness landscapes', 'Misevic, Dusan|Kouyos, Roger D|Bonhoeffer, Sebastian', 'Institute of Integrative Biology, ETH Zürich, Zürich, Switzerland.|Institute of Integrative Biology, ETH Zürich, Zürich, Switzerland.|Institute of Integrative Biology, ETH Zürich, Zürich, Switzerland.', 'Switzerland|Switzerland|Switzerland', 13, 'Computer Simulation|Discriminant Analysis|Epistasis, Genetic|Evolution, Molecular|Genetic Fitness|Genotype|Models, Genetic|Sample Size|Sex|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000510', '19763171', 'Most population genetic theories on the evolution of sex or recombination are based on fairly restrictive assumptions about the nature of the underlying fitness landscapes. Here we use computer simulations to study the evolution of sex on fitness landscapes with different degrees of complexity and epistasis. We evaluate predictors of the evolution of sex, which are derived from the conditions established in the population genetic literature for the evolution of sex on simpler fitness landscapes. These predictors are based on quantities such as the variance of Hamming distance, mean fitness, additive genetic variance, and epistasis. We show that for complex fitness landscapes all the predictors generally perform poorly. Interestingly, while the simplest predictor, Delta Var(HD), also suffers from a lack of accuracy, it turns out to be the most robust across different types of fitness landscapes. Delta Var(HD) is based on the change in Hamming distance variance induced by recombination and thus does not require individual fitness measurements. The presence of loci that are not under selection can, however, severely diminish predictor accuracy. Our study thus highlights the difficulty of establishing reliable criteria for the evolution of sex on complex fitness landscapes and illustrates the challenge for both theoretical and experimental research on the origin and maintenance of sexual reproduction.'),
(84349, 2009, 'plos', 'A statistical model to identify differentially expressed proteins in 2D PAGE gels', 'Wu, Steven H|Black, Michael A|North, Robyn A|Atkinson, Kelly R|Rodrigo, Allen G', 'Bioinformatics Institute, University of Auckland, Auckland, New Zealand.|Bioinformatics Institute, University of Auckland, Auckland, New Zealand.|Bioinformatics Institute, University of Auckland, Auckland, New Zealand.|Bioinformatics Institute, University of Auckland, Auckland, New Zealand.|Bioinformatics Institute, University of Auckland, Auckland, New Zealand.', 'New Zealand|New Zealand|New Zealand|New Zealand|New Zealand', 5, 'Algorithms|Analysis of Variance|Computer Simulation|Electrophoresis, Gel, Two-Dimensional|Female|Humans|Likelihood Functions|Models, Biological|Models, Statistical|Pre-Eclampsia|Pregnancy|Proteins|Proteomics|Sensitivity and Specificity', 'Journal Article', '10.1371/journal.pcbi.1000509', '19763172', 'Two dimensional polyacrylamide gel electrophoresis (2D PAGE) is used to identify differentially expressed proteins and may be applied to biomarker discovery. A limitation of this approach is the inability to detect a protein when its concentration falls below the limit of detection. Consequently, differential expression of proteins may be missed when the level of a protein in the cases or controls is below the limit of detection for 2D PAGE. Standard statistical techniques have difficulty dealing with undetected proteins. To address this issue, we propose a mixture model that takes into account both detected and non-detected proteins. Non-detected proteins are classified either as (a) proteins that are not expressed in at least one replicate, or (b) proteins that are expressed but are below the limit of detection. We obtain maximum likelihood estimates of the parameters of the mixture model, including the group-specific probability of expression and mean expression intensities. Differentially expressed proteins can be detected by using a Likelihood Ratio Test (LRT). Our simulation results, using data generated from biological experiments, show that the likelihood model has higher statistical power than standard statistical approaches to detect differentially expressed proteins. An R package, Slider (Statistical Likelihood model for Identifying Differential Expression in R), is freely available at http://www.cebl.auckland.ac.nz/slider.php.'),
(84350, 2009, 'plos', 'Transcriptional profiling of the dose response: a more powerful approach for characterizing drug activities', 'Ji, Rui-Ru|de Silva, Heshani|Jin, Yisheng|Bruccoleri, Robert E|Cao, Jian|He, Aiqing|Huang, Wenjun|Kayne, Paul S|Neuhaus, Isaac M|Ott, Karl-Heinz|Penhallow, Becky|Cockett, Mark I|Neubauer, Michael G|Siemers, Nathan O|Ross-Macdonald, Petra', 'Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. ruiruji@gmail.com|Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. ruiruji@gmail.com|Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. ruiruji@gmail.com|Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. ruiruji@gmail.com|Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. ruiruji@gmail.com|Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. ruiruji@gmail.com|Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. ruiruji@gmail.com|Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. ruiruji@gmail.com|Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. ruiruji@gmail.com|Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. ruiruji@gmail.com|Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. ruiruji@gmail.com|Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. ruiruji@gmail.com|Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. ruiruji@gmail.com|Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. ruiruji@gmail.com|Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. ruiruji@gmail.com', 'Jersey|Jersey|Jersey|Jersey|Jersey|Jersey|Jersey|Jersey|Jersey|Jersey|Jersey|Jersey|Jersey|Jersey|Je', 19, 'Algorithms|Benzamides|Cell Cycle|Cell Line|Cluster Analysis|Computational Biology|Dasatinib|Diphenylamine|Dose-Response Relationship, Drug|Gene Expression|Gene Expression Profiling|Humans|Imatinib Mesylate|Oligonucleotide Array Sequence Analysis|Piperazines|Protein Kinase Inhibitors|Pyrimidines|Signal Transduction|Thiazoles', 'Journal Article', '10.1371/journal.pcbi.1000512', '19763178', 'The dose response curve is the gold standard for measuring the effect of a drug treatment, but is rarely used in genomic scale transcriptional profiling due to perceived obstacles of cost and analysis. One barrier to examining transcriptional dose responses is that existing methods for microarray data analysis can identify patterns, but provide no quantitative pharmacological information. We developed analytical methods that identify transcripts responsive to dose, calculate classical pharmacological parameters such as the EC50, and enable an in-depth analysis of coordinated dose-dependent treatment effects. The approach was applied to a transcriptional profiling study that evaluated four kinase inhibitors (imatinib, nilotinib, dasatinib and PD0325901) across a six-logarithm dose range, using 12 arrays per compound. The transcript responses proved a powerful means to characterize and compare the compounds: the distribution of EC50 values for the transcriptome was linked to specific targets, dose-dependent effects on cellular processes were identified using automated pathway analysis, and a connection was seen between EC50s in standard cellular assays and transcriptional EC50s. Our approach greatly enriches the information that can be obtained from standard transcriptional profiling technology. Moreover, these methods are automated, robust to non-optimized assays, and could be applied to other sources of quantitative data.'),
(84351, 2009, 'plos', 'Conserved expression patterns predict microRNA targets', 'Ritchie, William|Rajasekhar, Megha|Flamant, Stephane|Rasko, John E J', 'Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, Australia.', 'Australia|Australia|Australia|Australia', 0, 'Animals|Computational Biology|Gene Expression Profiling|Gene Expression Regulation|Genes, Reporter|HeLa Cells|Humans|Luciferases|Mice|MicroRNAs|Oligonucleotide Array Sequence Analysis|RNA, Messenger|ROC Curve|Reproducibility of Results|Statistics as Topic', 'Journal Article', '10.1371/journal.pcbi.1000513', '19779543', 'microRNAs (miRNAs) are major regulators of gene expression and thereby modulate many biological processes. Computational methods have been instrumental in understanding how miRNAs bind to mRNAs to induce their repression but have proven inaccurate. Here we describe a novel method that combines expression data from human and mouse to discover conserved patterns of expression between orthologous miRNAs and mRNA genes. This method allowed us to predict thousands of putative miRNA targets. Using the luciferase reporter assay, we confirmed 4 out of 6 of our predictions. In addition, this method predicted many miRNAs that act as expression enhancers. We show that many miRNA enhancer effects are mediated through the repression of negative transcriptional regulators and that this effect could be as common as the widely reported repression activity of miRNAs. Our findings suggest that the indirect enhancement of gene expression by miRNAs could be an important component of miRNA regulation that has been widely neglected to date.'),
(84352, 2009, 'plos', 'Brief overview of bioinformatics activities in Singapore', 'Eisenhaber, Frank|Kwoh, Chee-Keong|Ng, See-Kiong|Sung, Wing-Kin|Sung, Wing-King|Wong, Limsoon', 'BioInformatics Institute, Singapore.|BioInformatics Institute, Singapore.|BioInformatics Institute, Singapore.|BioInformatics Institute, Singapore.|BioInformatics Institute, Singapore.|BioInformatics Institute, Singapore.', 'Singapore|Singapore|Singapore|Singapore|Singapore|Singapore', 7, 'Biomedical Research|Computational Biology|Singapore', 'Journal Article', '10.1371/journal.pcbi.1000508', '19779544', '-');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84353, 2009, 'plos', 'A novel scoring approach for protein co-purification data reveals high interaction specificity', 'Yu, Xueping|Ivanic, Joseph|Wallqvist, Anders|Reifman, Jaques', 'Biotechnology HPC Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Ft. Detrick, Maryland, USA.|Biotechnology HPC Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Ft. Detrick, Maryland, USA.|Biotechnology HPC Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Ft. Detrick, Maryland, USA.|Biotechnology HPC Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Ft. Detrick, Maryland, USA.', 'United States|United States|United States|United States', 27, 'Chromatography, Affinity|Cluster Analysis|Computational Biology|Databases, Protein|Mass Spectrometry|Protein Interaction Domains and Motifs|Protein Interaction Mapping|Proteins|Two-Hybrid System Techniques', 'Journal Article', '10.1371/journal.pcbi.1000515', '19779545', 'Large-scale protein interaction networks (PINs) have typically been discerned using affinity purification followed by mass spectrometry (AP/MS) and yeast two-hybrid (Y2H) techniques. It is generally recognized that Y2H screens detect direct binary interactions while the AP/MS method captures co-complex associations, however, the latter technique is known to yield prevalent false positives arising from a number of effects, including abundance. We describe a novel approach to compute the propensity for two proteins to co-purify in an AP/MS data set, thereby allowing us to assess the detected level of interaction specificity by analyzing the corresponding distribution of interaction scores. We find that two recent AP/MS data sets of yeast contain enrichments of specific, or high-scoring, associations as compared to commensurate random profiles, and that curated, direct physical interactions in two prominent data bases have consistently high scores. Our scored interaction data sets are generally more comprehensive than those of previous studies when compared against four diverse, high-quality reference sets. Furthermore, we find that our scored data sets are more enriched with curated, direct physical associations than Y2H sets. A high-confidence protein interaction network (PIN) derived from the AP/MS data is revealed to be highly modular, and we show that this topology is not the result of misrepresenting indirect associations as direct interactions. In fact, we propose that the modularity in Y2H data sets may be underrepresented, as they contain indirect associations that are significantly enriched with false negatives. The AP/MS PIN is also found to contain significant assortative mixing, however, in line with a previous study we confirm that Y2H interaction data show weak disassortativeness, thus revealing more clearly the distinctive natures of the interaction detection methods. We expect that our scored yeast data sets are ideal for further biological discovery and that our scoring system will prove useful for other AP/MS data sets.'),
(84354, 2009, 'plos', 'Ten simple rules for chairing a scientific session', 'Bateman, Alex|Bourne, Philip E', 'Biotechnology HPC Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Ft. Detrick, Maryland, USA.|Biotechnology HPC Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Ft. Detrick, Maryland, USA.', 'United States|United States', 2, 'Congresses as Topic|Humans|Leadership', 'Editorial', '10.1371/journal.pcbi.1000517', '19779547', '-'),
(84355, 2009, 'plos', 'A computational analysis of ATP binding of SV40 large tumor antigen helicase motor', 'Shi, Yemin|Liu, Hanbin|Gai, Dahai|Ma, Jianpeng|Chen, Xiaojiang S', 'Molecular and Computational Biology, University of Southern California, Los Angeles, California, USA.|Molecular and Computational Biology, University of Southern California, Los Angeles, California, USA.|Molecular and Computational Biology, University of Southern California, Los Angeles, California, USA.|Molecular and Computational Biology, University of Southern California, Los Angeles, California, USA.|Molecular and Computational Biology, University of Southern California, Los Angeles, California, USA.', 'United States|United States|United States|United States|United States', 4, 'Adenosine Triphosphate|Antigens, Polyomavirus Transforming|Computational Biology|Computer Simulation|DNA Helicases|Hydrogen Bonding|Magnesium|Models, Molecular|Protein Binding|Protein Conformation|Protein Structure, Tertiary|Simian virus 40|Thermodynamics|Water', 'Journal Article', '10.1371/journal.pcbi.1000514', '19779548', 'Simian virus 40 large tumor antigen (LTag) is an efficient helicase motor that unwinds and translocates DNA. The DNA unwinding and translocation of LTag is powered by ATP binding and hydrolysis at the nucleotide pocket between two adjacent subunits of an LTag hexamer. Based on the set of high-resolution hexameric structures of LTag helicase in different nucleotide binding states, we simulated a conformational transition pathway of the ATP binding process using the targeted molecular dynamics method and calculated the corresponding energy profile using the linear response approximation (LRA) version of the semi-macroscopic Protein Dipoles Langevin Dipoles method (PDLD/S). The simulation results suggest a three-step process for the ATP binding from the initial interaction to the final tight binding at the nucleotide pocket, in which ATP is eventually locked by three pairs of charge-charge interactions across the pocket. Such a cross-locking ATP binding process is similar to the binding zipper model reported for the F1-ATPase hexameric motor. The simulation also shows a transition mechanism of Mg2+ coordination to form the Mg-ATP complex during ATP binding, which is accompanied by the large conformational changes of LTag. This simulation study of the ATP binding process to an LTag and the accompanying conformational changes in the context of a hexamer leads to a refined cooperative iris model that has been proposed previously.'),
(84356, 2009, 'plos', 'Disease-aging network reveals significant roles of aging genes in connecting genetic diseases', 'Wang, Jiguang|Zhang, Shihua|Wang, Yong|Chen, Luonan|Zhang, Xiang-Sun', 'Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, China.|Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, China.|Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, China.|Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, China.|Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, China.', 'China|China|China|China|China', 71, 'Aging|Chromosome Mapping|Cluster Analysis|Computational Biology|Disease|Genetic Predisposition to Disease|Humans|Models, Genetic|Protein Interaction Mapping', 'Journal Article', '10.1371/journal.pcbi.1000521', '19779549', 'One of the challenging problems in biology and medicine is exploring the underlying mechanisms of genetic diseases. Recent studies suggest that the relationship between genetic diseases and the aging process is important in understanding the molecular mechanisms of complex diseases. Although some intricate associations have been investigated for a long time, the studies are still in their early stages. In this paper, we construct a human disease-aging network to study the relationship among aging genes and genetic disease genes. Specifically, we integrate human protein-protein interactions (PPIs), disease-gene associations, aging-gene associations, and physiological system-based genetic disease classification information in a single graph-theoretic framework and find that (1) human disease genes are much closer to aging genes than expected by chance, and (2) diseases can be categorized into two types according to their relationships with aging. Type I diseases have their genes significantly close to aging genes, while type II diseases do not. Furthermore, we examine the topological characters of the disease-aging network from a systems perspective. Theoretical results reveal that the genes of type I diseases are in a central position of a PPI network while type II are not, (3) more importantly, we define an asymmetric closeness based on the PPI network to describe relationships between diseases, and find that aging genes make a significant contribution to associations among diseases, especially among type I diseases. In conclusion, the network-based study provides not only evidence for the intricate relationship between the aging process and genetic diseases, but also biological implications for prying into the nature of human diseases.'),
(84357, 2009, 'plos', 'Statistical use of argonaute expression and RISC assembly in microRNA target identification', 'Stanhope, Stephen A|Sengupta, Srikumar|den Boon, Johan|Ahlquist, Paul|Newton, Michael A', 'Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin, USA. sstanhop@bsd.uchicago.edu|Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin, USA. sstanhop@bsd.uchicago.edu|Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin, USA. sstanhop@bsd.uchicago.edu|Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin, USA. sstanhop@bsd.uchicago.edu|Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin, USA. sstanhop@bsd.uchicago.edu', 'United States|United States|United States|United States|United States', 9, 'Computational Biology|Databases, Genetic|E2F1 Transcription Factor|Gene Expression Regulation|MicroRNAs|Models, Genetic|Models, Statistical|RNA, Messenger|RNA-Induced Silencing Complex|Random Allocation|Regression Analysis|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000516', '19779550', 'MicroRNAs (miRNAs) posttranscriptionally regulate targeted messenger RNAs (mRNAs) by inducing cleavage or otherwise repressing their translation. We address the problem of detecting m/miRNA targeting relationships in homo sapiens from microarray data by developing statistical models that are motivated by the biological mechanisms used by miRNAs. The focus of our modeling is the construction, activity, and mediation of RNA-induced silencing complexes (RISCs) competent for targeted mRNA cleavage. We demonstrate that regression models accommodating RISC abundance and controlling for other mediating factors fit the expression profiles of known target pairs substantially better than models based on m/miRNA expressions alone, and lead to verifications of computational target pair predictions that are more sensitive than those based on marginal expression levels. Because our models are fully independent of exogenous results from sequence-based computational methods, they are appropriate for use as either a primary or secondary source of information regarding m/miRNA target pair relationships, especially in conjunction with high-throughput expression studies.'),
(84358, 2009, 'plos', 'Chemically based mathematical model for development of cerebral cortical folding patterns', 'Striegel, Deborah A|Hurdal, Monica K', 'Department of Mathematics, Florida State University, Tallahassee, Florida, USA. dsmith@math.fsu.edu|Department of Mathematics, Florida State University, Tallahassee, Florida, USA. dsmith@math.fsu.edu', 'United States|United States', 18, 'Animals|Cerebral Cortex|Humans|Models, Chemical|Models, Neurological', 'Journal Article', '10.1371/journal.pcbi.1000524', '19779554', 'The mechanism for cortical folding pattern formation is not fully understood. Current models represent scenarios that describe pattern formation through local interactions, and one recent model is the intermediate progenitor model. The intermediate progenitor (IP) model describes a local chemically driven scenario, where an increase in intermediate progenitor cells in the subventricular zone correlates to gyral formation. Here we present a mathematical model that uses features of the IP model and further captures global characteristics of cortical pattern formation. A prolate spheroidal surface is used to approximate the ventricular zone. Prolate spheroidal harmonics are applied to a Turing reaction-diffusion system, providing a chemically based framework for cortical folding. Our model reveals a direct correlation between pattern formation and the size and shape of the lateral ventricle. Additionally, placement and directionality of sulci and the relationship between domain scaling and cortical pattern elaboration are explained. The significance of this model is that it elucidates the consistency of cortical patterns among individuals within a species and addresses inter-species variability based on global characteristics and provides a critical piece to the puzzle of cortical pattern formation.'),
(84359, 2009, 'plos', 'Bayesian phylogeography finds its roots', 'Lemey, Philippe|Rambaut, Andrew|Drummond, Alexei J|Suchard, Marc A', 'Department of Microbiology and Immunology, Katholieke Universiteit Leuven, Leuven, Belgium. philippe.lemey@uz.kuleuven.be|Department of Microbiology and Immunology, Katholieke Universiteit Leuven, Leuven, Belgium. philippe.lemey@uz.kuleuven.be|Department of Microbiology and Immunology, Katholieke Universiteit Leuven, Leuven, Belgium. philippe.lemey@uz.kuleuven.be|Department of Microbiology and Immunology, Katholieke Universiteit Leuven, Leuven, Belgium. philippe.lemey@uz.kuleuven.be', 'Belgium|Belgium|Belgium|Belgium', 874, 'Animals|Bayes Theorem|Computational Biology|Dogs|Geography|Humans|Influenza A Virus, H5N1 Subtype|Influenza, Human|Markov Chains|Models, Biological|Molecular Epidemiology|Phylogeny|Rabies|Rabies virus|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1000520', '19779555', 'As a key factor in endemic and epidemic dynamics, the geographical distribution of viruses has been frequently interpreted in the light of their genetic histories. Unfortunately, inference of historical dispersal or migration patterns of viruses has mainly been restricted to model-free heuristic approaches that provide little insight into the temporal setting of the spatial dynamics. The introduction of probabilistic models of evolution, however, offers unique opportunities to engage in this statistical endeavor. Here we introduce a Bayesian framework for inference, visualization and hypothesis testing of phylogeographic history. By implementing character mapping in a Bayesian software that samples time-scaled phylogenies, we enable the reconstruction of timed viral dispersal patterns while accommodating phylogenetic uncertainty. Standard Markov model inference is extended with a stochastic search variable selection procedure that identifies the parsimonious descriptions of the diffusion process. In addition, we propose priors that can incorporate geographical sampling distributions or characterize alternative hypotheses about the spatial dynamics. To visualize the spatial and temporal information, we summarize inferences using virtual globe software. We describe how Bayesian phylogeography compares with previous parsimony analysis in the investigation of the influenza A H5N1 origin and H5N1 epidemiological linkage among sampling localities. Analysis of rabies in West African dog populations reveals how virus diffusion may enable endemic maintenance through continuous epidemic cycles. From these analyses, we conclude that our phylogeographic framework will make an important asset in molecular epidemiology that can be easily generalized to infer biogeogeography from genetic data for many organisms.'),
(84360, 2009, 'plos', 'Network-state modulation of power-law frequency-scaling in visual cortical neurons', 'El Boustani, Sami|Marre, Olivier|Béhuret, Sébastien|Baudot, Pierre|Yger, Pierre|Bal, Thierry|Destexhe, Alain|Frégnac, Yves', 'Unité de Neurosciences Intégratives et Computationnelles (UNIC), UPR CNRS 2191, Gif-sur-Yvette, France.|Unité de Neurosciences Intégratives et Computationnelles (UNIC), UPR CNRS 2191, Gif-sur-Yvette, France.|Unité de Neurosciences Intégratives et Computationnelles (UNIC), UPR CNRS 2191, Gif-sur-Yvette, France.|Unité de Neurosciences Intégratives et Computationnelles (UNIC), UPR CNRS 2191, Gif-sur-Yvette, France.|Unité de Neurosciences Intégratives et Computationnelles (UNIC), UPR CNRS 2191, Gif-sur-Yvette, France.|Unité de Neurosciences Intégratives et Computationnelles (UNIC), UPR CNRS 2191, Gif-sur-Yvette, France.|Unité de Neurosciences Intégratives et Computationnelles (UNIC), UPR CNRS 2191, Gif-sur-Yvette, France.|Unité de Neurosciences Intégratives et Computationnelles (UNIC), UPR CNRS 2191, Gif-sur-Yvette, France.', 'France|France|France|France|France|France|France|France', 47, 'Animals|Cats|Computational Biology|Computer Simulation|Eye Movements|Fractals|Membrane Potentials|Models, Neurological|Neurons|Patch-Clamp Techniques|Photic Stimulation|Rats|Rats, Wistar|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1000519', '19779556', 'Various types of neural-based signals, such as EEG, local field potentials and intracellular synaptic potentials, integrate multiple sources of activity distributed across large assemblies. They have in common a power-law frequency-scaling structure at high frequencies, but it is still unclear whether this scaling property is dominated by intrinsic neuronal properties or by network activity. The latter case is particularly interesting because if frequency-scaling reflects the network state it could be used to characterize the functional impact of the connectivity. In intracellularly recorded neurons of cat primary visual cortex in vivo, the power spectral density of V(m) activity displays a power-law structure at high frequencies with a fractional scaling exponent. We show that this exponent is not constant, but depends on the visual statistics used to drive the network. To investigate the determinants of this frequency-scaling, we considered a generic recurrent model of cortex receiving a retinotopically organized external input. Similarly to the in vivo case, our in computo simulations show that the scaling exponent reflects the correlation level imposed in the input. This systematic dependence was also replicated at the single cell level, by controlling independently, in a parametric way, the strength and the temporal decay of the pairwise correlation between presynaptic inputs. This last model was implemented in vitro by imposing the correlation control in artificial presynaptic spike trains through dynamic-clamp techniques. These in vitro manipulations induced a modulation of the scaling exponent, similar to that observed in vivo and predicted in computo. We conclude that the frequency-scaling exponent of the V(m) reflects stimulus-driven correlations in the cortical network activity. Therefore, we propose that the scaling exponent could be used to read-out the effective connectivity responsible for the dynamical signature of the population signals measured at different integration levels, from Vm to LFP, EEG and fMRI.'),
(84361, 2009, 'plos', 'Integration of evolutionary features for the identification of functionally important residues in major facilitator superfamily transporters', 'Jeon, Jouhyun|Yang, Jae-Seong|Kim, Sanguk', 'Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Korea.|Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Korea.|Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Korea.', '-|-|-', 12, 'Amino Acid Sequence|Conserved Sequence|Evolution, Molecular|Membrane Transport Proteins|Molecular Sequence Data|Multigene Family|Sequence Analysis, Protein|Sequence Homology, Amino Acid', 'Journal Article', '10.1371/journal.pcbi.1000522', '19798434', 'The identification of functionally important residues is an important challenge for understanding the molecular mechanisms of proteins. Membrane protein transporters operate two-state allosteric conformational changes using functionally important cooperative residues that mediate long-range communication from the substrate binding site to the translocation pathway. In this study, we identified functionally important cooperative residues of membrane protein transporters by integrating sequence conservation and co-evolutionary information. A newly derived evolutionary feature, the co-evolutionary coupling number, was introduced to measure the connectivity of co-evolving residue pairs and was integrated with the sequence conservation score. We tested this method on three Major Facilitator Superfamily (MFS) transporters, LacY, GlpT, and EmrD. MFS transporters are an important family of membrane protein transporters, which utilize diverse substrates, catalyze different modes of transport using unique combinations of functional residues, and have enough characterized functional residues to validate the performance of our method. We found that the conserved cores of evolutionarily coupled residues are involved in specific substrate recognition and translocation of MFS transporters. Furthermore, a subset of the residues forms an interaction network connecting functional sites in the protein structure. We also confirmed that our method is effective on other membrane protein transporters. Our results provide insight into the location of functional residues important for the molecular mechanisms of membrane protein transporters.'),
(84362, 2009, 'plos', 'The Modular Organization of Protein Interactions in Escherichia coli', 'Peregrín-Alvarez, José M|Xiong, Xuejian|Su, Chong|Parkinson, John', 'Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada. peregrin@ebi.ac.uk|Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada. peregrin@ebi.ac.uk|Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada. peregrin@ebi.ac.uk|Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada. peregrin@ebi.ac.uk', 'Canada|Canada|Canada|Canada', 59, 'Computer Simulation|Escherichia coli|Escherichia coli Proteins|Models, Biological|Multienzyme Complexes|Protein Interaction Mapping|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000523', '19798435', 'Escherichia coli serves as an excellent model for the study of fundamental cellular processes such as metabolism, signalling and gene expression. Understanding the function and organization of proteins within these processes is an important step towards a systems view of E. coli. Integrating experimental and computational interaction data, we present a reliable network of 3,989 functional interactions between 1,941 E. coli proteins ( approximately 45% of its proteome). These were combined with a recently generated set of 3,888 high-quality physical interactions between 918 proteins and clustered to reveal 316 discrete modules. In addition to known protein complexes (e.g., RNA and DNA polymerases), we identified modules that represent biochemical pathways (e.g., nitrate regulation and cell wall biosynthesis) as well as batteries of functionally and evolutionarily related processes. To aid the interpretation of modular relationships, several case examples are presented, including both well characterized and novel biochemical systems. Together these data provide a global view of the modular organization of the E. coli proteome and yield unique insights into structural and evolutionary relationships in bacterial networks.'),
(84363, 2009, 'plos', 'Combining fungal biopesticides and insecticide-treated bednets to enhance malaria control', 'Hancock, Penelope A', 'Centre for Population Biology, Imperial College London, Silwood Park Campus, Ascot, Berkshire, United Kingdom. p.hancock@imperial.ac.uk', 'United Kingdom', 35, 'Africa|Animals|Bedding and Linens|Community Participation|Computer Simulation|Decision Making|Health Care Sector|Health Plan Implementation|Humans|Insect Vectors|Insecticides|Malaria|Models, Biological|Mosquito Control|Pest Control, Biological|World Health Organization', 'Journal Article', '10.1371/journal.pcbi.1000525', '19798436', 'In developing strategies to control malaria vectors, there is increased interest in biological methods that do not cause instant vector mortality, but have sublethal and lethal effects at different ages and stages in the mosquito life cycle. These techniques, particularly if integrated with other vector control interventions, may produce substantial reductions in malaria transmission due to the total effect of alterations to multiple life history parameters at relevant points in the life-cycle and transmission-cycle of the vector. To quantify this effect, an analytically tractable gonotrophic cycle model of mosquito-malaria interactions is developed that unites existing continuous and discrete feeding cycle approaches. As a case study, the combined use of fungal biopesticides and insecticide treated bednets (ITNs) is considered. Low values of the equilibrium EIR and human prevalence were obtained when fungal biopesticides and ITNs were combined, even for scenarios where each intervention acting alone had relatively little impact. The effect of the combined interventions on the equilibrium EIR was at least as strong as the multiplicative effect of both interventions. For scenarios representing difficult conditions for malaria control, due to high transmission intensity and widespread insecticide resistance, the effect of the combined interventions on the equilibrium EIR was greater than the multiplicative effect, as a result of synergistic interactions between the interventions. Fungal biopesticide application was found to be most effective when ITN coverage was high, producing significant reductions in equilibrium prevalence for low levels of biopesticide coverage. By incorporating biological mechanisms relevant to vectorial capacity, continuous-time vector population models can increase their applicability to integrated vector management.'),
(84364, 2009, 'plos', 'Perturbation-based Markovian transmission model for probing allosteric dynamics of large macromolecular assembling: a study of GroEL-GroES', 'Lu, Hsiao-Mei|Liang, Jie', 'Department of Bioengineering, University of Illinois at Chicago, Chicago, Illinois, USA.|Department of Bioengineering, University of Illinois at Chicago, Chicago, Illinois, USA.', 'United States|United States', 10, 'Binding Sites|Chaperonin 10|Chaperonin 60|Markov Chains|Models, Chemical|Models, Statistical|Multiprotein Complexes|Protein Binding', 'Journal Article', '10.1371/journal.pcbi.1000526', '19798437', 'Large macromolecular assemblies are often important for biological processes in cells. Allosteric communications between different parts of these molecular machines play critical roles in cellular signaling. Although studies of the topology and fluctuation dynamics of coarse-grained residue networks can yield important insights, they do not provide characterization of the time-dependent dynamic behavior of these macromolecular assemblies. Here we develop a novel approach called Perturbation-based Markovian Transmission (PMT) model to study globally the dynamic responses of the macromolecular assemblies. By monitoring simultaneous responses of all residues (>8,000) across many (>6) decades of time spanning from the initial perturbation until reaching equilibrium using a Krylov subspace projection method, we show that this approach can yield rich information. With criteria based on quantitative measurements of relaxation half-time, flow amplitude change, and oscillation dynamics, this approach can identify pivot residues that are important for macromolecular movement, messenger residues that are key to signal mediating, and anchor residues important for binding interactions. Based on a detailed analysis of the GroEL-GroES chaperone system, we found that our predictions have an accuracy of 71-84% judged by independent experimental studies reported in the literature. This approach is general and can be applied to other large macromolecular machineries such as the virus capsid and ribosomal complex.'),
(84365, 2009, 'plos', 'The mechanism of ubiquitination in the cullin-RING E3 ligase machinery: conformational control of substrate orientation', 'Liu, Jin|Nussinov, Ruth', 'Basic Science Program, SAIC-Frederick, Inc., Center for Cancer Research Nanobiology Program, NCI-Frederick, Frederick, Maryland, USA.|Basic Science Program, SAIC-Frederick, Inc., Center for Cancer Research Nanobiology Program, NCI-Frederick, Frederick, Maryland, USA.', 'United States|United States', 40, 'Binding Sites|Computer Simulation|Cullin Proteins|Models, Chemical|Models, Molecular|Protein Binding|Protein Conformation|Ubiquitin-Protein Ligases|Ubiquitination|Ubiquitins', 'Journal Article', '10.1371/journal.pcbi.1000527', '19798438', 'In cullin-RING E3 ubiquitin ligases, substrate binding proteins, such as VHL-box, SOCS-box or the F-box proteins, recruit substrates for ubiquitination, accurately positioning and orienting the substrates for ubiquitin transfer. Yet, how the E3 machinery precisely positions the substrate is unknown. Here, we simulated nine substrate binding proteins: Skp2, Fbw7, beta-TrCP1, Cdc4, Fbs1, TIR1, pVHL, SOCS2, and SOCS4, in the unbound form and bound to Skp1, ASK1 or Elongin C. All nine proteins have two domains: one binds to the substrate, the other to E3 ligase modules Skp1/ASK1/Elongin C. We discovered that in all cases the flexible inter-domain linker serves as a hinge, rotating the substrate binding domain, optimally and accurately positioning it for ubiquitin transfer. We observed a conserved proline in the linker of all nine proteins. In all cases, the prolines pucker substantially and the pucker is associated with the backbone rotation toward the E2/ubiquitin. We further observed that the linker flexibility could be regulated allosterically by binding events associated with either domain. We conclude that the flexible linker in the substrate binding proteins orients the substrate for the ubiquitin transfer. Our findings provide a mechanism for ubiquitination and polyubiquitination, illustrating that these processes are under conformational control.'),
(84366, 2009, 'plos', 'High-performance drug discovery: computational screening by combining docking and molecular dynamics simulations', 'Okimoto, Noriaki|Futatsugi, Noriyuki|Fuji, Hideyoshi|Suenaga, Atsushi|Morimoto, Gentaro|Yanai, Ryoko|Ohno, Yousuke|Narumi, Tetsu|Taiji, Makoto', 'High-performance Molecular Simulation Team, Computational Systems Biology Research Group, Advanced Computational Sciences Department, RIKEN Advanced Science Institute, Yokohama, Kanagawa, Japan. okimoto@gsc.riken.jp|High-performance Molecular Simulation Team, Computational Systems Biology Research Group, Advanced Computational Sciences Department, RIKEN Advanced Science Institute, Yokohama, Kanagawa, Japan. okimoto@gsc.riken.jp|High-performance Molecular Simulation Team, Computational Systems Biology Research Group, Advanced Computational Sciences Department, RIKEN Advanced Science Institute, Yokohama, Kanagawa, Japan. okimoto@gsc.riken.jp|High-performance Molecular Simulation Team, Computational Systems Biology Research Group, Advanced Computational Sciences Department, RIKEN Advanced Science Institute, Yokohama, Kanagawa, Japan. okimoto@gsc.riken.jp|High-performance Molecular Simulation Team, Computational Systems Biology Research Group, Advanced Computational Sciences Department, RIKEN Advanced Science Institute, Yokohama, Kanagawa, Japan. okimoto@gsc.riken.jp|High-performance Molecular Simulation Team, Computational Systems Biology Research Group, Advanced Computational Sciences Department, RIKEN Advanced Science Institute, Yokohama, Kanagawa, Japan. okimoto@gsc.riken.jp|High-performance Molecular Simulation Team, Computational Systems Biology Research Group, Advanced Computational Sciences Department, RIKEN Advanced Science Institute, Yokohama, Kanagawa, Japan. okimoto@gsc.riken.jp|High-performance Molecular Simulation Team, Computational Systems Biology Research Group, Advanced Computational Sciences Department, RIKEN Advanced Science Institute, Yokohama, Kanagawa, Japan. okimoto@gsc.riken.jp|High-performance Molecular Simulation Team, Computational Systems Biology Research Group, Advanced Computational Sciences Department, RIKEN Advanced Science Institute, Yokohama, Kanagawa, Japan. okimoto@gsc.riken.jp', 'Japan|Japan|Japan|Japan|Japan|Japan|Japan|Japan|Japan', 107, 'Acetylcholinesterase|Area Under Curve|Binding Sites|Computational Biology|Computer Simulation|Crystallography, X-Ray|Cyclin-Dependent Kinase 2|Drug Discovery|HIV Protease|Ligands|Models, Chemical|Models, Molecular|Pharmacokinetics|ROC Curve|Thermodynamics|Trypsin', 'Journal Article', '10.1371/journal.pcbi.1000528', '19816553', 'Virtual compound screening using molecular docking is widely used in the discovery of new lead compounds for drug design. However, this method is not completely reliable and therefore unsatisfactory. In this study, we used massive molecular dynamics simulations of protein-ligand conformations obtained by molecular docking in order to improve the enrichment performance of molecular docking. Our screening approach employed the molecular mechanics/Poisson-Boltzmann and surface area method to estimate the binding free energies. For the top-ranking 1,000 compounds obtained by docking to a target protein, approximately 6,000 molecular dynamics simulations were performed using multiple docking poses in about a week. As a result, the enrichment performance of the top 100 compounds by our approach was improved by 1.6-4.0 times that of the enrichment performance of molecular dockings. This result indicates that the application of molecular dynamics simulations to virtual screening for lead discovery is both effective and practical. However, further optimization of the computational protocols is required for screening various target proteins.'),
(84367, 2009, 'plos', 'Modeling structure-function relationships in synthetic DNA sequences using attribute grammars', 'Cai, Yizhi|Lux, Matthew W|Adam, Laura|Peccoud, Jean', 'Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.|Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.|Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.|Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.', 'United States|United States|United States|United States', 23, 'Artificial Intelligence|Base Sequence|Chromosome Mapping|DNA|Databases, Genetic|Genes|Genetic Engineering|Models, Genetic|Semantics|Sequence Analysis, DNA|Structure-Activity Relationship|Terminology as Topic', 'Journal Article', '10.1371/journal.pcbi.1000529', '19816554', 'Recognizing that certain biological functions can be associated with specific DNA sequences has led various fields of biology to adopt the notion of the genetic part. This concept provides a finer level of granularity than the traditional notion of the gene. However, a method of formally relating how a set of parts relates to a function has not yet emerged. Synthetic biology both demands such a formalism and provides an ideal setting for testing hypotheses about relationships between DNA sequences and phenotypes beyond the gene-centric methods used in genetics. Attribute grammars are used in computer science to translate the text of a program source code into the computational operations it represents. By associating attributes with parts, modifying the value of these attributes using rules that describe the structure of DNA sequences, and using a multi-pass compilation process, it is possible to translate DNA sequences into molecular interaction network models. These capabilities are illustrated by simple example grammars expressing how gene expression rates are dependent upon single or multiple parts. The translation process is validated by systematically generating, translating, and simulating the phenotype of all the sequences in the design space generated by a small library of genetic parts. Attribute grammars represent a flexible framework connecting parts with models of biological function. They will be instrumental for building mathematical models of libraries of genetic constructs synthesized to characterize the function of genetic parts. This formalism is also expected to provide a solid foundation for the development of computer assisted design applications for synthetic biology.'),
(84368, 2009, 'plos', 'Structure-based predictive models for allosteric hot spots', 'Demerdash, Omar N A|Daily, Michael D|Mitchell, Julie C', 'Biophysics Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Biophysics Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Biophysics Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.', 'United States|United States|United States', 0, 'Algorithms|Allosteric Site|Artificial Intelligence|Cluster Analysis|Lac Repressors|Models, Chemical|Models, Molecular|Protein Binding|Proteins|Reproducibility of Results|Signal Transduction|Structure-Activity Relationship|Thermodynamics|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000531', '19816556', 'In allostery, a binding event at one site in a protein modulates the behavior of a distant site. Identifying residues that relay the signal between sites remains a challenge. We have developed predictive models using support-vector machines, a widely used machine-learning method. The training data set consisted of residues classified as either hotspots or non-hotspots based on experimental characterization of point mutations from a diverse set of allosteric proteins. Each residue had an associated set of calculated features. Two sets of features were used, one consisting of dynamical, structural, network, and informatic measures, and another of structural measures defined by Daily and Gray. The resulting models performed well on an independent data set consisting of hotspots and non-hotspots from five allosteric proteins. For the independent data set, our top 10 models using Feature Set 1 recalled 68-81% of known hotspots, and among total hotspot predictions, 58-67% were actual hotspots. Hence, these models have precision P = 58-67% and recall R = 68-81%. The corresponding models for Feature Set 2 had P = 55-59% and R = 81-92%. We combined the features from each set that produced models with optimal predictive performance. The top 10 models using this hybrid feature set had R = 73-81% and P = 64-71%, the best overall performance of any of the sets of models. Our methods identified hotspots in structural regions of known allosteric significance. Moreover, our predicted hotspots form a network of contiguous residues in the interior of the structures, in agreement with previous work. In conclusion, we have developed models that discriminate between known allosteric hotspots and non-hotspots with high accuracy and sensitivity. Moreover, the pattern of predicted hotspots corresponds to known functional motifs implicated in allostery, and is consistent with previous work describing sparse networks of allosterically important residues.'),
(84369, 2009, 'plos', 'Towards a mathematical theory of cortical micro-circuits', 'George, Dileep|Hawkins, Jeff', 'Numenta Inc., Redwood City, California, United States of America. dgeorge@numenta.com|Numenta Inc., Redwood City, California, United States of America. dgeorge@numenta.com', 'United States|United States', 240, 'Artificial Intelligence|Bayes Theorem|Cerebral Cortex|Feedback|Markov Chains|Memory|Models, Neurological|Pattern Recognition, Automated|Pyramidal Cells', 'Journal Article', '10.1371/journal.pcbi.1000532', '19816557', 'The theoretical setting of hierarchical Bayesian inference is gaining acceptance as a framework for understanding cortical computation. In this paper, we describe how Bayesian belief propagation in a spatio-temporal hierarchical model, called Hierarchical Temporal Memory (HTM), can lead to a mathematical model for cortical circuits. An HTM node is abstracted using a coincidence detector and a mixture of Markov chains. Bayesian belief propagation equations for such an HTM node define a set of functional constraints for a neuronal implementation. Anatomical data provide a contrasting set of organizational constraints. The combination of these two constraints suggests a theoretically derived interpretation for many anatomical and physiological features and predicts several others. We describe the pattern recognition capabilities of HTM networks and demonstrate the application of the derived circuits for modeling the subjective contour effect. We also discuss how the theory and the circuit can be extended to explain cortical features that are not explained by the current model and describe testable predictions that can be derived from the model.'),
(84370, 2009, 'plos', 'Modeling latently infected cell activation: viral and latent reservoir persistence, and viral blips in HIV-infected patients on potent therapy', 'Rong, Libin|Perelson, Alan S', 'Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.', 'Mexico|Mexico', 0, 'Anti-HIV Agents|CD4-Positive T-Lymphocytes|Disease Reservoirs|HIV Infections|Humans|Lymphocyte Activation|Models, Biological|Virus Latency', 'Journal Article', '10.1371/journal.pcbi.1000533', '19834532', 'Although potent combination therapy is usually able to suppress plasma viral loads in HIV-1 patients to below the detection limit of conventional clinical assays, a low level of viremia frequently can be detected in plasma by more sensitive assays. Additionally, many patients experience transient episodes of viremia above the detection limit, termed viral blips, even after being on highly suppressive therapy for many years. An obstacle to viral eradication is the persistence of a latent reservoir for HIV-1 in resting memory CD4(+) T cells. The mechanisms underlying low viral load persistence, slow decay of the latent reservoir, and intermittent viral blips are not fully characterized. The quantitative contributions of residual viral replication to viral and the latent reservoir persistence remain unclear. In this paper, we probe these issues by developing a mathematical model that considers latently infected cell activation in response to stochastic antigenic stimulation. We demonstrate that programmed expansion and contraction of latently infected cells upon immune activation can generate both low-level persistent viremia and intermittent viral blips. Also, a small fraction of activated T cells revert to latency, providing a potential to replenish the latent reservoir. By this means, occasional activation of latently infected cells can explain the variable decay characteristics of the latent reservoir observed in different clinical studies. Finally, we propose a phenomenological model that includes a logistic term representing homeostatic proliferation of latently infected cells. The model is simple but can robustly generate the multiphasic viral decline seen after initiation of therapy, as well as low-level persistent viremia and intermittent HIV-1 blips. Using these models, we provide a quantitative and integrated prospective into the long-term dynamics of HIV-1 and the latent reservoir in the setting of potent antiretroviral therapy.'),
(84371, 2009, 'plos', 'Grasping objects with environmentally induced position uncertainty', 'Christopoulos, Vassilios N|Schrater, Paul R', 'Department of Computer Science and Engineering, University of Minnesota, Twin Cities, Minneapolis, Minnesota, United States of America. vchristo@cs.umn.edu|Department of Computer Science and Engineering, University of Minnesota, Twin Cities, Minneapolis, Minnesota, United States of America. vchristo@cs.umn.edu', 'United States|United States', 0, 'Adult|Female|Hand Strength|Humans|Male|Probability|Uncertainty', 'Journal Article', '10.1371/journal.pcbi.1000538', '19834543', 'Due to noisy motor commands and imprecise and ambiguous sensory information, there is often substantial uncertainty about the relative location between our body and objects in the environment. Little is known about how well people manage and compensate for this uncertainty in purposive movement tasks like grasping. Grasping objects requires reach trajectories to generate object-fingers contacts that permit stable lifting. For objects with position uncertainty, some trajectories are more efficient than others in terms of the probability of producing stable grasps. We hypothesize that people attempt to generate efficient grasp trajectories that produce stable grasps at first contact without requiring post-contact adjustments. We tested this hypothesis by comparing human uncertainty compensation in grasping objects against optimal predictions. Participants grasped and lifted a cylindrical object with position uncertainty, introduced by moving the cylinder with a robotic arm over a sequence of 5 positions sampled from a strongly oriented 2D Gaussian distribution. Preceding each reach, vision of the object was removed for the remainder of the trial and the cylinder was moved one additional time. In accord with optimal predictions, we found that people compensate by aligning the approach direction with covariance angle to maintain grasp efficiency. This compensation results in higher probability to achieve stable grasps at first contact than non-compensation strategies in grasping objects with directional position uncertainty, and the results provide the first demonstration that humans compensate for uncertainty in a complex purposive task.'),
(84372, 2009, 'plos', 'Multilevel selection in models of prebiotic evolution II: a direct comparison of compartmentalization and spatial self-organization', 'Takeuchi, Nobuto|Hogeweg, Paulien', 'Theoretical Biology and Bioinformatics Group, Utrecht University, Utrecht, The Netherlands. takeuchi.nobuto@gmail.com|Theoretical Biology and Bioinformatics Group, Utrecht University, Utrecht, The Netherlands. takeuchi.nobuto@gmail.com', 'Netherlands|Netherlands', 57, 'Biological Evolution|Models, Theoretical', 'Comparative Study', '10.1371/journal.pcbi.1000542', '19834556', 'Multilevel selection has been indicated as an essential factor for the evolution of complexity in interacting RNA-like replicator systems. There are two types of multilevel selection mechanisms: implicit and explicit. For implicit multilevel selection, spatial self-organization of replicator populations has been suggested, which leads to higher level selection among emergent mesoscopic spatial patterns (traveling waves). For explicit multilevel selection, compartmentalization of replicators by vesicles has been suggested, which leads to higher level evolutionary dynamics among explicitly imposed mesoscopic entities (protocells). Historically, these mechanisms have been given separate consideration for the interests on its own. Here, we make a direct comparison between spatial self-organization and compartmentalization in simulated RNA-like replicator systems. Firstly, we show that both mechanisms achieve the macroscopic stability of a replicator system through the evolutionary dynamics on mesoscopic entities that counteract that of microscopic entities. Secondly, we show that a striking difference exists between the two mechanisms regarding their possible influence on the long-term evolutionary dynamics, which happens under an emergent trade-off situation arising from the multilevel selection. The difference is explained in terms of the difference in the stability between self-organized mesoscopic entities and externally imposed mesoscopic entities. Thirdly, we show that a sharp transition happens in the long-term evolutionary dynamics of the compartmentalized system as a function of replicator mutation rate. Fourthly, the results imply that spatial self-organization can allow the evolution of stable folding in parasitic replicators without any specific functionality in the folding itself. Finally, the results are discussed in relation to the experimental synthesis of chemical Darwinian systems and to the multilevel selection theory of evolutionary biology in general. To conclude, novel evolutionary directions can emerge through interactions between the evolutionary dynamics on multiple levels of organization. Different multilevel selection mechanisms can produce a difference in the long-term evolutionary trend of identical microscopic entities.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84373, 2009, 'plos', 'Glocal robustness analysis and model discrimination for circadian oscillators', 'Hafner, Marc|Koeppl, Heinz|Hasler, Martin|Wagner, Andreas', 'School of Computer and Communication Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|School of Computer and Communication Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|School of Computer and Communication Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|School of Computer and Communication Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.', 'Switzerland|Switzerland|Switzerland|Switzerland', 0, 'Circadian Rhythm|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1000534', '19834597', 'To characterize the behavior and robustness of cellular circuits with many unknown parameters is a major challenge for systems biology. Its difficulty rises exponentially with the number of circuit components. We here propose a novel analysis method to meet this challenge. Our method identifies the region of a high-dimensional parameter space where a circuit displays an experimentally observed behavior. It does so via a Monte Carlo approach guided by principal component analysis, in order to allow efficient sampling of this space. This global analysis is then supplemented by a local analysis, in which circuit robustness is determined for each of the thousands of parameter sets sampled in the global analysis. We apply this method to two prominent, recent models of the cyanobacterial circadian oscillator, an autocatalytic model, and a model centered on consecutive phosphorylation at two sites of the KaiC protein, a key circadian regulator. For these models, we find that the two-sites architecture is much more robust than the autocatalytic one, both globally and locally, based on five different quantifiers of robustness, including robustness to parameter perturbations and to molecular noise. Our glocal combination of global and local analyses can also identify key causes of high or low robustness. In doing so, our approach helps to unravel the architectural origin of robust circuit behavior. Complementarily, identifying fragile aspects of system behavior can aid in designing perturbation experiments that may discriminate between competing mechanisms and different parameter sets.'),
(84374, 2009, 'plos', 'Subbarrel patterns in somatosensory cortical barrels can emerge from local dynamic instabilities', 'Ermentrout, Bard|Simons, Daniel J|Land, Peter W', 'Department of Mathematics, University of Pittsburgh, Pittsburgh, Pennsylvannia, United States of America. bard@pitt.edu|Department of Mathematics, University of Pittsburgh, Pittsburgh, Pennsylvannia, United States of America. bard@pitt.edu|Department of Mathematics, University of Pittsburgh, Pittsburgh, Pennsylvannia, United States of America. bard@pitt.edu', 'United States|United States|United States', 2, 'Humans|Somatosensory Cortex', 'Journal Article', '10.1371/journal.pcbi.1000537', '19834600', 'Complex spatial patterning, common in the brain as well as in other biological systems, can emerge as a result of dynamic interactions that occur locally within developing structures. In the rodent somatosensory cortex, groups of neurons called barrels correspond to individual whiskers on the contralateral face. Barrels themselves often contain subbarrels organized into one of a few characteristic patterns. Here we demonstrate that similar patterns can be simulated by means of local growth-promoting and growth-retarding interactions within the circular domains of single barrels. The model correctly predicts that larger barrels contain more spatially complex subbarrel patterns, suggesting that the development of barrels and of the patterns within them may be understood in terms of some relatively simple dynamic processes. We also simulate the full nonlinear equations to demonstrate the predictive value of our linear analysis. Finally, we show that the pattern formation is robust with respect to the geometry of the barrel by simulating patterns on a realistically shaped barrel domain. This work shows how simple pattern forming mechanisms can explain neural wiring both qualitatively and quantitatively even in complex and irregular domains.'),
(84375, 2009, 'plos', 'Antigenic diversity, transmission mechanisms, and the evolution of pathogens', 'Lange, Alexander|Ferguson, Neil M', 'MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom. alange.publ@gmail.com|MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom. alange.publ@gmail.com', 'United Kingdom|United Kingdom', 32, 'Algorithms|Antigenic Variation|Computational Biology|Disease Transmission, Infectious|Evolution, Molecular|Genetic Fitness|HIV Infections|Host-Pathogen Interactions|Humans|Models, Biological|Molecular Epidemiology|Mutation|Viral Load|Virus Diseases', 'Journal Article', '10.1371/journal.pcbi.1000536', '19847288', 'Pathogens have evolved diverse strategies to maximize their transmission fitness. Here we investigate these strategies for directly transmitted pathogens using mathematical models of disease pathogenesis and transmission, modeling fitness as a function of within- and between-host pathogen dynamics. The within-host model includes realistic constraints on pathogen replication via resource depletion and cross-immunity between pathogen strains. We find three distinct types of infection emerge as maxima in the fitness landscape, each characterized by particular within-host dynamics, host population contact network structure, and transmission mode. These three infection types are associated with distinct non-overlapping ranges of levels of antigenic diversity, and well-defined patterns of within-host dynamics and between-host transmissibility. Fitness, quantified by the basic reproduction number, also falls within distinct ranges for each infection type. Every type is optimal for certain contact structures over a range of contact rates. Sexually transmitted infections and childhood diseases are identified as exemplar types for low and high contact rates, respectively. This work generates a plausible mechanistic hypothesis for the observed tradeoff between pathogen transmissibility and antigenic diversity, and shows how different classes of pathogens arise evolutionarily as fitness optima for different contact network structures and host contact rates.'),
(84376, 2009, 'plos', 'An atlas of the thioredoxin fold class reveals the complexity of function-enabling adaptations', 'Atkinson, Holly J|Babbitt, Patricia C', 'Graduate Program in Biological and Medical Informatics, University of California, San Francisco, California, United States of America.|Graduate Program in Biological and Medical Informatics, University of California, San Francisco, California, United States of America.', 'United States|United States', 0, 'Amino Acid Sequence|Animals|Computer Simulation|Databases, Protein|Humans|Models, Chemical|Models, Molecular|Peroxiredoxins|Protein Folding|Protein Structure, Tertiary|Proteins|Structure-Activity Relationship|Thioredoxins', 'Journal Article', '10.1371/journal.pcbi.1000541', '19851441', 'The group of proteins that contain a thioredoxin (Trx) fold is huge and diverse. Assessment of the variation in catalytic machinery of Trx fold proteins is essential in providing a foundation for understanding their functional diversity and predicting the function of the many uncharacterized members of the class. The proteins of the Trx fold class retain common features-including variations on a dithiol CxxC active site motif-that lead to delivery of function. We use protein similarity networks to guide an analysis of how structural and sequence motifs track with catalytic function and taxonomic categories for 4,082 representative sequences spanning the known superfamilies of the Trx fold. Domain structure in the fold class is varied and modular, with 2.8% of sequences containing more than one Trx fold domain. Most member proteins are bacterial. The fold class exhibits many modifications to the CxxC active site motif-only 56.8% of proteins have both cysteines, and no functional groupings have absolute conservation of the expected catalytic motif. Only a small fraction of Trx fold sequences have been functionally characterized. This work provides a global view of the complex distribution of domains and catalytic machinery throughout the fold class, showing that each superfamily contains remnants of the CxxC active site. The unifying context provided by this work can guide the comparison of members of different Trx fold superfamilies to gain insight about their structure-function relationships, illustrated here with the thioredoxins and peroxiredoxins.'),
(84377, 2009, 'plos', 'Invariant distribution of promoter activities in Escherichia coli', 'Zaslaver, Alon|Kaplan, Shai|Bren, Anat|Jinich, Adrian|Mayo, Avi|Dekel, Erez|Alon, Uri|Itzkovitz, Shalev', 'Division of Biology, California Institute of Technology, Pasadena, California, United States of America. alonzo@caltech.edu|Division of Biology, California Institute of Technology, Pasadena, California, United States of America. alonzo@caltech.edu|Division of Biology, California Institute of Technology, Pasadena, California, United States of America. alonzo@caltech.edu|Division of Biology, California Institute of Technology, Pasadena, California, United States of America. alonzo@caltech.edu|Division of Biology, California Institute of Technology, Pasadena, California, United States of America. alonzo@caltech.edu|Division of Biology, California Institute of Technology, Pasadena, California, United States of America. alonzo@caltech.edu|Division of Biology, California Institute of Technology, Pasadena, California, United States of America. alonzo@caltech.edu|Division of Biology, California Institute of Technology, Pasadena, California, United States of America. alonzo@caltech.edu', 'United States|United States|United States|United States|United States|United States|United States|Un', 58, 'Algorithms|Culture Media|Escherichia coli|Escherichia coli Proteins|Fluorescence|Gene Expression Regulation, Bacterial|Genome, Bacterial|Glucose|Glycerol|Linear Models|Models, Genetic|Plasmids|Promoter Regions, Genetic|Ribosomes', 'Journal Article', '10.1371/journal.pcbi.1000545', '19851443', 'Cells need to allocate their limited resources to express a wide range of genes. To understand how Escherichia coli partitions its transcriptional resources between its different promoters, we employ a robotic assay using a comprehensive reporter strain library for E. coli to measure promoter activity on a genomic scale at high-temporal resolution and accuracy. This allows continuous tracking of promoter activity as cells change their growth rate from exponential to stationary phase in different media. We find a heavy-tailed distribution of promoter activities, with promoter activities spanning several orders of magnitude. While the shape of the distribution is almost completely independent of the growth conditions, the identity of the promoters expressed at different levels does depend on them. Translation machinery genes, however, keep the same relative expression levels in the distribution across conditions, and their fractional promoter activity tracks growth rate tightly. We present a simple optimization model for resource allocation which suggests that the observed invariant distributions might maximize growth rate. These invariant features of the distribution of promoter activities may suggest design constraints that shape the allocation of transcriptional resources.'),
(84378, 2009, 'plos', 'Perturbation-response scanning reveals ligand entry-exit mechanisms of ferric binding protein', 'Atilgan, Canan|Atilgan, Ali Rana', 'Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey. canan@sabanciuniv.edu|Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey. canan@sabanciuniv.edu', 'Turkey|Turkey', 101, 'Algorithms|Amino Acid Sequence|Amino Acid Substitution|Apoproteins|Bacterial Proteins|Binding Sites|Computer Simulation|Ferric Compounds|Haemophilus influenzae|Iron-Binding Proteins|Models, Chemical|Models, Molecular|Periplasmic Binding Proteins|Protein Binding|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000544', '19851447', 'We study apo and holo forms of the bacterial ferric binding protein (FBP) which exhibits the so-called ferric transport dilemma: it uptakes iron from the host with remarkable affinity, yet releases it with ease in the cytoplasm for subsequent use. The observations fit the conformational selection model whereby the existence of a weakly populated, higher energy conformation that is stabilized in the presence of the ligand is proposed. We introduce a new tool that we term perturbation-response scanning (PRS) for the analysis of remote control strategies utilized. The approach relies on the systematic use of computational perturbation/response techniques based on linear response theory, by sequentially applying directed forces on single-residues along the chain and recording the resulting relative changes in the residue coordinates. We further obtain closed-form expressions for the magnitude and the directionality of the response. Using PRS, we study the ligand release mechanisms of FBP and support the findings by molecular dynamics simulations. We find that the residue-by-residue displacements between the apo and the holo forms, as determined from the X-ray structures, are faithfully reproduced by perturbations applied on the majority of the residues of the apo form. However, once the stabilizing ligand (Fe) is integrated to the system in holo FBP, perturbing only a few select residues successfully reproduces the experimental displacements. Thus, iron uptake by FBP is a favored process in the fluctuating environment of the protein, whereas iron release is controlled by mechanisms including chelation and allostery. The directional analysis that we implement in the PRS methodology implicates the latter mechanism by leading to a few distant, charged, and exposed loop residues. Upon perturbing these, irrespective of the direction of the operating forces, we find that the cap residues involved in iron release are made to operate coherently, facilitating release of the ion.'),
(84379, 2009, 'plos', 'Steps in the bacterial flagellar motor', 'Mora, Thierry|Yu, Howard|Sowa, Yoshiyuki|Wingreen, Ned S', 'Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.|Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.|Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.|Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.', 'Jersey|Jersey|Jersey|Jersey', 0, 'Algorithms|Bacterial Physiological Phenomena|Bacterial Proteins|Computer Simulation|Models, Biological|Molecular Motor Proteins|Rotation|Torque', 'Journal Article', '10.1371/journal.pcbi.1000540', '19851449', 'The bacterial flagellar motor is a highly efficient rotary machine used by many bacteria to propel themselves. It has recently been shown that at low speeds its rotation proceeds in steps. Here we propose a simple physical model, based on the storage of energy in protein springs, that accounts for this stepping behavior as a random walk in a tilted corrugated potential that combines torque and contact forces. We argue that the absolute angular position of the rotor is crucial for understanding step properties and show this hypothesis to be consistent with the available data, in particular the observation that backward steps are smaller on average than forward steps. We also predict a sublinear speed versus torque relationship for fixed load at low torque, and a peak in rotor diffusion as a function of torque. Our model provides a comprehensive framework for understanding and analyzing stepping behavior in the bacterial flagellar motor and proposes novel, testable predictions. More broadly, the storage of energy in protein springs by the flagellar motor may provide useful general insights into the design of highly efficient molecular machines.'),
(84380, 2009, 'plos', 'A model of cardiovascular disease giving a plausible mechanism for the effect of fractionated low-dose ionizing radiation exposure', 'Little, Mark P|Gola, Anna|Tzoulaki, Ioanna', 'Department of Epidemiology and Public Health, Faculty of Medicine, Imperial College London, London, United Kingdom. mark.little@imperial.ac.uk|Department of Epidemiology and Public Health, Faculty of Medicine, Imperial College London, London, United Kingdom. mark.little@imperial.ac.uk|Department of Epidemiology and Public Health, Faculty of Medicine, Imperial College London, London, United Kingdom. mark.little@imperial.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 44, 'Algorithms|Atherosclerosis|Chemokine CCL2|Cholesterol, LDL|Dose-Response Relationship, Radiation|Endothelial Cells|Humans|Linear Models|Models, Cardiovascular|Monocytes|Occupational Exposure|Radiation Injuries|Radiation, Ionizing|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1000539', '19851450', 'Atherosclerosis is the main cause of coronary heart disease and stroke, the two major causes of death in developed society. There is emerging evidence of excess risk of cardiovascular disease at low radiation doses in various occupationally exposed groups receiving small daily radiation doses. Assuming that they are causal, the mechanisms for effects of chronic fractionated radiation exposures on cardiovascular disease are unclear. We outline a spatial reaction-diffusion model for atherosclerosis and perform stability analysis, based wherever possible on human data. We show that a predicted consequence of multiple small radiation doses is to cause mean chemo-attractant (MCP-1) concentration to increase linearly with cumulative dose. The main driver for the increase in MCP-1 is monocyte death, and consequent reduction in MCP-1 degradation. The radiation-induced risks predicted by the model are quantitatively consistent with those observed in a number of occupationally-exposed groups. The changes in equilibrium MCP-1 concentrations with low density lipoprotein cholesterol concentration are also consistent with experimental and epidemiologic data. This proposed mechanism would be experimentally testable. If true, it also has substantive implications for radiological protection, which at present does not take cardiovascular disease into account. The Japanese A-bomb survivor data implies that cardiovascular disease and cancer mortality contribute similarly to radiogenic risk. The major uncertainty in assessing the low-dose risk of cardiovascular disease is the shape of the dose response relationship, which is unclear in the Japanese data. The analysis of the present paper suggests that linear extrapolation would be appropriate for this endpoint.'),
(84381, 2009, 'plos', 'Discovering the phylodynamics of RNA viruses', 'Holmes, Edward C|Grenfell, Bryan T', 'Center for Infectious Disease Dynamics, Department of Biology, The Pennsylvania State University, Mueller Laboratory, University Park, Pennsylvania, United States of America. ech15@psu.edu|Center for Infectious Disease Dynamics, Department of Biology, The Pennsylvania State University, Mueller Laboratory, University Park, Pennsylvania, United States of America. ech15@psu.edu', 'United States|United States', 86, 'Animals|Computational Biology|Databases, Genetic|Genetic Variation|Humans|Immune System|Influenza A Virus, H1N1 Subtype|Phylogeny|RNA Viruses|RNA, Viral|Sequence Analysis, DNA|Time Factors|Virus Diseases', 'Journal Article', '10.1371/journal.pcbi.1000505', '19855824', '-'),
(84382, 2009, 'plos', 'Computational resources in infectious disease: limitations and challenges', 'Berglund, Eva C|Nystedt, Björn|Andersson, Siv G E', 'Department of Molecular Evolution, Uppsala University, Uppsala, Sweden.|Department of Molecular Evolution, Uppsala University, Uppsala, Sweden.|Department of Molecular Evolution, Uppsala University, Uppsala, Sweden.', 'Sweden|Sweden|Sweden', 0, 'Animals|Bacterial Infections|Communicable Disease Control|Communicable Diseases|Disease Outbreaks|Disease Reservoirs|Genome|Humans|Internationality|Internet|Microbiology|Population Surveillance|Program Development|United States|Virulence', 'Journal Article', '10.1371/journal.pcbi.1000481', '19855825', '-'),
(84383, 2009, 'plos', 'The role of medical structural genomics in discovering new drugs for infectious diseases', 'Van Voorhis, Wesley C|Hol, Wim G J|Myler, Peter J|Stewart, Lance J', 'Department of Medicine, University of Washington, Seattle, Washington, United States of America.|Department of Medicine, University of Washington, Seattle, Washington, United States of America.|Department of Medicine, University of Washington, Seattle, Washington, United States of America.|Department of Medicine, University of Washington, Seattle, Washington, United States of America.', 'United States|United States|United States|United States', 31, 'Animals|Anti-Infective Agents|Chemistry, Pharmaceutical|Communicable Diseases|Databases, Protein|Drug Design|Genomics|Humans|Models, Chemical|Models, Molecular|Pharmacogenetics|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000530', '19855826', '-'),
(84384, 2009, 'plos', 'Investigation of the interaction between the large and small subunits of potato ADP-glucose pyrophosphorylase', 'Baris, Ibrahim|Tuncel, Aytug|Ozber, Natali|Keskin, Ozlem|Kavakli, Ibrahim Halil', 'Department of Chemical and Biological Engineering, College of Engineering, Koc University, Rumeli Feneri Yolu, Istanbul, Turkey.|Department of Chemical and Biological Engineering, College of Engineering, Koc University, Rumeli Feneri Yolu, Istanbul, Turkey.|Department of Chemical and Biological Engineering, College of Engineering, Koc University, Rumeli Feneri Yolu, Istanbul, Turkey.|Department of Chemical and Biological Engineering, College of Engineering, Koc University, Rumeli Feneri Yolu, Istanbul, Turkey.|Department of Chemical and Biological Engineering, College of Engineering, Koc University, Rumeli Feneri Yolu, Istanbul, Turkey.', 'Turkey|Turkey|Turkey|Turkey|Turkey', 17, 'Amino Acid Sequence|Computational Biology|Genetic Complementation Test|Glucose-1-Phosphate Adenylyltransferase|Hydrogen Bonding|Models, Molecular|Molecular Sequence Data|Protein Interaction Domains and Motifs|Protein Multimerization|Protein Subunits|Sequence Alignment|Solanum tuberosum|Thermodynamics|Two-Hybrid System Techniques|Water', 'Journal Article', '10.1371/journal.pcbi.1000546', '19876371', 'ADP-glucose pyrophosphorylase (AGPase), a key allosteric enzyme involved in higher plant starch biosynthesis, is composed of pairs of large (LS) and small subunits (SS). Current evidence indicates that the two subunit types play distinct roles in enzyme function. Recently the heterotetrameric structure of potato AGPase has been modeled. In the current study, we have applied the molecular mechanics generalized born surface area (MM-GBSA) method and identified critical amino acids of the potato AGPase LS and SS subunits that interact with each other during the native heterotetrameric structure formation. We have further shown the role of the LS amino acids in subunit-subunit interaction by yeast two-hybrid, bacterial complementation assay and native gel. Comparison of the computational results with the experiments has indicated that the backbone energy contribution (rather than the side chain energies) of the interface residues is more important in identifying critical residues. We have found that lateral interaction of the LS-SS is much stronger than the longitudinal one, and it is mainly mediated by hydrophobic interactions. This study will not only enhance our understanding of the interaction between the SS and the LS of AGPase, but will also enable us to engineer proteins to obtain better assembled variants of AGPase which can be used for the improvement of plant yield.'),
(84385, 2009, 'plos', 'Mechanical strength of 17,134 model proteins and cysteine slipknots', 'Sikora, Mateusz|Suxc5x82kowska, Joanna I|Cieplak, Marek', 'Institute of Physics, Polish Academy of Sciences, Warsaw, Poland.|Institute of Physics, Polish Academy of Sciences, Warsaw, Poland.|Institute of Physics, Polish Academy of Sciences, Warsaw, Poland.', 'Poland|Poland|Poland', 79, 'Amino Acids|Cysteine|Elasticity|Humans|Models, Molecular|Molecular Dynamics Simulation|Protein Folding|Proteins|Tensile Strength', 'Journal Article', '10.1371/journal.pcbi.1000547', '19876372', 'A new theoretical survey of proteins resistance to constant speed stretching is performed for a set of 17,134 proteins as described by a structure-based model. The proteins selected have no gaps in their structure determination and consist of no more than 250 amino acids. Our previous studies have dealt with 7510 proteins of no more than 150 amino acids. The proteins are ranked according to the strength of the resistance. Most of the predicted top-strength proteins have not yet been studied experimentally. Architectures and folds which are likely to yield large forces are identified. New types of potent force clamps are discovered. They involve disulphide bridges and, in particular, cysteine slipknots. An effective energy parameter of the model is estimated by comparing the theoretical data on characteristic forces to the corresponding experimental values combined with an extrapolation of the theoretical data to the experimental pulling speeds. These studies provide guidance for future experiments on single molecule manipulation and should lead to selection of proteins for applications. A new class of proteins, involving cysteine slipknots, is identified as one that is expected to lead to the strongest force clamps known. This class is characterized through molecular dynamics simulations.'),
(84386, 2009, 'plos', 'Structure of protein interaction networks and their implications on drug design', 'Hase, Takeshi|Tanaka, Hiroshi|Suzuki, Yasuhiro|Nakagawa, So|Kitano, Hiroaki', 'Department of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.|Department of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.|Department of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.|Department of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.|Department of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.', 'Japan|Japan|Japan|Japan|Japan', 89, 'Cluster Analysis|Drug Delivery Systems|Drug Design|Fungal Proteins|Genomics|Humans|Protein Interaction Domains and Motifs|Proteins|Signal Transduction|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1000550', '19876376', 'Protein-protein interaction networks (PINs) are rich sources of information that enable the network properties of biological systems to be understood. A study of the topological and statistical properties of budding yeast and human PINs revealed that they are scale-rich and configured as highly optimized tolerance (HOT) networks that are similar to the router-level topology of the Internet. This is different from claims that such networks are scale-free and configured through simple preferential-attachment processes. Further analysis revealed that there are extensive interconnections among middle-degree nodes that form the backbone of the networks. Degree distributions of essential genes, synthetic lethal genes, synthetic sick genes, and human drug-target genes indicate that there are advantageous drug targets among nodes with middle- to low-degree nodes. Such network properties provide the rationale for combinatorial drugs that target less prominent nodes to increase synergetic efficacy and create fewer side effects.'),
(84387, 2009, 'plos', 'Specific entrainment of mitral cells during gamma oscillation in the rat olfactory bulb', 'David, François O|Hugues, Etienne|Cenier, Tristan|Fourcaud-Trocmé, Nicolas|Buonviso, Nathalie', 'Neurosciences Sensorielles, Comportement, Cognition, CNRS-Université Claude Bernard, Lyon, France. fdavid@snv.jussieu.fr|Neurosciences Sensorielles, Comportement, Cognition, CNRS-Université Claude Bernard, Lyon, France. fdavid@snv.jussieu.fr|Neurosciences Sensorielles, Comportement, Cognition, CNRS-Université Claude Bernard, Lyon, France. fdavid@snv.jussieu.fr|Neurosciences Sensorielles, Comportement, Cognition, CNRS-Université Claude Bernard, Lyon, France. fdavid@snv.jussieu.fr|Neurosciences Sensorielles, Comportement, Cognition, CNRS-Université Claude Bernard, Lyon, France. fdavid@snv.jussieu.fr', 'France|France|France|France|France', 32, 'Action Potentials|Animals|Male|Models, Neurological|Neurons|Odorants|Olfactory Bulb|Pattern Recognition, Automated|Rats|Rats, Wistar|Respiration|Signal Processing, Computer-Assisted|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000551', '19876377', 'Local field potential (LFP) oscillations are often accompanied by synchronization of activity within a widespread cerebral area. Thus, the LFP and neuronal coherence appear to be the result of a common mechanism that underlies neuronal assembly formation. We used the olfactory bulb as a model to investigate: (1) the extent to which unitary dynamics and LFP oscillations can be correlated and (2) the precision with which a model of the hypothesized underlying mechanisms can accurately explain the experimental data. For this purpose, we analyzed simultaneous recordings of mitral cell (MC) activity and LFPs in anesthetized and freely breathing rats in response to odorant stimulation. Spike trains were found to be phase-locked to the gamma oscillation at specific firing rates and to form odor-specific temporal patterns. The use of a conductance-based MC model driven by an approximately balanced excitatory-inhibitory input conductance and a relatively small inhibitory conductance that oscillated at the gamma frequency allowed us to provide one explanation of the experimental data via a mode-locking mechanism. This work sheds light on the way network and intrinsic MC properties participate in the locking of MCs to the gamma oscillation in a realistic physiological context and may result in a particular time-locked assembly. Finally, we discuss how a self-synchronization process with such entrainment properties can explain, under experimental conditions: (1) why the gamma bursts emerge transiently with a maximal amplitude position relative to the stimulus time course, (2) why the oscillations are prominent at a specific gamma frequency, and (3) why the oscillation amplitude depends on specific stimulus properties. We also discuss information processing and functional consequences derived from this mechanism.'),
(84388, 2009, 'plos', 'Gene circuit analysis of the terminal gap gene huckebein', 'Ashyraliyev, Maksat|Siggens, Ken|Janssens, Hilde|Blom, Joke|Akam, Michael|Jaeger, Johannes', 'Center for Mathematics and Computer Science, Centrum Wiskunde and Informatica, Amsterdam, The Netherlands.|Center for Mathematics and Computer Science, Centrum Wiskunde and Informatica, Amsterdam, The Netherlands.|Center for Mathematics and Computer Science, Centrum Wiskunde and Informatica, Amsterdam, The Netherlands.|Center for Mathematics and Computer Science, Centrum Wiskunde and Informatica, Amsterdam, The Netherlands.|Center for Mathematics and Computer Science, Centrum Wiskunde and Informatica, Amsterdam, The Netherlands.|Center for Mathematics and Computer Science, Centrum Wiskunde and Informatica, Amsterdam, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 51, 'Algorithms|Animals|Computer Simulation|DNA-Binding Proteins|Drosophila Proteins|Drosophila melanogaster|Embryo, Nonmammalian|Gene Regulatory Networks|Immunohistochemistry|Least-Squares Analysis|Models, Genetic|Mutation|Systems Biology|Transcription Factors|ras GTPase-Activating Proteins', 'Journal Article', '10.1371/journal.pcbi.1000548', '19876378', 'The early embryo of Drosophila melanogaster provides a powerful model system to study the role of genes in pattern formation. The gap gene network constitutes the first zygotic regulatory tier in the hierarchy of the segmentation genes involved in specifying the position of body segments. Here, we use an integrative, systems-level approach to investigate the regulatory effect of the terminal gap gene huckebein (hkb) on gap gene expression. We present quantitative expression data for the Hkb protein, which enable us to include hkb in gap gene circuit models. Gap gene circuits are mathematical models of gene networks used as computational tools to extract regulatory information from spatial expression data. This is achieved by fitting the model to gap gene expression patterns, in order to obtain estimates for regulatory parameters which predict a specific network topology. We show how considering variability in the data combined with analysis of parameter determinability significantly improves the biological relevance and consistency of the approach. Our models are in agreement with earlier results, which they extend in two important respects: First, we show that Hkb is involved in the regulation of the posterior hunchback (hb) domain, but does not have any other essential function. Specifically, Hkb is required for the anterior shift in the posterior border of this domain, which is now reproduced correctly in our models. Second, gap gene circuits presented here are able to reproduce mutants of terminal gap genes, while previously published models were unable to reproduce any null mutants correctly. As a consequence, our models now capture the expression dynamics of all posterior gap genes and some variational properties of the system correctly. This is an important step towards a better, quantitative understanding of the developmental and evolutionary dynamics of the gap gene network.'),
(84389, 2009, 'plos', 'Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis', 'Bentley, Katie|Mariggi, Giovanni|Gerhardt, Holger|Bates, Paul A', 'Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London, United Kingdom. Katie.Bentley@cancer.org.uk|Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London, United Kingdom. Katie.Bentley@cancer.org.uk|Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London, United Kingdom. Katie.Bentley@cancer.org.uk|Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London, United Kingdom. Katie.Bentley@cancer.org.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 131, 'Astrocytes|Cell Fusion|Cell Movement|Computer Simulation|Endothelial Cells|Models, Cardiovascular|Neovascularization, Pathologic|Neovascularization, Physiologic|Pseudopodia|Reproducibility of Results|Shear Strength|Systems Biology|Vascular Endothelial Growth Factor A', 'Journal Article', '10.1371/journal.pcbi.1000549', '19876379', 'Vascular abnormalities contribute to many diseases such as cancer and diabetic retinopathy. In angiogenesis new blood vessels, headed by a migrating tip cell, sprout from pre-existing vessels in response to signals, e.g., vascular endothelial growth factor (VEGF). Tip cells meet and fuse (anastomosis) to form blood-flow supporting loops. Tip cell selection is achieved by Dll4-Notch mediated lateral inhibition resulting, under normal conditions, in an interleaved arrangement of tip and non-migrating stalk cells. Previously, we showed that the increased VEGF levels found in many diseases can cause the delayed negative feedback of lateral inhibition to produce abnormal oscillations of tip/stalk cell fates. Here we describe the development and implementation of a novel physics-based hierarchical agent model, tightly coupled to in vivo data, to explore the system dynamics as perpetual lateral inhibition combines with tip cell migration and fusion. We explore the tipping point between normal and abnormal sprouting as VEGF increases. A novel filopodia-adhesion driven migration mechanism is presented and validated against in vivo data. Due to the unique feature of ongoing lateral inhibition, stabilised tip/stalk cell patterns show sensitivity to the formation of new cell-cell junctions during fusion: we predict cell fates can reverse. The fusing tip cells become inhibited and neighbouring stalk cells flip fate, recursively providing new tip cells. Junction size emerges as a key factor in establishing a stable tip/stalk pattern. Cell-cell junctions elongate as tip cells migrate, which is shown to provide positive feedback to lateral inhibition, causing it to be more susceptible to pathological oscillations. Importantly, down-regulation of the migratory pathway alone is shown to be sufficient to rescue the sprouting system from oscillation and restore stability. Thus we suggest the use of migration inhibitors as therapeutic agents for vascular normalisation in cancer.'),
(84390, 2009, 'plos', 'Getting started in gene expression microarray analysis', 'Slonim, Donna K|Yanai, Itai', 'Department of Computer Science, Tufts University, Medford, Massachusetts, USA. Donna.Slonim@tufts.edu|Department of Computer Science, Tufts University, Medford, Massachusetts, USA. Donna.Slonim@tufts.edu', 'United States|United States', 90, 'Computational Biology|Oligonucleotide Array Sequence Analysis', 'Journal Article', '10.1371/journal.pcbi.1000543', '19876380', '-'),
(84391, 2009, 'plos', 'Computational biology in Colombia', 'Restrepo, Silvia|Pinzón, Andrés|Rodríguez-R, Luis Miguel|Sierra, Roberto|Grajales, Alejandro|Bernal, Adriana|Barreto, Emiliano|Moreno, Pedro A|Moreno, Pedro|Zambrano, Maria Mercedes|Cristancho, Marco|González, Andrés|Castro, Harold', 'Laboratorio de Micología y Fitopatología, Departamento de Ciencias biológicas, Universidad de los Andes, Bogotá, Colombia. srestrep@uniandes.edu.co|Laboratorio de Micología y Fitopatología, Departamento de Ciencias biológicas, Universidad de los Andes, Bogotá, Colombia. srestrep@uniandes.edu.co|Laboratorio de Micología y Fitopatología, Departamento de Ciencias biológicas, Universidad de los Andes, Bogotá, Colombia. srestrep@uniandes.edu.co|Laboratorio de Micología y Fitopatología, Departamento de Ciencias biológicas, Universidad de los Andes, Bogotá, Colombia. srestrep@uniandes.edu.co|Laboratorio de Micología y Fitopatología, Departamento de Ciencias biológicas, Universidad de los Andes, Bogotá, Colombia. srestrep@uniandes.edu.co|Laboratorio de Micología y Fitopatología, Departamento de Ciencias biológicas, Universidad de los Andes, Bogotá, Colombia. srestrep@uniandes.edu.co|Laboratorio de Micología y Fitopatología, Departamento de Ciencias biológicas, Universidad de los Andes, Bogotá, Colombia. srestrep@uniandes.edu.co|Laboratorio de Micología y Fitopatología, Departamento de Ciencias biológicas, Universidad de los Andes, Bogotá, Colombia. srestrep@uniandes.edu.co|Laboratorio de Micología y Fitopatología, Departamento de Ciencias biológicas, Universidad de los Andes, Bogotá, Colombia. srestrep@uniandes.edu.co|Laboratorio de Micología y Fitopatología, Departamento de Ciencias biológicas, Universidad de los Andes, Bogotá, Colombia. srestrep@uniandes.edu.co|Laboratorio de Micología y Fitopatología, Departamento de Ciencias biológicas, Universidad de los Andes, Bogotá, Colombia. srestrep@uniandes.edu.co|Laboratorio de Micología y Fitopatología, Departamento de Ciencias biológicas, Universidad de los Andes, Bogotá, Colombia. srestrep@uniandes.edu.co|Laboratorio de Micología y Fitopatología, Departamento de Ciencias biológicas, Universidad de los Andes, Bogotá, Colombia. srestrep@uniandes.edu.co', 'Colombia|Colombia|Colombia|Colombia|Colombia|Colombia|Colombia|Colombia|Colombia|Colombia|Colombia|C', 7, 'Colombia|Computational Biology', 'Journal Article', '10.1371/journal.pcbi.1000535', '19876381', '-'),
(84392, 2009, 'plos', 'Intrinsic structural disorder confers cellular viability on oncogenic fusion proteins', 'Hegyi, Hedi|Buday, László|Tompa, Peter', 'Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary.|Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary.|Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary.', 'Hungary|Hungary|Hungary', 0, 'Algorithms|Cell Survival|Cell Transformation, Neoplastic|Chromosome Breakage|Computational Biology|Computer Simulation|Humans|Logistic Models|Models, Molecular|Oncogene Proteins, Fusion|Oncogenes|Protein Conformation|Protein Folding|Translocation, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000552', '19888473', 'Chromosomal translocations, which often generate chimeric proteins by fusing segments of two distinct genes, represent the single major genetic aberration leading to cancer. We suggest that the unifying theme of these events is a high level of intrinsic structural disorder, enabling fusion proteins to evade cellular surveillance mechanisms that eliminate misfolded proteins. Predictions in 406 translocation-related human proteins show that they are significantly enriched in disorder (43.3% vs. 20.7% in all human proteins), they have fewer Pfam domains, and their translocation breakpoints tend to avoid domain splitting. The vicinity of the breakpoint is significantly more disordered than the rest of these already highly disordered fusion proteins. In the unlikely event of domain splitting in fusion it usually spares much of the domain or splits at locations where the newly exposed hydrophobic surface area approximates that of an intact domain. The mechanisms of action of fusion proteins suggest that in most cases their structural disorder is also essential to the acquired oncogenic function, enabling the long-range structural communication of remote binding and/or catalytic elements. In this respect, there are three major mechanisms that contribute to generating an oncogenic signal: (i) a phosphorylation site and a tyrosine-kinase domain are fused, and structural disorder of the intervening region enables intramolecular phosphorylation (e.g., BCR-ABL), (ii) a dimerisation domain fuses with a tyrosine kinase domain and disorder enables the two subunits within the homodimer to engage in permanent intermolecular phosphorylations (e.g., TFG-ALK), (iii) the fusion of a DNA-binding element to a transactivator domain results in an aberrant transcription factor that causes severe misregulation of transcription (e.g. EWS-ATF). Our findings also suggest novel strategies of intervention against the ensuing neoplastic transformations.'),
(84393, 2009, 'plos', 'Alternative splicing in the differentiation of human embryonic stem cells into cardiac precursors', 'Salomonis, Nathan|Nelson, Brandon|Vranizan, Karen|Pico, Alexander R|Hanspers, Kristina|Kuchinsky, Allan|Ta, Linda|Mercola, Mark|Conklin, Bruce R', 'Gladstone Institute of Cardiovascular Disease, San Francisco, California, United States of America.|Gladstone Institute of Cardiovascular Disease, San Francisco, California, United States of America.|Gladstone Institute of Cardiovascular Disease, San Francisco, California, United States of America.|Gladstone Institute of Cardiovascular Disease, San Francisco, California, United States of America.|Gladstone Institute of Cardiovascular Disease, San Francisco, California, United States of America.|Gladstone Institute of Cardiovascular Disease, San Francisco, California, United States of America.|Gladstone Institute of Cardiovascular Disease, San Francisco, California, United States of America.|Gladstone Institute of Cardiovascular Disease, San Francisco, California, United States of America.|Gladstone Institute of Cardiovascular Disease, San Francisco, California, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 65, 'Alternative Splicing|Cell Differentiation|Cell Line|Embryonic Stem Cells|Humans|Myocytes, Cardiac|Proteome|RNA, Messenger', 'Journal Article', '10.1371/journal.pcbi.1000553', '19893621', 'The role of alternative splicing in self-renewal, pluripotency and tissue lineage specification of human embryonic stem cells (hESCs) is largely unknown. To better define these regulatory cues, we modified the H9 hESC line to allow selection of pluripotent hESCs by neomycin resistance and cardiac progenitors by puromycin resistance. Exon-level microarray expression data from undifferentiated hESCs and cardiac and neural precursors were used to identify splice isoforms with cardiac-restricted or common cardiac/neural differentiation expression patterns. Splice events for these groups corresponded to the pathways of cytoskeletal remodeling, RNA splicing, muscle specification, and cell cycle checkpoint control as well as genes with serine/threonine kinase and helicase activity. Using a new program named AltAnalyze (http://www.AltAnalyze.org), we identified novel changes in protein domain and microRNA binding site architecture that were predicted to affect protein function and expression. These included an enrichment of splice isoforms that oppose cell-cycle arrest in hESCs and that promote calcium signaling and cardiac development in cardiac precursors. By combining genome-wide predictions of alternative splicing with new functional annotations, our data suggest potential mechanisms that may influence lineage commitment and hESC maintenance at the level of specific splice isoforms and microRNA regulation.'),
(84394, 2009, 'plos', 'Evolution of resistance to targeted anti-cancer therapies during continuous and pulsed administration strategies', 'Foo, Jasmine|Michor, Franziska', 'Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.|Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.', 'United States|United States', 75, 'Animals|Antineoplastic Agents|Computer Simulation|Drug Resistance, Neoplasm|Epigenesis, Genetic|Evolution, Molecular|Humans|Models, Genetic|Neoplasm Proteins|Neoplasms|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1000557', '19893626', 'The discovery of small molecules targeted to specific oncogenic pathways has revolutionized anti-cancer therapy. However, such therapy often fails due to the evolution of acquired resistance. One long-standing question in clinical cancer research is the identification of optimum therapeutic administration strategies so that the risk of resistance is minimized. In this paper, we investigate optimal drug dosing schedules to prevent, or at least delay, the emergence of resistance. We design and analyze a stochastic mathematical model describing the evolutionary dynamics of a tumor cell population during therapy. We consider drug resistance emerging due to a single (epi)genetic alteration and calculate the probability of resistance arising during specific dosing strategies. We then optimize treatment protocols such that the risk of resistance is minimal while considering drug toxicity and side effects as constraints. Our methodology can be used to identify optimum drug administration schedules to avoid resistance conferred by one (epi)genetic alteration for any cancer and treatment type.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84395, 2009, 'plos', 'Robust models for optic flow coding in natural scenes inspired by insect biology', 'Brinkworth, Russell S A|OCarroll, David C', 'Discipline of Physiology, School of Molecular and Biomedical Science, The University of Adelaide, South Australia, Australia. russell.brinkworth@adelaide.edu.au|Discipline of Physiology, School of Molecular and Biomedical Science, The University of Adelaide, South Australia, Australia. russell.brinkworth@adelaide.edu.au', 'Australia|Australia', 67, 'Animals|Biomimetics|Computer Simulation|Drosophila melanogaster|Models, Neurological|Motion Perception|Nerve Net|Visual Cortex|Visual Pathways', 'Journal Article', '10.1371/journal.pcbi.1000555', '19893631', 'The extraction of accurate self-motion information from the visual world is a difficult problem that has been solved very efficiently by biological organisms utilizing non-linear processing. Previous bio-inspired models for motion detection based on a correlation mechanism have been dogged by issues that arise from their sensitivity to undesired properties of the image, such as contrast, which vary widely between images. Here we present a model with multiple levels of non-linear dynamic adaptive components based directly on the known or suspected responses of neurons within the visual motion pathway of the fly brain. By testing the model under realistic high-dynamic range conditions we show that the addition of these elements makes the motion detection model robust across a large variety of images, velocities and accelerations. Furthermore the performance of the entire system is more than the incremental improvements offered by the individual components, indicating beneficial non-linear interactions between processing stages. The algorithms underlying the model can be implemented in either digital or analog hardware, including neuromorphic analog VLSI, but defy an analytical solution due to their dynamic non-linear operation. The successful application of this algorithm has applications in the development of miniature autonomous systems in defense and civilian roles, including robotics, miniature unmanned aerial vehicles and collision avoidance sensors.'),
(84396, 2009, 'plos', 'Looking at cerebellar malformations through text-mined interactomes of mice and humans', 'Iossifov, Ivan|Rodriguez-Esteban, Raul|Mayzus, Ilya|Millen, Kathleen J|Rzhetsky, Andrey', 'Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Animals|Cerebellum|Humans|Metabolome|Mice|Natural Language Processing|Nerve Tissue Proteins|Species Specificity|Spinocerebellar Degenerations', 'Journal Article', '10.1371/journal.pcbi.1000559', '19893633', 'We have generated and made publicly available two very large networks of molecular interactions: 49,493 mouse-specific and 52,518 human-specific interactions. These networks were generated through automated analysis of 368,331 full-text research articles and 8,039,972 article abstracts from the PubMed database, using the GeneWays system. Our networks cover a wide spectrum of molecular interactions, such as bind, phosphorylate, glycosylate, and activate, 207 of these interaction types occur more than 1,000 times in our unfiltered, multi-species data set. Because mouse and human genes are linked through an orthological relationship, human and mouse networks are amenable to straightforward, joint computational analysis. Using our newly generated networks and known associations between mouse genes and cerebellar malformation phenotypes, we predicted a number of new associations between genes and five cerebellar phenotypes (small cerebellum, absent cerebellum, cerebellar degeneration, abnormal foliation, and abnormal vermis). Using a battery of statistical tests, we showed that genes that are associated with cerebellar phenotypes tend to form compact network clusters. Further, we observed that cerebellar malformation phenotypes tend to be associated with highly connected genes. This tendency was stronger for developmental phenotypes and weaker for cerebellar degeneration.'),
(84397, 2009, 'plos', 'A hidden Markov model for single particle tracks quantifies dynamic interactions between LFA-1 and the actin cytoskeleton', 'Das, Raibatak|Cairo, Christopher W|Coombs, Daniel', 'Department of Mathematics and Institute of Applied Mathematics, University of British Columbia, Vancouver, British Columbia, Canada. dodo@math.ubc.ca|Department of Mathematics and Institute of Applied Mathematics, University of British Columbia, Vancouver, British Columbia, Canada. dodo@math.ubc.ca|Department of Mathematics and Institute of Applied Mathematics, University of British Columbia, Vancouver, British Columbia, Canada. dodo@math.ubc.ca', 'Canada|Canada|Canada', 74, 'Actins|Computer Simulation|Cytoskeleton|Lymphocyte Function-Associated Antigen-1|Markov Chains|Models, Biological|Models, Statistical|Motion|Protein Interaction Mapping|T-Lymphocytes', 'Journal Article', '10.1371/journal.pcbi.1000556', '19893741', 'The extraction of hidden information from complex trajectories is a continuing problem in single-particle and single-molecule experiments. Particle trajectories are the result of multiple phenomena, and new methods for revealing changes in molecular processes are needed. We have developed a practical technique that is capable of identifying multiple states of diffusion within experimental trajectories. We model single particle tracks for a membrane-associated protein interacting with a homogeneously distributed binding partner and show that, with certain simplifying assumptions, particle trajectories can be regarded as the outcome of a two-state hidden Markov model. Using simulated trajectories, we demonstrate that this model can be used to identify the key biophysical parameters for such a system, namely the diffusion coefficients of the underlying states, and the rates of transition between them. We use a stochastic optimization scheme to compute maximum likelihood estimates of these parameters. We have applied this analysis to single-particle trajectories of the integrin receptor lymphocyte function-associated antigen-1 (LFA-1) on live T cells. Our analysis reveals that the diffusion of LFA-1 is indeed approximately two-state, and is characterized by large changes in cytoskeletal interactions upon cellular activation.'),
(84398, 2009, 'plos', 'Integrating extrinsic and intrinsic cues into a minimal model of lineage commitment for hematopoietic progenitors', 'Palani, Santhosh|Sarkar, Casim A', 'Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.', 'United States|United States', 0, 'Algorithms|Cell Differentiation|Cell Lineage|Computational Biology|Computer Simulation|Feedback, Physiological|Hematopoiesis|Hematopoietic Stem Cells|Models, Biological|Oligonucleotide Array Sequence Analysis|Receptors, Cell Surface|Signal Transduction|Stochastic Processes|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000518', '19911036', 'Autoregulation of transcription factors and cross-antagonism between lineage-specific transcription factors are a recurrent theme in cell differentiation. An equally prevalent event that is frequently overlooked in lineage commitment models is the upregulation of lineage-specific receptors, often through lineage-specific transcription factors. Here, we use a minimal model that combines cell-extrinsic and cell-intrinsic elements of regulation in order to understand how both instructive and stochastic events can inform cell commitment decisions in hematopoiesis. Our results suggest that cytokine-mediated positive receptor feedback can induce a switch-like response to external stimuli during multilineage differentiation by providing robustness to both bipotent and committed states while protecting progenitors from noise-induced differentiation or decommitment. Our model provides support to both the instructive and stochastic theories of commitment: cell fates are ultimately driven by lineage-specific transcription factors, but cytokine signaling can strongly bias lineage commitment by regulating these inherently noisy cell-fate decisions with complex, pertinent behaviors such as ligand-mediated ultrasensitivity and robust multistability. The simulations further suggest that the kinetics of differentiation to a mature cell state can depend on the starting progenitor state as well as on the route of commitment that is chosen. Lastly, our model shows good agreement with lineage-specific receptor expression kinetics from microarray experiments and provides a computational framework that can integrate both classical and alternative commitment paths in hematopoiesis that have been observed experimentally.'),
(84399, 2009, 'plos', 'Dynamics of trimming the content of face representations for categorization in the brain', 'van Rijsbergen, Nicola J|Schyns, Philippe G', 'Department of Psychology, University of Glasgow, Glasgow, United Kingdom. nicola@psy.gla.ac.uk|Department of Psychology, University of Glasgow, Glasgow, United Kingdom. nicola@psy.gla.ac.uk', 'United Kingdom|United Kingdom', 32, 'Brain|Electroencephalography|Evoked Potentials|Facial Expression|Female|Humans|Least-Squares Analysis|Male|Models, Neurological|Pattern Recognition, Visual|Photic Stimulation|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1000561', '19911045', 'To understand visual cognition, it is imperative to determine when, how and with what information the human brain categorizes the visual input. Visual categorization consistently involves at least an early and a late stage: the occipito-temporal N170 event related potential related to stimulus encoding and the parietal P300 involved in perceptual decisions. Here we sought to understand how the brain globally transforms its representations of face categories from their early encoding to the later decision stage over the 400 ms time window encompassing the N170 and P300 brain events. We applied classification image techniques to the behavioral and electroencephalographic data of three observers who categorized seven facial expressions of emotion and report two main findings: (1) over the 400 ms time course, processing of facial features initially spreads bilaterally across the left and right occipito-temporal regions to dynamically converge onto the centro-parietal region, (2) concurrently, information processing gradually shifts from encoding common face features across all spatial scales (e.g., the eyes) to representing only the finer scales of the diagnostic features that are richer in useful information for behavior (e.g., the wide opened eyes in fear, the detailed mouth in happy). Our findings suggest that the brain refines its diagnostic representations of visual categories over the first 400 ms of processing by trimming a thorough encoding of features over the N170, to leave only the detailed information important for perceptual decisions over the P300.'),
(84400, 2009, 'plos', 'The evolutionary dynamics of a rapidly mutating virus within and between hosts: the case of hepatitis C virus', 'Luciani, Fabio|Alizon, Samuel', 'Centre for Infection and Inflammation Research (CIIR), School of Medical Sciences, University of New South Wales, Sydney, Australia. luciani@unsw.edu.au|Centre for Infection and Inflammation Research (CIIR), School of Medical Sciences, University of New South Wales, Sydney, Australia. luciani@unsw.edu.au', 'Australia|Australia', 31, 'Algorithms|Antiviral Agents|Computational Biology|Evolution, Molecular|Hepacivirus|Hepatitis C|Host-Pathogen Interactions|Humans|Lymphocyte Activation|Models, Genetic|Mutation|Stochastic Processes|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.1000565', '19911046', 'Many pathogens associated with chronic infections evolve so rapidly that strains found late in an infection have little in common with the initial strain. This raises questions at different levels of analysis because rapid within-host evolution affects the course of an infection, but it can also affect the possibility for natural selection to act at the between-host level. We present a nested approach that incorporates within-host evolutionary dynamics of a rapidly mutating virus (hepatitis C virus) targeted by a cellular cross-reactive immune response, into an epidemiological perspective. The viral trait we follow is the replication rate of the strain initiating the infection. We find that, even for rapidly evolving viruses, the replication rate of the initial strain has a strong effect on the fitness of an infection. Moreover, infections caused by slowly replicating viruses have the highest infection fitness (i.e., lead to more secondary infections), but strains with higher replication rates tend to dominate within a host in the long-term. We also study the effect of cross-reactive immunity and viral mutation rate on infection life history traits. For instance, because of the stochastic nature of our approach, we can identify factors affecting the outcome of the infection (acute or chronic infections). Finally, we show that anti-viral treatments modify the value of the optimal initial replication rate and that the timing of the treatment administration can have public health consequences due to within-host evolution. Our results support the idea that natural selection can act on the replication rate of rapidly evolving viruses at the between-host level. It also provides a mechanistic description of within-host constraints, such as cross-reactive immunity, and shows how these constraints affect the infection fitness. This model raises questions that can be tested experimentally and underlines the necessity to consider the evolution of quantitative traits to understand the outcome and the fitness of an infection.'),
(84401, 2009, 'plos', 'A threading-based method for the prediction of DNA-binding proteins with application to the human genome', 'Gao, Mu|Skolnick, Jeffrey', 'Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, Atlanta, Georgia, USA.|Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, Atlanta, Georgia, USA.', 'Georgia|Georgia', 0, 'Animals|Computational Biology|DNA-Binding Proteins|Data Interpretation, Statistical|Drosophila melanogaster|Genes|Genome, Human|Humans|Models, Molecular|Protein Binding|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1000567', '19911048', 'Diverse mechanisms for DNA-protein recognition have been elucidated in numerous atomic complex structures from various protein families. These structural data provide an invaluable knowledge base not only for understanding DNA-protein interactions, but also for developing specialized methods that predict the DNA-binding function from protein structure. While such methods are useful, a major limitation is that they require an experimental structure of the target as input. To overcome this obstacle, we develop a threading-based method, DNA-Binding-Domain-Threader (DBD-Threader), for the prediction of DNA-binding domains and associated DNA-binding protein residues. Our method, which uses a template library composed of DNA-protein complex structures, requires only the target proteins sequence. In our approach, fold similarity and DNA-binding propensity are employed as two functional discriminating properties. In benchmark tests on 179 DNA-binding and 3,797 non-DNA-binding proteins, using templates whose sequence identity is less than 30% to the target, DBD-Threader achieves a sensitivity/precision of 56%/86%. This performance is considerably better than the standard sequence comparison method PSI-BLAST and is comparable to DBD-Hunter, which requires an experimental structure as input. Moreover, for over 70% of predicted DNA-binding domains, the backbone Root Mean Square Deviations (RMSDs) of the top-ranked structural models are within 6.5 A of their experimental structures, with their associated DNA-binding sites identified at satisfactory accuracy. Additionally, DBD-Threader correctly assigned the SCOP superfamily for most predicted domains. To demonstrate that DBD-Threader is useful for automatic function annotation on a large-scale, DBD-Threader was applied to 18,631 protein sequences from the human genome, 1,654 proteins are predicted to have DNA-binding function. Comparison with existing Gene Ontology (GO) annotations suggests that approximately 30% of our predictions are new. Finally, we present some interesting predictions in detail. In particular, it is estimated that approximately 20% of classic zinc finger domains play a functional role not related to direct DNA-binding.'),
(84402, 2009, 'plos', 'Discovery of regulatory elements is improved by a discriminatory approach', 'Valen, Eivind|Sandelin, Albin|Winther, Ole|Krogh, Anders', 'The Bioinformatics Centre, Department of Biology and the Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark. eivind@binf.ku.dk|The Bioinformatics Centre, Department of Biology and the Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark. eivind@binf.ku.dk|The Bioinformatics Centre, Department of Biology and the Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark. eivind@binf.ku.dk|The Bioinformatics Centre, Department of Biology and the Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark. eivind@binf.ku.dk', 'Denmark|Denmark|Denmark|Denmark', 0, 'Algorithms|Gene Regulatory Networks|Genome, Human|Humans|Models, Genetic|Models, Statistical|Regulatory Elements, Transcriptional', 'Journal Article', '10.1371/journal.pcbi.1000562', '19911049', 'A major goal in post-genome biology is the complete mapping of the gene regulatory networks for every organism. Identification of regulatory elements is a prerequisite for realizing this ambitious goal. A common problem is finding regulatory patterns in promoters of a group of co-expressed genes, but contemporary methods are challenged by the size and diversity of regulatory regions in higher metazoans. Two key issues are the small amount of information contained in a pattern compared to the large promoter regions and the repetitive characteristics of genomic DNA, which both lead to pattern drowning. We present a new computational method for identifying transcription factor binding sites in promoters using a discriminatory approach with a large negative set encompassing a significant sample of the promoters from the relevant genome. The sequences are described by a probabilistic model and the most discriminatory motifs are identified by maximizing the probability of the sets given the motif model and prior probabilities of motif occurrences in both sets. Due to the large number of promoters in the negative set, an enhanced suffix array is used to improve speed and performance. Using our method, we demonstrate higher accuracy than the best of contemporary methods, high robustness when extending the length of the input sequences and a strong correlation between our objective function and the correct solution. Using a large background set of real promoters instead of a simplified model leads to higher discriminatory power and markedly reduces the need for repeat masking, a common pre-processing step for other pattern finders.'),
(84403, 2009, 'plos', 'Interactions between connected half-sarcomeres produce emergent mechanical behavior in a mathematical model of muscle', 'Campbell, Kenneth S', 'Department of Physiology and Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, USA. k.s.campbell@uky.edu', 'United States', 56, 'Actins|Animals|Biomechanical Phenomena|Computer Simulation|Linear Models|Models, Biological|Myofibrils|Myosins|Nonlinear Dynamics|Psoas Muscles|Rabbits|Sarcomeres|Stress, Mechanical|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000560', '19911050', 'Most reductionist theories of muscle attribute a fibers mechanical properties to the scaled behavior of a single half-sarcomere. Mathematical models of this type can explain many of the known mechanical properties of muscle but have to incorporate a passive mechanical component that becomes approximately 300% stiffer in activating conditions to reproduce the force response elicited by stretching a fast mammalian muscle fiber. The available experimental data suggests that titin filaments, which are the mostly likely source of the passive component, become at most approximately 30% stiffer in saturating Ca2+ solutions. The work described in this manuscript used computer modeling to test an alternative systems theory that attributes the stretch response of a mammalian fiber to the composite behavior of a collection of half-sarcomeres. The principal finding was that the stretch response of a chemically permeabilized rabbit psoas fiber could be reproduced with a framework consisting of 300 half-sarcomeres arranged in 6 parallel myofibrils without requiring titin filaments to stiffen in activating solutions. Ablation of inter-myofibrillar links in the computer simulations lowered isometric force values and lowered energy absorption during a stretch. This computed behavior mimics effects previously observed in experiments using muscles from desmin-deficient mice in which the connections between Z-disks in adjacent myofibrils are presumably compromised. The current simulations suggest that muscle fibers exhibit emergent properties that reflect interactions between half-sarcomeres and are not properties of a single half-sarcomere in isolation. It is therefore likely that full quantitative understanding of a fibers mechanical properties requires detailed analysis of a complete fiber system and cannot be achieved by focusing solely on the properties of a single half-sarcomere.'),
(84404, 2009, 'plos', 'Identifying changes in selective constraints: host shifts in influenza', 'Tamuri, Asif U|Dos Reis, Mario|Hay, Alan J|Goldstein, Richard A', 'National Institute for Medical Research, London, United Kingdom.|National Institute for Medical Research, London, United Kingdom.|National Institute for Medical Research, London, United Kingdom.|National Institute for Medical Research, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 82, 'Animals|Anseriformes|Computational Biology|Genetic Drift|Host-Pathogen Interactions|Humans|Influenza A virus|Models, Genetic|Phylogeny|Selection, Genetic|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1000564', '19911053', 'The natural reservoir of Influenza A is waterfowl. Normally, waterfowl viruses are not adapted to infect and spread in the human population. Sometimes, through reassortment or through whole host shift events, genetic material from waterfowl viruses is introduced into the human population causing worldwide pandemics. Identifying which mutations allow viruses from avian origin to spread successfully in the human population is of great importance in predicting and controlling influenza pandemics. Here we describe a novel approach to identify such mutations. We use a sitewise non-homogeneous phylogenetic model that explicitly takes into account differences in the equilibrium frequencies of amino acids in different hosts and locations. We identify 172 amino acid sites with strong support and 518 sites with moderate support of different selection constraints in human and avian viruses. The sites that we identify provide an invaluable resource to experimental virologists studying adaptation of avian flu viruses to the human host. Identification of the sequence changes necessary for host shifts would help us predict the pandemic potential of various strains. The method is of broad applicability to investigating changes in selective constraints when the timing of the changes is known.'),
(84405, 2009, 'plos', 'Optimal experimental design for parameter estimation of a cell signaling model', 'Bandara, Samuel|Schlöder, Johannes P|Eils, Roland|Bock, Hans Georg|Meyer, Tobias', 'Department of Chemical and Systems Biology, Stanford University, Stanford, California, USA. sbandara@stanford.edu|Department of Chemical and Systems Biology, Stanford University, Stanford, California, USA. sbandara@stanford.edu|Department of Chemical and Systems Biology, Stanford University, Stanford, California, USA. sbandara@stanford.edu|Department of Chemical and Systems Biology, Stanford University, Stanford, California, USA. sbandara@stanford.edu|Department of Chemical and Systems Biology, Stanford University, Stanford, California, USA. sbandara@stanford.edu', 'United States|United States|United States|United States|United States', 0, 'Algorithms|Animals|Cell Communication|Kinetics|Mice|Microscopy, Confocal|NIH 3T3 Cells|Phosphatidylinositol 3-Kinases|Protein Structure, Tertiary|Research Design|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000558', '19911077', 'Differential equation models that describe the dynamic changes of biochemical signaling states are important tools to understand cellular behavior. An essential task in building such representations is to infer the affinities, rate constants, and other parameters of a model from actual measurement data. However, intuitive measurement protocols often fail to generate data that restrict the range of possible parameter values. Here we utilized a numerical method to iteratively design optimal live-cell fluorescence microscopy experiments in order to reveal pharmacological and kinetic parameters of a phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) second messenger signaling process that is deregulated in many tumors. The experimental approach included the activation of endogenous phosphoinositide 3-kinase (PI3K) by chemically induced recruitment of a regulatory peptide, reversible inhibition of PI3K using a kinase inhibitor, and monitoring of the PI3K-mediated production of PIP(3) lipids using the pleckstrin homology (PH) domain of Akt. We found that an intuitively planned and established experimental protocol did not yield data from which relevant parameters could be inferred. Starting from a set of poorly defined model parameters derived from the intuitively planned experiment, we calculated concentration-time profiles for both the inducing and the inhibitory compound that would minimize the predicted uncertainty of parameter estimates. Two cycles of optimization and experimentation were sufficient to narrowly confine the model parameters, with the mean variance of estimates dropping more than sixty-fold. Thus, optimal experimental design proved to be a powerful strategy to minimize the number of experiments needed to infer biological parameters from a cell signaling assay.'),
(84406, 2009, 'plos', 'Discovery and annotation of functional chromatin signatures in the human genome', 'Hon, Gary|Wang, Wei|Ren, Bing', 'Bioinformatics Program, University of California at San Diego, La Jolla, California, United States of America.|Bioinformatics Program, University of California at San Diego, La Jolla, California, United States of America.|Bioinformatics Program, University of California at San Diego, La Jolla, California, United States of America.', 'United States|United States|United States', 0, 'Algorithms|Alternative Splicing|Chromatin|Exons|Gene Expression Regulation|Genome, Human|Humans|Models, Genetic|Normal Distribution|Nucleosomes|Regulatory Elements, Transcriptional|Regulatory Sequences, Nucleic Acid|Statistics, Nonparametric', 'Journal Article', '10.1371/journal.pcbi.1000566', '19918365', 'Transcriptional regulation in human cells is a complex process involving a multitude of regulatory elements encoded by the genome. Recent studies have shown that distinct chromatin signatures mark a variety of functional genomic elements and that subtle variations of these signatures mark elements with different functions. To identify novel chromatin signatures in the human genome, we apply a de novo pattern-finding algorithm to genome-wide maps of histone modifications. We recover previously known chromatin signatures associated with promoters and enhancers. We also observe several chromatin signatures with strong enrichment of H3K36me3 marking exons. Closer examination reveals that H3K36me3 is found on well-positioned nucleosomes at exon 5 ends, and that this modification is a global mark of exon expression that also correlates with alternative splicing. Additionally, we observe strong enrichment of H2BK5me1 and H4K20me1 at highly expressed exons near the 5 end, in contrast to the opposite distribution of H3K36me3-marked exons. Finally, we also recover frequently occurring chromatin signatures displaying enrichment of repressive histone modifications. These signatures mark distinct repeat sequences and are associated with distinct modes of gene repression. Together, these results highlight the rich information embedded in the human epigenome and underscore its value in studying gene regulation.'),
(84407, 2009, 'plos', 'Stochastic drift in mitochondrial DNA point mutations: a novel perspective ex silico', 'Poovathingal, Suresh Kumar|Gruber, Jan|Halliwell, Barry|Gunawan, Rudiyanto', 'Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore.|Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore.|Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore.|Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore.', 'Singapore|Singapore|Singapore|Singapore', 24, 'Aging|Algorithms|Animals|Antioxidants|Computational Biology|Computer Simulation|DNA Mutational Analysis|DNA, Mitochondrial|Mice|Monte Carlo Method|Oxidative Stress|Point Mutation|Reactive Oxygen Species|Stochastic Processes|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1000572', '19936024', 'The mitochondrial free radical theory of aging (mFRTA) implicates Reactive Oxygen Species (ROS)-induced mutations of mitochondrial DNA (mtDNA) as a major cause of aging. However, fifty years after its inception, several of its premises are intensely debated. Much of this uncertainty is due to the large range of values in the reported experimental data, for example on oxidative damage and mutational burden in mtDNA. This is in part due to limitations with available measurement technologies. Here we show that sample preparations in some assays necessitating high dilution of DNA (single molecule level) may introduce significant statistical variability. Adding to this complexity is the intrinsically stochastic nature of cellular processes, which manifests in cells from the same tissue harboring varying mutation load. In conjunction, these random elements make the determination of the underlying mutation dynamics extremely challenging. Our in silico stochastic study reveals the effect of coupling the experimental variability and the intrinsic stochasticity of aging process in some of the reported experimental data. We also show that the stochastic nature of a de novo point mutation generated during embryonic development is a major contributor of different mutation burdens in the individuals of mouse population. Analysis of simulation results leads to several new insights on the relevance of mutation stochasticity in the context of dividing tissues and the plausibility of ROS vicious cycle hypothesis.'),
(84408, 2009, 'plos', 'Circadian KaiC phosphorylation: a multi-layer network', 'Li, Congxin|Chen, Xiaofang|Wang, Pengye|Wang, Weichi', 'Laboratory of Soft Matter Physics, Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China.|Laboratory of Soft Matter Physics, Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China.|Laboratory of Soft Matter Physics, Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China.|Laboratory of Soft Matter Physics, Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China.', 'China|China|China|China', 7, 'Adenosine Triphosphate|Bacterial Proteins|Biological Clocks|Circadian Rhythm|Circadian Rhythm Signaling Peptides and Proteins|Computational Biology|Gene Expression Regulation, Bacterial|Models, Biological|Models, Chemical|Models, Statistical|Oscillometry|Phosphorylation|Stochastic Processes|Streptococcus|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000568', '19936045', 'Circadian KaiC phosphorylation in cyanobacteria reconstituted in vitro recently initiates a series of studies experimentally and theoretically to explore its mechanism. In this paper, we report a dynamic diversity in hexameric KaiC phosphoforms using a multi-layer reaction network based on the nonequivalence of the dual phosphorylation sites (S431 and T432) in each KaiC subunit. These diverse oscillatory profiles can generate a kaleidoscopic phase modulation pattern probably responsible for the genome-wide transcription rhythms directly and/or indirectly in cyanobacteria. Particularly, our model reveals that a single KaiC hexamer is an energy-based, phosphorylation-dependent and self-regulated circadian oscillator modulated by KaiA and KaiB. We suggest that T432 is the main regulator for the oscillation amplitude, while S431 is the major phase regulator. S431 and T432 coordinately control the phosphorylation period. Robustness of the Kai network was examined by mixing samples in different phases, and varying protein concentrations and temperature. Similar results were obtained regardless of the deterministic or stochastic method employed. Therefore, the dynamic diversities and robustness of Kai oscillator make it a qualified core pacemaker that controls the cellular processes in cyanobacteria pervasively and accurately.'),
(84409, 2009, 'plos', 'Exon array analysis of head and neck cancers identifies a hypoxia related splice variant of LAMA3 associated with a poor prognosis', 'Moller-Levet, Carla S|Betts, Guy N J|Harris, Adrian L|Homer, Jarrod J|West, Catharine M L|Miller, Crispin J', 'Applied Computational Biology and Bioinformatics Group, Cancer Research UK Paterson Institute for Cancer Research, The University of Manchester, Christie Hospital, Manchester, United Kingdom. cmoller@picr.man.ac.uk|Applied Computational Biology and Bioinformatics Group, Cancer Research UK Paterson Institute for Cancer Research, The University of Manchester, Christie Hospital, Manchester, United Kingdom. cmoller@picr.man.ac.uk|Applied Computational Biology and Bioinformatics Group, Cancer Research UK Paterson Institute for Cancer Research, The University of Manchester, Christie Hospital, Manchester, United Kingdom. cmoller@picr.man.ac.uk|Applied Computational Biology and Bioinformatics Group, Cancer Research UK Paterson Institute for Cancer Research, The University of Manchester, Christie Hospital, Manchester, United Kingdom. cmoller@picr.man.ac.uk|Applied Computational Biology and Bioinformatics Group, Cancer Research UK Paterson Institute for Cancer Research, The University of Manchester, Christie Hospital, Manchester, United Kingdom. cmoller@picr.man.ac.uk|Applied Computational Biology and Bioinformatics Group, Cancer Research UK Paterson Institute for Cancer Research, The University of Manchester, Christie Hospital, Manchester, United Kingdom. cmoller@picr.man.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 29, 'Alternative Splicing|Carcinoma, Squamous Cell|Cell Line, Tumor|Cluster Analysis|Exons|Gene Expression Regulation, Neoplastic|Head and Neck Neoplasms|Humans|Hypoxia|Laminin|Oligonucleotide Array Sequence Analysis|Prognosis|RNA Splicing|Reverse Transcriptase Polymerase Chain Reaction|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1000571', '19936049', 'The identification of alternatively spliced transcript variants specific to particular biological processes in tumours should increase our understanding of cancer. Hypoxia is an important factor in cancer biology, and associated splice variants may present new markers to help with planning treatment. A method was developed to analyse alternative splicing in exon array data, using probeset multiplicity to identify genes with changes in expression across their loci, and a combination of the splicing index and a new metric based on the variation of reliability weighted fold changes to detect changes in the splicing patterns. The approach was validated on a cancer/normal sample dataset in which alternative splicing events had been confirmed using RT-PCR. We then analysed ten head and neck squamous cell carcinomas using exon arrays and identified differentially expressed splice variants in five samples with high versus five with low levels of hypoxia-associated genes. The analysis identified a splice variant of LAMA3 (Laminin alpha 3), LAMA3-A, known to be involved in tumour cell invasion and progression. The full-length transcript of the gene (LAMA3-B) did not appear to be hypoxia-associated. The results were confirmed using qualitative RT-PCR. In a series of 59 prospectively collected head and neck tumours, expression of LAMA3-A had prognostic significance whereas LAMA3-B did not. This work illustrates the potential for alternatively spliced transcripts to act as biomarkers of disease prognosis with improved specificity for particular tissues or conditions over assays which do not discriminate between splice variants.'),
(84410, 2009, 'plos', 'Evaluation of the oscillatory interference model of grid cell firing through analysis and measured period variance of some biological oscillators', 'Zilli, Eric A|Yoshida, Motoharu|Tahvildari, Babak|Giocomo, Lisa M|Hasselmo, Michael E', 'Department of Psychology, Boston University, Boston, Massachusetts, USA. zilli@bu.edu|Department of Psychology, Boston University, Boston, Massachusetts, USA. zilli@bu.edu|Department of Psychology, Boston University, Boston, Massachusetts, USA. zilli@bu.edu|Department of Psychology, Boston University, Boston, Massachusetts, USA. zilli@bu.edu|Department of Psychology, Boston University, Boston, Massachusetts, USA. zilli@bu.edu', 'United States|United States|United States|United States|United States', 40, 'Action Potentials|Algorithms|Animals|Biological Clocks|Brain|Cell Membrane|Computer Simulation|Male|Models, Biological|Models, Statistical|Neurons|Oscillometry|Patch-Clamp Techniques|Rats|Rats, Long-Evans', 'Journal Article', '10.1371/journal.pcbi.1000573', '19936051', 'Models of the hexagonally arrayed spatial activity pattern of grid cell firing in the literature generally fall into two main categories: continuous attractor models or oscillatory interference models. Burak and Fiete (2009, PLoS Comput Biol) recently examined noise in two continuous attractor models, but did not consider oscillatory interference models in detail. Here we analyze an oscillatory interference model to examine the effects of noise on its stability and spatial firing properties. We show analytically that the square of the drift in encoded position due to noise is proportional to time and inversely proportional to the number of oscillators. We also show there is a relatively fixed breakdown point, independent of many parameters of the model, past which noise overwhelms the spatial signal. Based on this result, we show that a pair of oscillators are expected to maintain a stable grid for approximately t = 5mu(3)/(4pisigma)(2) seconds where mu is the mean period of an oscillator in seconds and sigma(2) its variance in seconds(2). We apply this criterion to recordings of individual persistent spiking neurons in postsubiculum (dorsal presubiculum) and layers III and V of entorhinal cortex, to subthreshold membrane potential oscillation recordings in layer II stellate cells of medial entorhinal cortex and to values from the literature regarding medial septum theta bursting cells. All oscillators examined have expected stability times far below those seen in experimental recordings of grid cells, suggesting the examined biological oscillators are unfit as a substrate for current implementations of oscillatory interference models. However, oscillatory interference models can tolerate small amounts of noise, suggesting the utility of circuit level effects which might reduce oscillator variability. Further implications for grid cell models are discussed.'),
(84411, 2009, 'plos', 'Computational model of membrane fission catalyzed by ESCRT-III', 'Fabrikant, Gur|Lata, Suman|Riches, James D|Briggs, John A G|Weissenhorn, Winfried|Kozlov, Michael M', 'Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.', 'Israel|Israel|Israel|Israel|Israel|Israel', 0, 'Carrier Proteins|Catalysis|Cell Membrane|Computational Biology|Computer Simulation|Electron Microscope Tomography|Endosomal Sorting Complexes Required for Transport|Endosomes|Membrane Lipids|Multiprotein Complexes|Protein Binding|Protein Structure, Tertiary|Stress, Mechanical|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1000575', '19936052', 'ESCRT-III proteins catalyze membrane fission during multi vesicular body biogenesis, budding of some enveloped viruses and cell division. We suggest and analyze a novel mechanism of membrane fission by the mammalian ESCRT-III subunits CHMP2 and CHMP3. We propose that the CHMP2-CHMP3 complexes self-assemble into hemi-spherical dome-like structures within the necks of the initial membrane buds generated by CHMP4 filaments. The dome formation is accompanied by the membrane attachment to the dome surface, which drives narrowing of the membrane neck and accumulation of the elastic stresses leading, ultimately, to the neck fission. Based on the bending elastic model of lipid bilayers, we determine the degree of the membrane attachment to the dome enabling the neck fission and compute the required values of the protein-membrane binding energy. We estimate the feasible values of this energy and predict a high efficiency for the CHMP2-CHMP3 complexes in mediating membrane fission. We support the computational model by electron tomography imaging of CHMP2-CHMP3 assemblies in vitro. We predict a high efficiency for the CHMP2-CHMP3 complexes in mediating membrane fission.'),
(84412, 2009, 'plos', 'Spatial analysis of expression patterns predicts genetic interactions at the mid-hindbrain boundary', 'Wittmann, Dominik M|Blöchl, Florian|Trümbach, Dietrich|Wurst, Wolfgang|Prakash, Nilima|Theis, Fabian J', 'Computational Modeling in Biology, Institute for Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Munich-Neuherberg, Germany.|Computational Modeling in Biology, Institute for Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Munich-Neuherberg, Germany.|Computational Modeling in Biology, Institute for Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Munich-Neuherberg, Germany.|Computational Modeling in Biology, Institute for Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Munich-Neuherberg, Germany.|Computational Modeling in Biology, Institute for Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Munich-Neuherberg, Germany.|Computational Modeling in Biology, Institute for Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Munich-Neuherberg, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany', 0, 'Algorithms|Animals|Brain|Brain Mapping|Computational Biology|Diffusion|Fibroblast Growth Factor 8|Gene Expression Profiling|Gene Expression Regulation, Developmental|Mice|Mice, Inbred C57BL|Models, Biological|Models, Statistical|Transcription, Genetic|Wnt1 Protein', 'Journal Article', '10.1371/journal.pcbi.1000569', '19936059', 'The isthmic organizer mediating differentiation of mid- and hindbrain during vertebrate development is characterized by a well-defined pattern of locally restricted gene expression domains around the mid-hindbrain boundary (MHB). This pattern is established and maintained by a regulatory network between several transcription and secreted factors that is not yet understood in full detail. In this contribution we show that a Boolean analysis of the characteristic spatial gene expression patterns at the murine MHB reveals key regulatory interactions in this network. Our analysis employs techniques from computational logic for the minimization of Boolean functions. This approach allows us to predict also the interplay of the various regulatory interactions. In particular, we predict a maintaining, rather than inducing, effect of Fgf8 on Wnt1 expression, an issue that remained unclear from published data. Using mouse anterior neural plate/tube explant cultures, we provide experimental evidence that Fgf8 in fact only maintains but does not induce ectopic Wnt1 expression in these explants. In combination with previously validated interactions, this finding allows for the construction of a regulatory network between key transcription and secreted factors at the MHB. Analyses of Boolean, differential equation and reaction-diffusion models of this network confirm that it is indeed able to explain the stable maintenance of the MHB as well as time-courses of expression patterns both under wild-type and various knock-out conditions. In conclusion, we demonstrate that similar to temporal also spatial expression patterns can be used to gain information about the structure of regulatory networks. We show, in particular, that the spatial gene expression patterns around the MHB help us to understand the maintenance of this boundary on a systems level.'),
(84413, 2009, 'plos', 'A novel extended Granger Causal Model approach demonstrates brain hemispheric differences during face recognition learning', 'Ge, Tian|Kendrick, Keith M|Feng, Jianfeng', 'Centre for Computational Systems Biology, Fudan University, Shanghai, Peoples Republic of China.|Centre for Computational Systems Biology, Fudan University, Shanghai, Peoples Republic of China.|Centre for Computational Systems Biology, Fudan University, Shanghai, Peoples Republic of China.', 'China|China|China', 0, 'Algorithms|Animals|Biophysics|Brain|Brain Mapping|Cerebral Cortex|Female|Learning|Models, Neurological|Nerve Net|Neural Pathways|Oscillometry|Pattern Recognition, Visual|Sheep|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1000570', '19936225', 'Two main approaches in exploring causal relationships in biological systems using time-series data are the application of Dynamic Causal model (DCM) and Granger Causal model (GCM). These have been extensively applied to brain imaging data and are also readily applicable to a wide range of temporal changes involving genes, proteins or metabolic pathways. However, these two approaches have always been considered to be radically different from each other and therefore used independently. Here we present a novel approach which is an extension of Granger Causal model and also shares the features of the bilinear approximation of Dynamic Causal model. We have first tested the efficacy of the extended GCM by applying it extensively in toy models in both time and frequency domains and then applied it to local field potential recording data collected from in vivo multi-electrode array experiments. We demonstrate face discrimination learning-induced changes in inter- and intra-hemispheric connectivity and in the hemispheric predominance of theta and gamma frequency oscillations in sheep inferotemporal cortex. The results provide the first evidence for connectivity changes between and within left and right inferotemporal cortexes as a result of face recognition learning.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84414, 2009, 'plos', 'Dynamic allostery in the methionine repressor revealed by force distribution analysis', 'Stacklies, Wolfram|Xia, Fei|Gräter, Frauke', 'CAS-MPG Partner Institute for Computational Biology, Key laboratory of Computational Biology, Chinese Academy of Sciences, Shanghai, China.|CAS-MPG Partner Institute for Computational Biology, Key laboratory of Computational Biology, Chinese Academy of Sciences, Shanghai, China.|CAS-MPG Partner Institute for Computational Biology, Key laboratory of Computational Biology, Chinese Academy of Sciences, Shanghai, China.', 'China|China|China', 0, 'Allosteric Site|Bacterial Proteins|Computational Biology|Computer Simulation|DNA|Dimerization|Entropy|Escherichia coli|Escherichia coli Proteins|Models, Molecular|Molecular Conformation|Normal Distribution|Protein Binding|Repressor Proteins|Stress, Mechanical|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000574', '19936294', 'Many fundamental cellular processes such as gene expression are tightly regulated by protein allostery. Allosteric signal propagation from the regulatory to the active site requires long-range communication, the molecular mechanism of which remains a matter of debate. A classical example for long-range allostery is the activation of the methionine repressor MetJ, a transcription factor. Binding of its co-repressor SAM increases its affinity for DNA several-fold, but has no visible conformational effect on its DNA binding interface. Our molecular dynamics simulations indicate correlated domain motions within MetJ, and quenching of these dynamics upon SAM binding entropically favors DNA binding. From monitoring conformational fluctuations alone, it is not obvious how the presence of SAM is communicated through the largely rigid core of MetJ and how SAM thereby is able to regulate MetJ dynamics. We here directly monitored the propagation of internal forces through the MetJ structure, instead of relying on conformational changes as conventionally done. Our force distribution analysis successfully revealed the molecular network for strain propagation, which connects collective domain motions through the protein core. Parts of the network are directly affected by SAM binding, giving rise to the observed quenching of fluctuations. Our results are in good agreement with experimental data. The force distribution analysis suggests itself as a valuable tool to gain insight into the molecular function of a whole class of allosteric proteins.'),
(84415, 2009, 'plos', 'Nutritional systems biology modeling: from molecular mechanisms to physiology', 'de Graaf, Albert A|Freidig, Andreas P|De Roos, Baukje|Jamshidi, Neema|Heinemann, Matthias|Rullmann, Johan A C|Hall, Kevin D|Adiels, Martin|van Ommen, Ben', 'Biosciences, TNO Quality of Life, Zeist, The Netherlands. albert.degraaf@tno.nl|Biosciences, TNO Quality of Life, Zeist, The Netherlands. albert.degraaf@tno.nl|Biosciences, TNO Quality of Life, Zeist, The Netherlands. albert.degraaf@tno.nl|Biosciences, TNO Quality of Life, Zeist, The Netherlands. albert.degraaf@tno.nl|Biosciences, TNO Quality of Life, Zeist, The Netherlands. albert.degraaf@tno.nl|Biosciences, TNO Quality of Life, Zeist, The Netherlands. albert.degraaf@tno.nl|Biosciences, TNO Quality of Life, Zeist, The Netherlands. albert.degraaf@tno.nl|Biosciences, TNO Quality of Life, Zeist, The Netherlands. albert.degraaf@tno.nl|Biosciences, TNO Quality of Life, Zeist, The Netherlands. albert.degraaf@tno.nl', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Neth', 0, 'Animals|Computer Simulation|Humans|Models, Biological|Nutritional Status|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000554', '19956660', 'The use of computational modeling and simulation has increased in many biological fields, but despite their potential these techniques are only marginally applied in nutritional sciences. Nevertheless, recent applications of modeling have been instrumental in answering important nutritional questions from the cellular up to the physiological levels. Capturing the complexity of todays important nutritional research questions poses a challenge for modeling to become truly integrative in the consideration and interpretation of experimental data at widely differing scales of space and time. In this review, we discuss a selection of available modeling approaches and applications relevant for nutrition. We then put these models into perspective by categorizing them according to their space and time domain. Through this categorization process, we identified a dearth of models that consider processes occurring between the microscopic and macroscopic scale. We propose a middle-out strategy to develop the required full-scale, multilevel computational models. Exhaustive and accurate phenotyping, the use of the virtual patient concept, and the development of biomarkers from -omics signatures are identified as key elements of a successful systems biology modeling approach in nutrition research--one that integrates physiological mechanisms and data at multiple space and time scales.'),
(84416, 2009, 'plos', 'An evolutionary model-based algorithm for accurate phylogenetic breakpoint mapping and subtype prediction in HIV-1', 'Kosakovsky Pond, Sergei L|Posada, David|Stawiski, Eric|Chappey, Colombe|Poon, Art F Y|Hughes, Gareth|Fearnhill, Esther|Gravenor, Mike B|Leigh Brown, Andrew J|Frost, Simon D W', 'Department of Medicine, University of California San Diego, La Jolla, California, USA. spond@ucsd.edu|Department of Medicine, University of California San Diego, La Jolla, California, USA. spond@ucsd.edu|Department of Medicine, University of California San Diego, La Jolla, California, USA. spond@ucsd.edu|Department of Medicine, University of California San Diego, La Jolla, California, USA. spond@ucsd.edu|Department of Medicine, University of California San Diego, La Jolla, California, USA. spond@ucsd.edu|Department of Medicine, University of California San Diego, La Jolla, California, USA. spond@ucsd.edu|Department of Medicine, University of California San Diego, La Jolla, California, USA. spond@ucsd.edu|Department of Medicine, University of California San Diego, La Jolla, California, USA. spond@ucsd.edu|Department of Medicine, University of California San Diego, La Jolla, California, USA. spond@ucsd.edu|Department of Medicine, University of California San Diego, La Jolla, California, USA. spond@ucsd.edu', 'United States|United States|United States|United States|United States|United States|United States|United States|United States|United States', 0, 'Algorithms|Biological Evolution|Chromosome Mapping|Computer Simulation|Genome, Viral|HIV-1|Models, Genetic|Phylogeny|Software', 'Journal Article', '10.1371/journal.pcbi.1000581', '19956739', 'Genetically diverse pathogens (such as Human Immunodeficiency virus type 1, HIV-1) are frequently stratified into phylogenetically or immunologically defined subtypes for classification purposes. Computational identification of such subtypes is helpful in surveillance, epidemiological analysis and detection of novel variants, e.g., circulating recombinant forms in HIV-1. A number of conceptually and technically different techniques have been proposed for determining the subtype of a query sequence, but there is not a universally optimal approach. We present a model-based phylogenetic method for automatically subtyping an HIV-1 (or other viral or bacterial) sequence, mapping the location of breakpoints and assigning parental sequences in recombinant strains as well as computing confidence levels for the inferred quantities. Our Subtype Classification Using Evolutionary ALgorithms (SCUEAL) procedure is shown to perform very well in a variety of simulation scenarios, runs in parallel when multiple sequences are being screened, and matches or exceeds the performance of existing approaches on typical empirical cases. We applied SCUEAL to all available polymerase (pol) sequences from two large databases, the Stanford Drug Resistance database and the UK HIV Drug Resistance Database. Comparing with subtypes which had previously been assigned revealed that a minor but substantial (approximately 5%) fraction of pure subtype sequences may in fact be within- or inter-subtype recombinants. A free implementation of SCUEAL is provided as a module for the HyPhy package and the Datamonkey web server. Our method is especially useful when an accurate automatic classification of an unknown strain is desired, and is positioned to complement and extend faster but less accurate methods. Given the increasingly frequent use of HIV subtype information in studies focusing on the effect of subtype on treatment, clinical outcome, pathogenicity and vaccine design, the importance of accurate, robust and extensible subtyping procedures is clear.'),
(84417, 2009, 'plos', 'Attention increases the temporal precision of conscious perception: verifying the Neural-ST Model', 'Chennu, Srivas|Craston, Patrick|Wyble, Brad|Bowman, Howard', 'Centre for Cognitive Neuroscience and Cognitive Systems, University of Kent, Canterbury, United Kingdom. srivas@gmail.com|Centre for Cognitive Neuroscience and Cognitive Systems, University of Kent, Canterbury, United Kingdom. srivas@gmail.com|Centre for Cognitive Neuroscience and Cognitive Systems, University of Kent, Canterbury, United Kingdom. srivas@gmail.com|Centre for Cognitive Neuroscience and Cognitive Systems, University of Kent, Canterbury, United Kingdom. srivas@gmail.com', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 18, 'Attention|Computer Simulation|Consciousness|Evoked Potentials, Visual|Humans|Models, Neurological|Task Performance and Analysis|Visual Cortex|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1000576', '19956744', 'What role does attention play in ensuring the temporal precision of visual perception? Behavioural studies have investigated feature selection and binding in time using fleeting sequences of stimuli in the Rapid Serial Visual Presentation (RSVP) paradigm, and found that temporal accuracy is reduced when attentional control is diminished. To reduce the efficacy of attentional deployment, these studies have employed the Attentional Blink (AB) phenomenon. In this article, we use electroencephalography (EEG) to directly investigate the temporal dynamics of conscious perception. Specifically, employing a combination of experimental analysis and neural network modelling, we test the hypothesis that the availability of attention reduces temporal jitter in the latency between a targets visual onset and its consolidation into working memory. We perform time-frequency analysis on data from an AB study to compare the EEG trials underlying the P3 ERPs (Event-related Potential) evoked by targets seen outside vs. inside the AB time window. We find visual differences in phase-sorted ERPimages and statistical differences in the variance of the P3 phase distributions. These results argue for increased variation in the latency of conscious perception during the AB. This experimental analysis is complemented by a theoretical exploration of temporal attention and target processing. Using activation traces from the Neural-ST(2) model, we generate virtual ERPs and virtual ERPimages. These are compared to their human counterparts to propose an explanation of how target consolidation in the context of the AB influences the temporal variability of selective attention. The AB provides us with a suitable phenomenon with which to investigate the interplay between attention and perception. The combination of experimental and theoretical elucidation in this article contributes to converging evidence for the notion that the AB reflects a reduction in the temporal acuity of selective attention and the timeliness of perception.'),
(84418, 2009, 'plos', 'A role for rebinding in rapid and reliable T cell responses to antigen', 'Dushek, Omer|Das, Raibatak|Coombs, Daniel', 'Department of Mathematics, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Mathematics, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Mathematics, University of British Columbia, Vancouver, British Columbia, Canada.', 'Canada|Canada|Canada', 0, 'Animals|Antigens|Computer Simulation|Humans|Immunity, Innate|Models, Neurological|Receptors, Antigen, T-Cell|T-Lymphocytes', 'Journal Article', '10.1371/journal.pcbi.1000578', '19956745', 'Experimental work has shown that T cells of the immune system rapidly and specifically respond to antigenic molecules presented on the surface of antigen-presenting-cells and are able to discriminate between potential stimuli based on the kinetic parameters of the T cell receptor-antigen bond. These antigenic molecules are presented among thousands of chemically similar endogenous peptides, raising the question of how T cells can reliably make a decision to respond to certain antigens but not others within minutes of encountering an antigen presenting cell. In this theoretical study, we investigate the role of localized rebinding between a T cell receptor and an antigen. We show that by allowing the signaling state of individual receptors to persist during brief unbinding events, T cells are able to discriminate antigens based on both their unbinding and rebinding rates. We demonstrate that T cell receptor coreceptors, but not receptor clustering, are important in promoting localized rebinding, and show that requiring rebinding for productive signaling reduces signals from a high concentration of endogenous pMHC. In developing our main results, we use a relatively simple model based on kinetic proofreading. However, we additionally show that all our results are recapitulated when we use a detailed T cell receptor signaling model. We discuss our results in the context of existing models and recent experimental work and propose new experiments to test our findings.'),
(84419, 2009, 'plos', 'A high-throughput screening approach to discovering good forms of biologically inspired visual representation', 'Pinto, Nicolas|Doukhan, David|DiCarlo, James J|Cox, David D', 'McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachussetts, USA. pinto@mit.edu|McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachussetts, USA. pinto@mit.edu|McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachussetts, USA. pinto@mit.edu|McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachussetts, USA. pinto@mit.edu', 'United States|United States|United States|United States', 157, 'Algorithms|Animals|Artificial Intelligence|Biomimetics|Computer Simulation|Humans|Models, Neurological|Pattern Recognition, Automated|Pattern Recognition, Visual|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1000579', '19956750', 'While many models of biological object recognition share a common set of broad-stroke properties, the performance of any one model depends strongly on the choice of parameters in a particular instantiation of that model--e.g., the number of units per layer, the size of pooling kernels, exponents in normalization operations, etc. Since the number of such parameters (explicit or implicit) is typically large and the computational cost of evaluating one particular parameter set is high, the space of possible model instantiations goes largely unexplored. Thus, when a model fails to approach the abilities of biological visual systems, we are left uncertain whether this failure is because we are missing a fundamental idea or because the correct parts have not been tuned correctly, assembled at sufficient scale, or provided with enough training. Here, we present a high-throughput approach to the exploration of such parameter sets, leveraging recent advances in stream processing hardware (high-end NVIDIA graphic cards and the PlayStation 3s IBM Cell Processor). In analogy to high-throughput screening approaches in molecular biology and genetics, we explored thousands of potential network architectures and parameter instantiations, screening those that show promising object recognition performance for further analysis. We show that this approach can yield significant, reproducible gains in performance across an array of basic object recognition tasks, consistently outperforming a variety of state-of-the-art purpose-built vision systems from the literature. As the scale of available computational power continues to expand, we argue that this approach has the potential to greatly accelerate progress in both artificial vision and our understanding of the computational underpinning of biological vision.'),
(84420, 2009, 'plos', 'The rat genome database curators: who, what, where, why', 'Shimoyama, Mary|Hayman, G Thomas|Laulederkind, Stanley J F|Nigam, Rajni|Lowry, Timothy F|Petri, Victoria|Smith, Jennifer R|Wang, Shur-Jen|Munzenmaier, Diane H|Dwinell, Melinda R|Twigger, Simon N|Jacob, Howard J|RGD Team', 'Rat Genome Database, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. shimoyama@mcw.edu|Rat Genome Database, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. shimoyama@mcw.edu|Rat Genome Database, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. shimoyama@mcw.edu|Rat Genome Database, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. shimoyama@mcw.edu|Rat Genome Database, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. shimoyama@mcw.edu|Rat Genome Database, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. shimoyama@mcw.edu|Rat Genome Database, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. shimoyama@mcw.edu|Rat Genome Database, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. shimoyama@mcw.edu|Rat Genome Database, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. shimoyama@mcw.edu|Rat Genome Database, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. shimoyama@mcw.edu|Rat Genome Database, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. shimoyama@mcw.edu|Rat Genome Database, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. shimoyama@mcw.edu|Rat Genome Database, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. shimoyama@mcw.edu', 'United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States', 0, 'Animals|Database Management Systems|Databases, Genetic|Information Dissemination|Information Storage and Retrieval|Internet|Rats', 'Journal Article', '10.1371/journal.pcbi.1000582', '19956751', '-'),
(84421, 2009, 'plos', 'Analyzing short-term noise dependencies of spike-counts in macaque prefrontal cortex using copulas and the flashlight transformation', 'Onken, Arno|Grünewälder, Steffen|Munk, Matthias H J|Obermayer, Klaus', 'School of Electrical Engineering and Computer Science, Technische Universität Berlin, Berlin, Germany. aonken@cs.tu-berlin.de|School of Electrical Engineering and Computer Science, Technische Universität Berlin, Berlin, Germany. aonken@cs.tu-berlin.de|School of Electrical Engineering and Computer Science, Technische Universität Berlin, Berlin, Germany. aonken@cs.tu-berlin.de|School of Electrical Engineering and Computer Science, Technische Universität Berlin, Berlin, Germany. aonken@cs.tu-berlin.de', 'Germany|Germany|Germany|Germany', 32, 'Action Potentials|Animals|Computer Simulation|Female|Macaca mulatta|Models, Neurological|Models, Statistical|Nerve Net|Prefrontal Cortex', 'Journal Article', '10.1371/journal.pcbi.1000577', '19956759', 'Simultaneous spike-counts of neural populations are typically modeled by a Gaussian distribution. On short time scales, however, this distribution is too restrictive to describe and analyze multivariate distributions of discrete spike-counts. We present an alternative that is based on copulas and can account for arbitrary marginal distributions, including Poisson and negative binomial distributions as well as second and higher-order interactions. We describe maximum likelihood-based procedures for fitting copula-based models to spike-count data, and we derive a so-called flashlight transformation which makes it possible to move the tail dependence of an arbitrary copula into an arbitrary orthant of the multivariate probability distribution. Mixtures of copulas that combine different dependence structures and thereby model different driving processes simultaneously are also introduced. First, we apply copula-based models to populations of integrate-and-fire neurons receiving partially correlated input and show that the best fitting copulas provide information about the functional connectivity of coupled neurons which can be extracted using the flashlight transformation. We then apply the new method to data which were recorded from macaque prefrontal cortex using a multi-tetrode array. We find that copula-based distributions with negative binomial marginals provide an appropriate stochastic model for the multivariate spike-count distributions rather than the multivariate Poisson latent variables distribution and the often used multivariate normal distribution. The dependence structure of these distributions provides evidence for common inhibitory input to all recorded stimulus encoding neurons. Finally, we show that copula-based models can be successfully used to evaluate neural codes, e.g., to characterize stimulus-dependent spike-count distributions with information measures. This demonstrates that copula-based models are not only a versatile class of models for multivariate distributions of spike-counts, but that those models can be exploited to understand functional dependencies.'),
(84422, 2009, 'plos', 'Quantification of circadian rhythms in single cells', 'Westermark, Pål O|Welsh, David K|Okamura, Hitoshi|Herzel, Hanspeter', 'Institute for Theoretical Biology, Humboldt University, Berlin, Germany. p.westermark@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt University, Berlin, Germany. p.westermark@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt University, Berlin, Germany. p.westermark@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt University, Berlin, Germany. p.westermark@biologie.hu-berlin.de', 'Germany|Germany|Germany|Germany', 0, 'Animals|Biological Clocks|CLOCK Proteins|Circadian Rhythm|Fibroblasts|Gene Expression Regulation|Luminescent Measurements|Mice|Neurons', 'Journal Article', '10.1371/journal.pcbi.1000580', '19956762', 'Bioluminescence techniques allow accurate monitoring of the circadian clock in single cells. We have analyzed bioluminescence data of Per gene expression in mouse SCN neurons and fibroblasts. From these data, we extracted parameters such as damping rate and noise intensity using two simple mathematical models, one describing a damped oscillator driven by noise, and one describing a self-sustained noisy oscillator. Both models describe the data well and enabled us to quantitatively characterize both wild-type cells and several mutants. It has been suggested that the circadian clock is self-sustained at the single cell level, but we conclude that present data are not sufficient to determine whether the circadian clock of single SCN neurons and fibroblasts is a damped or a self-sustained oscillator. We show how to settle this question, however, by testing the models predictions of different phases and amplitudes in response to a periodic entrainment signal (zeitgeber).'),
(84423, 2009, 'plos', 'Identifying drug effects via pathway alterations using an integer linear programming optimization formulation on phosphoproteomic data', 'Mitsos, Alexander|Melas, Ioannis N|Siminelakis, Paraskeuas|Chairakaki, Aikaterini D|Saez-Rodriguez, Julio|Alexopoulos, Leonidas G', 'Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States|United States', 93, 'Algorithms|Antineoplastic Agents|Databases, Protein|Hep G2 Cells|Humans|Models, Biological|Pharmacology|Phosphoproteins|Proteomics|Reproducibility of Results|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000591', '19997482', 'Understanding the mechanisms of cell function and drug action is a major endeavor in the pharmaceutical industry. Drug effects are governed by the intrinsic properties of the drug (i.e., selectivity and potency) and the specific signaling transduction network of the host (i.e., normal vs. diseased cells). Here, we describe an unbiased, phosphoproteomic-based approach to identify drug effects by monitoring drug-induced topology alterations. With our proposed method, drug effects are investigated under diverse stimulations of the signaling network. Starting with a generic pathway made of logical gates, we build a cell-type specific map by constraining it to fit 13 key phopshoprotein signals under 55 experimental conditions. Fitting is performed via an Integer Linear Program (ILP) formulation and solution by standard ILP solvers, a procedure that drastically outperforms previous fitting schemes. Then, knowing the cells topology, we monitor the same key phosphoprotein signals under the presence of drug and we re-optimize the specific map to reveal drug-induced topology alterations. To prove our case, we make a topology for the hepatocytic cell-line HepG2 and we evaluate the effects of 4 drugs: 3 selective inhibitors for the Epidermal Growth Factor Receptor (EGFR) and a non-selective drug. We confirm effects easily predictable from the drugs main target (i.e., EGFR inhibitors blocks the EGFR pathway) but we also uncover unanticipated effects due to either drug promiscuity or the cells specific topology. An interesting finding is that the selective EGFR inhibitor Gefitinib inhibits signaling downstream the Interleukin-1alpha (IL1alpha) pathway, an effect that cannot be extracted from binding affinity-based approaches. Our method represents an unbiased approach to identify drug effects on small to medium size pathways which is scalable to larger topologies with any type of signaling interventions (small molecules, RNAi, etc). The method can reveal drug effects on pathways, the cornerstone for identifying mechanisms of drugs efficacy.'),
(84424, 2009, 'plos', 'Predicting protein ligand binding sites by combining evolutionary sequence conservation and 3D structure', 'Capra, John A|Laskowski, Roman A|Thornton, Janet M|Singh, Mona|Funkhouser, Thomas A', 'Department of Computer Science, Princeton University, Princeton, New Jersey, United States of America.|Department of Computer Science, Princeton University, Princeton, New Jersey, United States of America.|Department of Computer Science, Princeton University, Princeton, New Jersey, United States of America.|Department of Computer Science, Princeton University, Princeton, New Jersey, United States of America.|Department of Computer Science, Princeton University, Princeton, New Jersey, United States of America.', 'Jersey|Jersey|Jersey|Jersey|Jersey', 0, 'Algorithms|Apoenzymes|Area Under Curve|Binding Sites|Catalytic Domain|Computational Biology|Conserved Sequence|Enzymes|Evolution, Molecular|Holoenzymes|Models, Molecular|Protein Binding|Protein Conformation|Proteins', 'Journal Article', '10.1371/journal.pcbi.1000585', '19997483', 'Identifying a proteins functional sites is an important step towards characterizing its molecular function. Numerous structure- and sequence-based methods have been developed for this problem. Here we introduce ConCavity, a small molecule binding site prediction algorithm that integrates evolutionary sequence conservation estimates with structure-based methods for identifying protein surface cavities. In large-scale testing on a diverse set of single- and multi-chain protein structures, we show that ConCavity substantially outperforms existing methods for identifying both 3D ligand binding pockets and individual ligand binding residues. As part of our testing, we perform one of the first direct comparisons of conservation-based and structure-based methods. We find that the two approaches provide largely complementary information, which can be combined to improve upon either approach alone. We also demonstrate that ConCavity has state-of-the-art performance in predicting catalytic sites and drug binding pockets. Overall, the algorithms and analysis presented here significantly improve our ability to identify ligand binding sites and further advance our understanding of the relationship between evolutionary sequence conservation and structural and functional attributes of proteins. Data, source code, and prediction visualizations are available on the ConCavity web site (http://compbio.cs.princeton.edu/concavity/).'),
(84425, 2009, 'plos', 'Inferring binding energies from selected binding sites', 'Zhao, Yue|Granas, David|Stormo, Gary D', 'Department of Genetics, Washington University School of Medicine, St Louis, Missouri, United States of America.|Department of Genetics, Washington University School of Medicine, St Louis, Missouri, United States of America.|Department of Genetics, Washington University School of Medicine, St Louis, Missouri, United States of America.', 'United States|United States|United States', 146, 'Algorithms|Base Sequence|Binding Sites|Computer Simulation|DNA|Ligands|Models, Chemical|Models, Molecular|Nonlinear Dynamics|Thermodynamics|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000590', '19997485', 'We employ a biophysical model that accounts for the non-linear relationship between binding energy and the statistics of selected binding sites. The model includes the chemical potential of the transcription factor, non-specific binding affinity of the protein for DNA, as well as sequence-specific parameters that may include non-independent contributions of bases to the interaction. We obtain maximum likelihood estimates for all of the parameters and compare the results to standard probabilistic methods of parameter estimation. On simulated data, where the true energy model is known and samples are generated with a variety of parameter values, we show that our method returns much more accurate estimates of the true parameters and much better predictions of the selected binding site distributions. We also introduce a new high-throughput SELEX (HT-SELEX) procedure to determine the binding specificity of a transcription factor in which the initial randomized library and the selected sites are sequenced with next generation methods that return hundreds of thousands of sites. We show that after a single round of selection our method can estimate binding parameters that give very good fits to the selected site distributions, much better than standard motif identification algorithms.'),
(84426, 2009, 'plos', 'Oxidized calmodulin kinase II regulates conduction following myocardial infarction: a computational analysis', 'Christensen, Matthew D|Dun, Wen|Boyden, Penelope A|Anderson, Mark E|Mohler, Peter J|Hund, Thomas J', 'Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.|Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.|Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.|Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.|Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.|Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.', 'United States|United States|United States|United States|United States|United States', 0, 'Action Potentials|Animals|Calcium-Calmodulin-Dependent Protein Kinase Type 2|Computational Biology|Disease Models, Animal|Dogs|Heart Conduction System|Immunoblotting|Models, Biological|Myocardial Infarction|Oxidation-Reduction|Oxidative Stress|Phosphorylation|Reproducibility of Results|Sodium Channels', 'Journal Article', '10.1371/journal.pcbi.1000583', '19997488', 'Calmodulin kinase II (CaMKII) mediates critical signaling pathways responsible for divergent functions in the heart including calcium cycling, hypertrophy and apoptosis. Dysfunction in the CaMKII signaling pathway occurs in heart disease and is associated with increased susceptibility to life-threatening arrhythmia. Furthermore, CaMKII inhibition prevents cardiac arrhythmia and improves heart function following myocardial infarction. Recently, a novel mechanism for oxidative CaMKII activation was discovered in the heart. Here, we provide the first report of CaMKII oxidation state in a well-validated, large-animal model of heart disease. Specifically, we observe increased levels of oxidized CaMKII in the infarct border zone (BZ). These unexpected new data identify an alternative activation pathway for CaMKII in common cardiovascular disease. To study the role of oxidation-dependent CaMKII activation in creating a pro-arrhythmia substrate following myocardial infarction, we developed a new mathematical model of CaMKII activity including both oxidative and autophosphorylation activation pathways. Computer simulations using a multicellular mathematical model of the cardiac fiber demonstrate that enhanced CaMKII activity in the infarct BZ, due primarily to increased oxidation, is associated with reduced conduction velocity, increased effective refractory period, and increased susceptibility to formation of conduction block at the BZ margin, a prerequisite for reentry. Furthermore, our model predicts that CaMKII inhibition improves conduction and reduces refractoriness in the BZ, thereby reducing vulnerability to conduction block and reentry. These results identify a novel oxidation-dependent pathway for CaMKII activation in the infarct BZ that may be an effective therapeutic target for improving conduction and reducing heterogeneity in the infarcted heart.'),
(84427, 2009, 'plos', 'Defining an essence of structure determining residue contacts in proteins', 'Sathyapriya, R|Duarte, Jose M|Stehr, Henning|Filippis, Ioannis|Lappe, Michael', 'Structural Genomics/Bioinformatics Group, Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Berlin, Germany.|Structural Genomics/Bioinformatics Group, Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Berlin, Germany.|Structural Genomics/Bioinformatics Group, Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Berlin, Germany.|Structural Genomics/Bioinformatics Group, Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Berlin, Germany.|Structural Genomics/Bioinformatics Group, Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Berlin, Germany.', 'Germany|Germany|Germany|Germany|Germany', 32, 'Algorithms|Computational Biology|Databases, Protein|Models, Molecular|Protein Conformation|Protein Interaction Domains and Motifs|Protein Interaction Mapping|Proteins', 'Journal Article', '10.1371/journal.pcbi.1000584', '19997489', 'The network of native non-covalent residue contacts determines the three-dimensional structure of a protein. However, not all contacts are of equal structural significance, and little knowledge exists about a minimal, yet sufficient, subset required to define the global features of a protein. Characterisation of this structural essence has remained elusive so far: no algorithmic strategy has been devised to-date that could outperform a random selection in terms of 3D reconstruction accuracy (measured as the Ca RMSD). It is not only of theoretical interest (i.e., for design of advanced statistical potentials) to identify the number and nature of essential native contacts-such a subset of spatial constraints is very useful in a number of novel experimental methods (like EPR) which rely heavily on constraint-based protein modelling. To derive accurate three-dimensional models from distance constraints, we implemented a reconstruction pipeline using distance geometry. We selected a test-set of 12 protein structures from the four major SCOP fold classes and performed our reconstruction analysis. As a reference set, series of random subsets (ranging from 10% to 90% of native contacts) are generated for each protein, and the reconstruction accuracy is computed for each subset. We have developed a rational strategy, termed cone-peeling that combines sequence features and network descriptors to select minimal subsets that outperform the reference sets. We present, for the first time, a rational strategy to derive a structural essence of residue contacts and provide an estimate of the size of this minimal subset. Our algorithm computes sparse subsets capable of determining the tertiary structure at approximately 4.8 A Ca RMSD with as little as 8% of the native contacts (Ca-Ca and Cb-Cb). At the same time, a randomly chosen subset of native contacts needs about twice as many contacts to reach the same level of accuracy. This structural essence opens new avenues in the fields of structure prediction, empirical potentials and docking.'),
(84428, 2009, 'plos', 'Effective reduced diffusion-models: a data driven approach to the analysis of neuronal dynamics', 'Deco, Gustavo|Martí, Daniel|Ledberg, Anders|Reig, Ramon|Sanchez Vives, Maria V', 'Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.', 'Spain|Spain|Spain|Spain|Spain', 34, 'Action Potentials|Animals|Auditory Cortex|Computational Biology|Computer Simulation|Ketamine|Models, Neurological|Nerve Net|Rats|Statistics, Nonparametric|Stochastic Processes|Xylazine', 'Journal Article', '10.1371/journal.pcbi.1000587', '19997490', 'We introduce in this paper a new method for reducing neurodynamical data to an effective diffusion equation, either experimentally or using simulations of biophysically detailed models. The dimensionality of the data is first reduced to the first principal component, and then fitted by the stationary solution of a mean-field-like one-dimensional Langevin equation, which describes the motion of a Brownian particle in a potential. The advantage of such description is that the stationary probability density of the dynamical variable can be easily derived. We applied this method to the analysis of cortical network dynamics during up and down states in an anesthetized animal. During deep anesthesia, intracellularly recorded up and down states transitions occurred with high regularity and could not be adequately described by a one-dimensional diffusion equation. Under lighter anesthesia, however, the distributions of the times spent in the up and down states were better fitted by such a model, suggesting a role for noise in determining the time spent in a particular state.'),
(84429, 2009, 'plos', 'Spike-based reinforcement learning in continuous state and action space: when policy gradient methods fail', 'Vasilaki, Eleni|Frémaux, Nicolas|Urbanczik, Robert|Senn, Walter|Gerstner, Wulfram', 'Laboratory of Computational Neuroscience, EPFL, Lausanne, Switzerland. E.Vasilaki@sheffield.ac.uk|Laboratory of Computational Neuroscience, EPFL, Lausanne, Switzerland. E.Vasilaki@sheffield.ac.uk|Laboratory of Computational Neuroscience, EPFL, Lausanne, Switzerland. E.Vasilaki@sheffield.ac.uk|Laboratory of Computational Neuroscience, EPFL, Lausanne, Switzerland. E.Vasilaki@sheffield.ac.uk|Laboratory of Computational Neuroscience, EPFL, Lausanne, Switzerland. E.Vasilaki@sheffield.ac.uk', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 63, 'Algorithms|Animals|Computational Biology|Computer Simulation|Maze Learning|Models, Neurological|Neurons|Rats|Reward|Signal Transduction|Synaptic Potentials', 'Journal Article', '10.1371/journal.pcbi.1000586', '19997492', 'Changes of synaptic connections between neurons are thought to be the physiological basis of learning. These changes can be gated by neuromodulators that encode the presence of reward. We study a family of reward-modulated synaptic learning rules for spiking neurons on a learning task in continuous space inspired by the Morris Water maze. The synaptic update rule modifies the release probability of synaptic transmission and depends on the timing of presynaptic spike arrival, postsynaptic action potentials, as well as the membrane potential of the postsynaptic neuron. The family of learning rules includes an optimal rule derived from policy gradient methods as well as reward modulated Hebbian learning. The synaptic update rule is implemented in a population of spiking neurons using a network architecture that combines feedforward input with lateral connections. Actions are represented by a population of hypothetical action cells with strong mexican-hat connectivity and are read out at theta frequency. We show that in this architecture, a standard policy gradient rule fails to solve the Morris watermaze task, whereas a variant with a Hebbian bias can learn the task within 20 trials, consistent with experiments. This result does not depend on implementation details such as the size of the neuronal populations. Our theoretical approach shows how learning new behaviors can be linked to reward-modulated plasticity at the level of single synapses and makes predictions about the voltage and spike-timing dependence of synaptic plasticity and the influence of neuromodulators such as dopamine. It is an important step towards connecting formal theories of reinforcement learning with neuronal and synaptic properties.'),
(84430, 2009, 'plos', 'A model analysis of arterial oxygen desaturation during apnea in preterm infants', 'Sands, Scott A|Edwards, Bradley A|Kelly, Vanessa J|Davidson, Malcolm R|Wilkinson, Malcolm H|Berger, Philip J', 'Ritchie Centre for Baby Health Research, Monash Institute of Medical Research, Monash University, Victoria, Australia.|Ritchie Centre for Baby Health Research, Monash Institute of Medical Research, Monash University, Victoria, Australia.|Ritchie Centre for Baby Health Research, Monash Institute of Medical Research, Monash University, Victoria, Australia.|Ritchie Centre for Baby Health Research, Monash Institute of Medical Research, Monash University, Victoria, Australia.|Ritchie Centre for Baby Health Research, Monash Institute of Medical Research, Monash University, Victoria, Australia.|Ritchie Centre for Baby Health Research, Monash Institute of Medical Research, Monash University, Victoria, Australia.', 'Australia|Australia|Australia|Australia|Australia|Australia', 30, 'Computational Biology|Hemoglobins|Humans|Infant, Newborn|Infant, Premature, Diseases|Models, Cardiovascular|Oxygen|Pulmonary Gas Exchange|Respiratory Physiological Phenomena|Sleep Apnea, Central', 'Journal Article', '10.1371/journal.pcbi.1000588', '19997495', 'Rapid arterial O(2) desaturation during apnea in the preterm infant has obvious clinical implications but to date no adequate explanation for why it exists. Understanding the factors influencing the rate of arterial O(2) desaturation during apnea (Sa(O)xe2x82x82) is complicated by the non-linear O(2) dissociation curve, falling pulmonary O(2) uptake, and by the fact that O(2) desaturation is biphasic, exhibiting a rapid phase (stage 1) followed by a slower phase when severe desaturation develops (stage 2). Using a mathematical model incorporating pulmonary uptake dynamics, we found that elevated metabolic O(2) consumption accelerates Sa(O)xe2x82x82throughout the entire desaturation process. By contrast, the remaining factors have a restricted temporal influence: low pre-apneic alveolar P(O)xe2x82x82causes an early onset of desaturation, but thereafter has little impact, reduced lung volume, hemoglobin content or cardiac output, accelerates Sa(O)xe2x82x82during stage 1, and finally, total blood O(2) capacity (blood volume and hemoglobin content) alone determines Sa(O)xe2x82x82during stage 2. Preterm infants with elevated metabolic rate, respiratory depression, low lung volume, impaired cardiac reserve, anemia, or hypovolemia, are at risk for rapid and profound apneic hypoxemia. Our insights provide a basic physiological framework that may guide clinical interpretation and design of interventions for preventing sudden apneic hypoxemia.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84431, 2009, 'plos', 'The GAAS metagenomic tool and its estimations of viral and microbial average genome size in four major biomes', 'Angly, Florent E|Willner, Dana|Prieto-Davó, Alejandra|Edwards, Robert A|Schmieder, Robert|Vega-Thurber, Rebecca|Antonopoulos, Dionysios A|Barott, Katie|Cottrell, Matthew T|Desnues, Christelle|Dinsdale, Elizabeth A|Furlan, Mike|Haynes, Matthew|Henn, Matthew R|Hu, Yongfei|Kirchman, David L|McDole, Tracey|McPherson, John D|Meyer, Folker|Miller, R Michael|Mundt, Egbert|Naviaux, Robert K|Rodriguez-Mueller, Beltran|Stevens, Rick|Wegley, Linda|Zhang, Lixin|Zhu, Baoli|Rohwer, Forest', 'Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com|Biology Department, San Diego State University, San Diego, California, United States of America. forent.angly@gmail.com', 'United States|United States|United States|United States|United States|United States|United States|Un', 157, 'Databases, Nucleic Acid|Genome, Bacterial|Genome, Viral|Metagenomics|Sequence Analysis, DNA|Software Design', 'Journal Article', '10.1371/journal.pcbi.1000593', '20011103', 'Metagenomic studies characterize both the composition and diversity of uncultured viral and microbial communities. BLAST-based comparisons have typically been used for such analyses, however, sampling biases, high percentages of unknown sequences, and the use of arbitrary thresholds to find significant similarities can decrease the accuracy and validity of estimates. Here, we present Genome relative Abundance and Average Size (GAAS), a complete software package that provides improved estimates of community composition and average genome length for metagenomes in both textual and graphical formats. GAAS implements a novel methodology to control for sampling bias via length normalization, to adjust for multiple BLAST similarities by similarity weighting, and to select significant similarities using relative alignment lengths. In benchmark tests, the GAAS method was robust to both high percentages of unknown sequences and to variations in metagenomic sequence read lengths. Re-analysis of the Sargasso Sea virome using GAAS indicated that standard methodologies for metagenomic analysis may dramatically underestimate the abundance and importance of organisms with small genomes in environmental systems. Using GAAS, we conducted a meta-analysis of microbial and viral average genome lengths in over 150 metagenomes from four biomes to determine whether genome lengths vary consistently between and within biomes, and between microbial and viral communities from the same environment. Significant differences between biomes and within aquatic sub-biomes (oceans, hypersaline systems, freshwater, and microbialites) suggested that average genome length is a fundamental property of environments driven by factors at the sub-biome level. The behavior of paired viral and microbial metagenomes from the same environment indicated that microbial and viral average genome sizes are independent of each other, but indicative of community responses to stressors and environmental conditions.'),
(84432, 2009, 'plos', 'Trade-off between positive and negative design of protein stability: from lattice models to real proteins', 'Noivirt-Brik, Orly|Horovitz, Amnon|Unger, Ron', 'Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel.|Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel.|Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel|Israel', 24, 'Models, Biological|Mutation|Protein Folding|Protein Stability|Proteins', 'Journal Article', '10.1371/journal.pcbi.1000592', '20011105', 'Two different strategies for stabilizing proteins are (i) positive design in which the native state is stabilized and (ii) negative design in which competing non-native conformations are destabilized. Here, the circumstances under which one strategy might be favored over the other are explored in the case of lattice models of proteins and then generalized and discussed with regard to real proteins. The balance between positive and negative design of proteins is found to be determined by their average contact-frequency, a property that corresponds to the fraction of states in the conformational ensemble of the sequence in which a pair of residues is in contact. Lattice model proteins with a high average contact-frequency are found to use negative design more than model proteins with a low average contact-frequency. A mathematical derivation of this result indicates that it is general and likely to hold also for real proteins. Comparison of the results of correlated mutation analysis for real proteins with typical contact-frequencies to those of proteins likely to have high contact-frequencies (such as disordered proteins and proteins that are dependent on chaperonins for their folding) indicates that the latter tend to have stronger interactions between residues that are not in contact in their native conformation. Hence, our work indicates that negative design is employed when insufficient stabilization is achieved via positive design owing to high contact-frequencies.'),
(84433, 2009, 'plos', 'An abundance of ubiquitously expressed genes revealed by tissue transcriptome sequence data', 'Ramsköld, Daniel|Wang, Eric T|Burge, Christopher B|Sandberg, Rickard', 'Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.|Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.|Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.|Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.', 'Sweden|Sweden|Sweden|Sweden', 533, '3 Untranslated Regions|Animals|Base Sequence|Cell Line|Gene Dosage|Gene Expression Profiling|Gene Expression Regulation|Humans|Mice|Models, Genetic|Organ Specificity|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000598', '20011106', 'The parts of the genome transcribed by a cell or tissue reflect the biological processes and functions it carries out. We characterized the features of mammalian tissue transcriptomes at the gene level through analysis of RNA deep sequencing (RNA-Seq) data across human and mouse tissues and cell lines. We observed that roughly 8,000 protein-coding genes were ubiquitously expressed, contributing to around 75% of all mRNAs by message copy number in most tissues. These mRNAs encoded proteins that were often intracellular, and tended to be involved in metabolism, transcription, RNA processing or translation. In contrast, genes for secreted or plasma membrane proteins were generally expressed in only a subset of tissues. The distribution of expression levels was broad but fairly continuous: no support was found for the concept of distinct expression classes of genes. Expression estimates that included reads mapping to coding exons only correlated better with qRT-PCR data than estimates which also included 3 untranslated regions (UTRs). Muscle and liver had the least complex transcriptomes, in that they expressed predominantly ubiquitous genes and a large fraction of the transcripts came from a few highly expressed genes, whereas brain, kidney and testis expressed more complex transcriptomes with the vast majority of genes expressed and relatively small contributions from the most expressed genes. mRNAs expressed in brain had unusually long 3UTRs, and mean 3UTR length was higher for genes involved in development, morphogenesis and signal transduction, suggesting added complexity of UTR-based regulation for these genes. Our results support a model in which variable exterior components feed into a large, densely connected core composed of ubiquitously expressed intracellular proteins.'),
(84434, 2009, 'plos', 'Challenges predicting ligand-receptor interactions of promiscuous proteins: the nuclear receptor PXR', 'Ekins, Sean|Kortagere, Sandhya|Iyer, Manisha|Reschly, Erica J|Lill, Markus A|Redinbo, Matthew R|Krasowski, Matthew D', 'Collaborations in Chemistry, Jenkintown, Pennsylvania, United States of America. ekinssean@yahoo.com|Collaborations in Chemistry, Jenkintown, Pennsylvania, United States of America. ekinssean@yahoo.com|Collaborations in Chemistry, Jenkintown, Pennsylvania, United States of America. ekinssean@yahoo.com|Collaborations in Chemistry, Jenkintown, Pennsylvania, United States of America. ekinssean@yahoo.com|Collaborations in Chemistry, Jenkintown, Pennsylvania, United States of America. ekinssean@yahoo.com|Collaborations in Chemistry, Jenkintown, Pennsylvania, United States of America. ekinssean@yahoo.com|Collaborations in Chemistry, Jenkintown, Pennsylvania, United States of America. ekinssean@yahoo.com', 'United States|United States|United States|United States|United States|United States|United States', 93, 'Computational Biology|Crystallography, X-Ray|Humans|Ligands|Models, Molecular|Molecular Structure|Pregnane X Receptor|Protein Structure, Tertiary|Quantitative Structure-Activity Relationship|Receptors, Steroid', 'Journal Article', '10.1371/journal.pcbi.1000594', '20011107', 'Transcriptional regulation of some genes involved in xenobiotic detoxification and apoptosis is performed via the human pregnane X receptor (PXR) which in turn is activated by structurally diverse agonists including steroid hormones. Activation of PXR has the potential to initiate adverse effects, altering drug pharmacokinetics or perturbing physiological processes. Reliable computational prediction of PXR agonists would be valuable for pharmaceutical and toxicological research. There has been limited success with structure-based modeling approaches to predict human PXR activators. Slightly better success has been achieved with ligand-based modeling methods including quantitative structure-activity relationship (QSAR) analysis, pharmacophore modeling and machine learning. In this study, we present a comprehensive analysis focused on prediction of 115 steroids for ligand binding activity towards human PXR. Six crystal structures were used as templates for docking and ligand-based modeling approaches (two-, three-, four- and five-dimensional analyses). The best success at external prediction was achieved with 5D-QSAR. Bayesian models with FCFP_6 descriptors were validated after leaving a large percentage of the dataset out and using an external test set. Docking of ligands to the PXR structure co-crystallized with hyperforin had the best statistics for this method. Sulfated steroids (which are activators) were consistently predicted as non-activators while, poorly predicted steroids were docked in a reverse mode compared to 5alpha-androstan-3beta-ol. Modeling of human PXR represents a complex challenge by virtue of the large, flexible ligand-binding cavity. This study emphasizes this aspect, illustrating modest success using the largest quantitative data set to date and multiple modeling approaches.'),
(84435, 2009, 'plos', 'ON/OFF and beyond--a boolean model of apoptosis', 'Schlatter, Rebekka|Schmich, Kathrin|Avalos Vizcarra, Ima|Scheurich, Peter|Sauter, Thomas|Borner, Christoph|Ederer, Michael|Merfort, Irmgard|Sawodny, Oliver', 'Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany. rebekka.schlatter@isys.uni-stuttgart.de|Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany. rebekka.schlatter@isys.uni-stuttgart.de|Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany. rebekka.schlatter@isys.uni-stuttgart.de|Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany. rebekka.schlatter@isys.uni-stuttgart.de|Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany. rebekka.schlatter@isys.uni-stuttgart.de|Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany. rebekka.schlatter@isys.uni-stuttgart.de|Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany. rebekka.schlatter@isys.uni-stuttgart.de|Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany. rebekka.schlatter@isys.uni-stuttgart.de|Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany. rebekka.schlatter@isys.uni-stuttgart.de', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany', 131, 'Animals|Apoptosis|Computational Biology|Humans|Mice|Models, Biological|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000595', '20011108', 'Apoptosis is regulated by several signaling pathways which are extensively linked by crosstalks. Boolean or logical modeling has become a promising approach to capture the qualitative behavior of such complex networks. Here we built a large-scale literature-based Boolean model of the central intrinsic and extrinsic apoptosis pathways as well as pathways connected with them. The model responds to several external stimuli such as Fas ligand, TNF-alpha, UV-B irradiation, interleukin-1beta and insulin. Timescales and multi-value node logic were used and turned out to be indispensable to reproduce the behavior of the apoptotic network. The coherence of the model was experimentally validated. Thereby an UV-B dose-effect is shown for the first time in mouse hepatocytes. Analysis of the model revealed a tight regulation emerging from high connectivity and spanning crosstalks and a particular importance of feedback loops. An unexpected feedback from Smac release to RIP could further increase complex II formation. The introduced Boolean model provides a comprehensive and coherent description of the apoptosis network behavior. It gives new insights into the complex interplay of pro- and antiapoptotic factors and can be easily expanded to other signaling pathways.'),
(84436, 2009, 'plos', 'Annotation error in public databases: misannotation of molecular function in enzyme superfamilies', 'Schnoes, Alexandra M|Brown, Shoshana D|Dodevski, Igor|Babbitt, Patricia C', 'Graduate Group in Biophysics, University of California San Francisco, San Francisco, California, United States of America.|Graduate Group in Biophysics, University of California San Francisco, San Francisco, California, United States of America.|Graduate Group in Biophysics, University of California San Francisco, San Francisco, California, United States of America.|Graduate Group in Biophysics, University of California San Francisco, San Francisco, California, United States of America.', 'United States|United States|United States|United States', 398, 'Biocatalysis|Database Management Systems|Databases, Protein', 'Journal Article', '10.1371/journal.pcbi.1000605', '20011109', 'Due to the rapid release of new data from genome sequencing projects, the majority of protein sequences in public databases have not been experimentally characterized, rather, sequences are annotated using computational analysis. The level of misannotation and the types of misannotation in large public databases are currently unknown and have not been analyzed in depth. We have investigated the misannotation levels for molecular function in four public protein sequence databases (UniProtKB/Swiss-Prot, GenBank NR, UniProtKB/TrEMBL, and KEGG) for a model set of 37 enzyme families for which extensive experimental information is available. The manually curated database Swiss-Prot shows the lowest annotation error levels (close to 0% for most families), the two other protein sequence databases (GenBank NR and TrEMBL) and the protein sequences in the KEGG pathways database exhibit similar and surprisingly high levels of misannotation that average 5%-63% across the six superfamilies studied. For 10 of the 37 families examined, the level of misannotation in one or more of these databases is >80%. Examination of the NR database over time shows that misannotation has increased from 1993 to 2005. The types of misannotation that were found fall into several categories, most associated with overprediction of molecular function. These results suggest that misannotation in enzyme superfamilies containing multiple families that catalyze different reactions is a larger problem than has been recognized. Strategies are suggested for addressing some of the systematic problems contributing to these high levels of misannotation.'),
(84437, 2009, 'plos', 'What do transitive inference and class inclusion have in common? Categorical (co)products and cognitive development', 'Phillips, Steven|Wilson, William H|Halford, Graeme S', 'Neuroscience Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan. steve@ni.aist.go.jp|Neuroscience Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan. steve@ni.aist.go.jp|Neuroscience Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan. steve@ni.aist.go.jp', 'Japan|Japan|Japan', 19, 'Behavior|Child|Child Development|Child, Preschool|Cognition|Finite Element Analysis|Humans', 'Journal Article', '10.1371/journal.pcbi.1000599', '20011111', 'Transitive inference, class inclusion and a variety of other inferential abilities have strikingly similar developmental profiles-all are acquired around the age of five. Yet, little is known about the reasons for this correspondence. Category theory was invented as a formal means of establishing commonalities between various mathematical structures. We use category theory to show that transitive inference and class inclusion involve dual mathematical structures, called product and coproduct. Other inferential tasks with similar developmental profiles, including matrix completion, cardinality, dimensional changed card sorting, balance-scale (weight-distance integration), and Theory of Mind also involve these structures. By contrast, (co)products are not involved in the behaviours exhibited by younger children on these tasks, or simplified versions that are within their ability. These results point to a fundamental cognitive principle under development during childhood that is the capacity to compute (co)products in the categorical sense.'),
(84438, 2009, 'plos', 'Population structure induces a symmetry breaking favoring the emergence of cooperation', 'Pacheco, Jorge M|Pinheiro, Flávio L|Santos, Francisco C', 'Departamento de Matemática da Universidade do Minho, Campus de Gualtar, Braga, Portugal. pacheco@cii.fc.ul.pt|Departamento de Matemática da Universidade do Minho, Campus de Gualtar, Braga, Portugal. pacheco@cii.fc.ul.pt|Departamento de Matemática da Universidade do Minho, Campus de Gualtar, Braga, Portugal. pacheco@cii.fc.ul.pt', 'Portugal|Portugal|Portugal', 0, 'Computer Simulation|Cooperative Behavior|Feasibility Studies|Game Theory|Humans', 'Journal Article', '10.1371/journal.pcbi.1000596', '20011116', 'The evolution of cooperation described in terms of simple two-person interactions has received considerable attention in recent years, where several key results were obtained. Among those, it is now well established that the web of social interaction networks promotes the emergence of cooperation when modeled in terms of symmetric two-person games. Up until now, however, the impacts of the heterogeneity of social interactions into the emergence of cooperation have not been fully explored, as other aspects remain to be investigated. Here we carry out a study employing the simplest example of a prisoners dilemma game in which the benefits collected by the participants may be proportional to the costs expended. We show that the heterogeneous nature of the social network naturally induces a symmetry breaking of the game, as contributions made by cooperators may become contingent on the social context in which the individual is embedded. A new, numerical, mean-field analysis reveals that prisoners dilemmas on networks no longer constitute a defector dominance dilemma--instead, individuals engage effectively in a general coordination game. We find that the symmetry breaking induced by population structure profoundly affects the evolutionary dynamics of cooperation, dramatically enhancing the feasibility of cooperators: cooperation blooms when each cooperator contributes the same cost, equally shared among the plethora of games in which she participates. This work provides clear evidence that, while individual rational reasoning may hinder cooperative actions, the intricate nature of social interactions may effectively transform a local dilemma of cooperation into a global coordination problem.'),
(84439, 2009, 'plos', 'Cortical gamma rhythms modulate NMDAR-mediated spike timing dependent plasticity in a biophysical model', 'Lee, Shane|Sen, Kamal|Kopell, Nancy', 'Program in Neuroscience, Boston University, Boston, Massachusetts, United States of America. shane@math.bu.edu|Program in Neuroscience, Boston University, Boston, Massachusetts, United States of America. shane@math.bu.edu|Program in Neuroscience, Boston University, Boston, Massachusetts, United States of America. shane@math.bu.edu', 'United States|United States|United States', 28, 'Animals|Auditory Cortex|Electroencephalography|Glutamine|Models, Neurological|Neuronal Plasticity|Receptors, N-Methyl-D-Aspartate', 'Journal Article', '10.1371/journal.pcbi.1000602', '20011119', 'Spike timing dependent plasticity (STDP) has been observed experimentally in vitro and is a widely studied neural algorithm for synaptic modification. While the functional role of STDP has been investigated extensively, the effect of rhythms on the precise timing of STDP has not been characterized as well. We use a simplified biophysical model of a cortical network that generates pyramidal interneuronal gamma rhythms (PING). Plasticity via STDP is investigated at the excitatory pyramidal cell synapse from a gamma frequency (30-90 Hz) input independent of the network gamma rhythm. The input may represent a corticocortical or an information-specific thalamocortical connection. This synapse is mediated by N-methyl-D-aspartate receptor mediated (NMDAR) currents. For distinct network and input frequencies, the model shows robust frequency regimes of potentiation and depression, providing a mechanism by which responses to certain inputs can potentiate while responses to other inputs depress. For potentiating regimes, the model suggests an optimal amount and duration of plasticity that can occur, which depends on the time course for the decay of the postsynaptic NMDAR current. Prolonging the duration of the input beyond this optimal time results in depression. Inserting pauses in the input can increase the total potentiation. The optimal pause length corresponds to the decay time of the NMDAR current. Thus, STDP in this model provides a mechanism for potentiation and depression depending on input frequency and suggests that the slow NMDAR current decay helps to regulate the optimal amplitude and duration of the plasticity. The optimal pause length is comparable to the time scale of the negative phase of a modulatory theta rhythm, which may pause gamma rhythm spiking. Our pause results may suggest a novel role for this theta rhythm in plasticity. Finally, we discuss our results in the context of auditory thalamocortical plasticity.'),
(84440, 2009, 'plos', 'Integrin clustering is driven by mechanical resistance from the glycocalyx and the substrate', 'Paszek, Matthew J|Boettiger, David|Weaver, Valerie M|Hammer, Daniel A', 'Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.', 'United States|United States|United States|United States', 0, 'Algorithms|Computer Simulation|Extracellular Matrix|Glycocalyx|Integrins|Ligands|Protein Binding|Stress, Physiological|Substrate Specificity', 'Journal Article', '10.1371/journal.pcbi.1000604', '20011123', 'Integrins have emerged as key sensory molecules that translate chemical and physical cues from the extracellular matrix (ECM) into biochemical signals that regulate cell behavior. Integrins function by clustering into adhesion plaques, but the molecular mechanisms that drive integrin clustering in response to interaction with the ECM remain unclear. To explore how deformations in the cell-ECM interface influence integrin clustering, we developed a spatial-temporal simulation that integrates the micro-mechanics of the cell, glycocalyx, and ECM with a simple chemical model of integrin activation and ligand interaction. Due to mechanical coupling, we find that integrin-ligand interactions are highly cooperative, and this cooperativity is sufficient to drive integrin clustering even in the absence of cytoskeletal crosslinking or homotypic integrin-integrin interactions. The glycocalyx largely mediates this cooperativity and hence may be a key regulator of integrin function. Remarkably, integrin clustering in the model is naturally responsive to the chemical and physical properties of the ECM, including ligand density, matrix rigidity, and the chemical affinity of ligand for receptor. Consistent with experimental observations, we find that integrin clustering is robust on rigid substrates with high ligand density, but is impaired on substrates that are highly compliant or have low ligand density. We thus demonstrate how integrins themselves could function as sensory molecules that begin sensing matrix properties even before large multi-molecular adhesion complexes are assembled.'),
(84441, 2009, 'plos', 'A multi-component model of the developing retinocollicular pathway incorporating axonal and synaptic growth', 'Godfrey, Keith B|Eglen, Stephen J|Swindale, Nicholas V', 'Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, United Kingdom. k.godfrey@damtp.cam.ac.uk|Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, United Kingdom. k.godfrey@damtp.cam.ac.uk|Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, United Kingdom. k.godfrey@damtp.cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Animals|Axons|Behavior, Animal|Mice|Models, Neurological|Probability|Retina|Synapses|Vision, Ocular', 'Journal Article', '10.1371/journal.pcbi.1000600', '20011124', 'During development, neurons extend axons to different brain areas and produce stereotypical patterns of connections. The mechanisms underlying this process have been intensively studied in the visual system, where retinal neurons form retinotopic maps in the thalamus and superior colliculus. The mechanisms active in map formation include molecular guidance cues, trophic factor release, spontaneous neural activity, spike-timing dependent plasticity (STDP), synapse creation and retraction, and axon growth, branching and retraction. To investigate how these mechanisms interact, a multi-component model of the developing retinocollicular pathway was produced based on phenomenological approximations of each of these mechanisms. Core assumptions of the model were that the probabilities of axonal branching and synaptic growth are highest where the combined influences of chemoaffinity and trophic factor cues are highest, and that activity-dependent release of trophic factors acts to stabilize synapses. Based on these behaviors, model axons produced morphologically realistic growth patterns and projected to retinotopically correct locations in the colliculus. Findings of the model include that STDP, gradient detection by axonal growth cones and lateral connectivity among collicular neurons were not necessary for refinement, and that the instructive cues for axonal growth appear to be mediated first by molecular guidance and then by neural activity. Although complex, the model appears to be insensitive to variations in how the component developmental mechanisms are implemented. Activity, molecular guidance and the growth and retraction of axons and synapses are common features of neural development, and the findings of this study may have relevance beyond organization in the retinocollicular pathway.'),
(84442, 2009, 'plos', 'Human cancer protein-protein interaction network: a structural perspective', 'Kar, Gozde|Gursoy, Attila|Keskin, Ozlem', 'Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Rumeli Feneri Yolu, Sariyer Istanbul, Turkey.|Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Rumeli Feneri Yolu, Sariyer Istanbul, Turkey.|Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Rumeli Feneri Yolu, Sariyer Istanbul, Turkey.', 'Turkey|Turkey|Turkey', 0, 'Animals|Binding Sites|Computational Biology|Gene Expression Regulation, Neoplastic|Humans|Hydrophobic and Hydrophilic Interactions|Models, Molecular|Neoplasms|Protein Binding|Protein Interaction Domains and Motifs|Proteins|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000601', '20011507', 'Protein-protein interaction networks provide a global picture of cellular function and biological processes. Some proteins act as hub proteins, highly connected to others, whereas some others have few interactions. The dysfunction of some interactions causes many diseases, including cancer. Proteins interact through their interfaces. Therefore, studying the interface properties of cancer-related proteins will help explain their role in the interaction networks. Similar or overlapping binding sites should be used repeatedly in single interface hub proteins, making them promiscuous. Alternatively, multi-interface hub proteins make use of several distinct binding sites to bind to different partners. We propose a methodology to integrate protein interfaces into cancer interaction networks (ciSPIN, cancer structural protein interface network). The interactions in the human protein interaction network are replaced by interfaces, coming from either known or predicted complexes. We provide a detailed analysis of cancer related human protein-protein interfaces and the topological properties of the cancer network. The results reveal that cancer-related proteins have smaller, more planar, more charged and less hydrophobic binding sites than non-cancer proteins, which may indicate low affinity and high specificity of the cancer-related interactions. We also classified the genes in ciSPIN according to phenotypes. Within phenotypes, for breast cancer, colorectal cancer and leukemia, interface properties were found to be discriminating from non-cancer interfaces with an accuracy of 71%, 67%, 61%, respectively. In addition, cancer-related proteins tend to interact with their partners through distinct interfaces, corresponding mostly to multi-interface hubs, which comprise 56% of cancer-related proteins, and constituting the nodes with higher essentiality in the network (76%). We illustrate the interface related affinity properties of two cancer-related hub proteins: Erbb3, a multi interface, and Raf1, a single interface hub. The results reveal that affinity of interactions of the multi-interface hub tends to be higher than that of the single-interface hub. These findings might be important in obtaining new targets in cancer as well as finding the details of specific binding regions of putative cancer drug candidates.'),
(84443, 2009, 'plos', 'Alu and b1 repeats have been selectively retained in the upstream and intronic regions of genes of specific functional classes', 'Tsirigos, Aristotelis|Rigoutsos, Isidore', 'Bioinformatics and Pattern Discovery Group, IBM Thomas J. Watson Research Center, Yorktown Heights, New York, USA. atsirigo@us.ibm.com|Bioinformatics and Pattern Discovery Group, IBM Thomas J. Watson Research Center, Yorktown Heights, New York, USA. atsirigo@us.ibm.com', 'United States|United States', 0, 'Alu Elements|Animals|Chromosome Mapping|Computational Biology|Genes|Humans|Introns|Mice|Models, Genetic|Pan troglodytes|Rats|Repetitive Sequences, Nucleic Acid|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000610', '20019790', 'Alu and B1 repeats are mobile elements that originated in an initial duplication of the 7SL RNA gene prior to the primate-rodent split about 80 million years ago and currently account for a substantial fraction of the human and mouse genome, respectively. Following the primate-rodent split, Alu and B1 elements spread independently in each of the two genomes in a seemingly random manner, and, according to the prevailing hypothesis, negative selection shaped their final distribution in each genome by forcing the selective loss of certain Alu and B1 copies. In this paper, contrary to the prevailing hypothesis, we present evidence that Alu and B1 elements have been selectively retained in the upstream and intronic regions of genes belonging to specific functional classes. At the same time, we found no evidence for selective loss of these elements in any functional class. A subset of the functional links we discovered corresponds to functions where Alu involvement has actually been experimentally validated, whereas the majority of the functional links we report are novel. Finally, the unexpected finding that Alu and B1 elements show similar biases in their distribution across functional classes, despite having spread independently in their respective genomes, further supports our claim that the extant instances of Alu and B1 elements are the result of positive selection.'),
(84444, 2009, 'plos', 'Predicting functional alternative splicing by measuring RNA selection pressure from multigenome alignments', 'Lu, Hongchao|Lin, Lan|Sato, Seiko|Xing, Yi|Lee, Christopher J', 'Molecular Biology Institute, Center for Computational Biology, Institute for Genomics and Proteomics, Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California, USA.|Molecular Biology Institute, Center for Computational Biology, Institute for Genomics and Proteomics, Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California, USA.|Molecular Biology Institute, Center for Computational Biology, Institute for Genomics and Proteomics, Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California, USA.|Molecular Biology Institute, Center for Computational Biology, Institute for Genomics and Proteomics, Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California, USA.|Molecular Biology Institute, Center for Computational Biology, Institute for Genomics and Proteomics, Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California, USA.', 'United States|United States|United States|United States|United States', 20, 'Alternative Splicing|Animals|Carrier Proteins|Computational Biology|Expressed Sequence Tags|Genome|Humans|Mice|Models, Genetic|Nerve Tissue Proteins|Oligonucleotide Array Sequence Analysis|RNA|Receptors, N-Methyl-D-Aspartate|Reproducibility of Results|Reverse Transcriptase Polymerase Chain Reaction|Sequence Alignment|Vesicular Transport Proteins', 'Journal Article', '10.1371/journal.pcbi.1000608', '20019791', 'High-throughput methods such as EST sequencing, microarrays and deep sequencing have identified large numbers of alternative splicing (AS) events, but studies have shown that only a subset of these may be functional. Here we report a sensitive bioinformatics approach that identifies exons with evidence of a strong RNA selection pressure ratio (RSPR)--i.e., evolutionary selection against mutations that change only the mRNA sequence while leaving the protein sequence unchanged--measured across an entire evolutionary family, which greatly amplifies its predictive power. Using the UCSC 28 vertebrate genome alignment, this approach correctly predicted half to three-quarters of AS exons that are known binding targets of the NOVA splicing regulatory factor, and predicted 345 strongly selected alternative splicing events in human, and 262 in mouse. These predictions were strongly validated by several experimental criteria of functional AS such as independent detection of the same AS event in other species, reading frame-preservation, and experimental evidence of tissue-specific regulation: 75% (15/20) of a sample of high-RSPR exons displayed tissue specific regulation in a panel of ten tissues, vs. only 20% (4/20) among a sample of low-RSPR exons. These data suggest that RSPR can identify exons with functionally important splicing regulation, and provides biologists with a dataset of over 600 such exons. We present several case studies, including both well-studied examples (GRIN1) and novel examples (EXOC7). These data also show that RSPR strongly outperforms other approaches such as standard sequence conservation (which fails to distinguish amino acid selection pressure from RNA selection pressure), or pairwise genome comparison (which lacks adequate statistical power for predicting individual exons).'),
(84445, 2009, 'plos', 'Dissecting early differentially expressed genes in a mixture of differentiating embryonic stem cells', 'Hong, Feng|Fang, Fang|He, Xuming|Cao, Xiaoyi|Chipperfield, Hiram|Xie, Dan|Wong, Wing H|Ng, Huck H|Zhong, Sheng', 'Department of Statistics, University of Illinois at Urbana-Champaign, Champaign, Illinois, USA.|Department of Statistics, University of Illinois at Urbana-Champaign, Champaign, Illinois, USA.|Department of Statistics, University of Illinois at Urbana-Champaign, Champaign, Illinois, USA.|Department of Statistics, University of Illinois at Urbana-Champaign, Champaign, Illinois, USA.|Department of Statistics, University of Illinois at Urbana-Champaign, Champaign, Illinois, USA.|Department of Statistics, University of Illinois at Urbana-Champaign, Champaign, Illinois, USA.|Department of Statistics, University of Illinois at Urbana-Champaign, Champaign, Illinois, USA.|Department of Statistics, University of Illinois at Urbana-Champaign, Champaign, Illinois, USA.|Department of Statistics, University of Illinois at Urbana-Champaign, Champaign, Illinois, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States|United States', 10, 'Animals|Cell Differentiation|Computational Biology|Embryonic Stem Cells|Gene Expression Profiling|Gene Expression Regulation, Developmental|Gene Regulatory Networks|Mice|Models, Genetic|Poisson Distribution', 'Journal Article', '10.1371/journal.pcbi.1000607', '20019792', 'The differentiation of embryonic stem cells is initiated by a gradual loss of pluripotency-associated transcripts and induction of differentiation genes. Accordingly, the detection of differentially expressed genes at the early stages of differentiation could assist the identification of the causal genes that either promote or inhibit differentiation. The previous methods of identifying differentially expressed genes by comparing different cell types would inevitably include a large portion of genes that respond to, rather than regulate, the differentiation process. We demonstrate through the use of biological replicates and a novel statistical approach that the gene expression data obtained without prior separation of cell types are informative for detecting differentially expressed genes at the early stages of differentiation. Applying the proposed method to analyze the differentiation of murine embryonic stem cells, we identified and then experimentally verified Smarcad1 as a novel regulator of pluripotency and self-renewal. We formalized this statistical approach as a statistical test that is generally applicable to analyze other differentiation processes.'),
(84446, 2009, 'plos', 'Evolutionary plasticity and innovations in complex metabolic reaction networks', 'Matias Rodrigues, João F|Wagner, Andreas', 'Department of Biochemistry, University of Zürich, Zürich, Switzerland. j.rodrigues@bioc.uzh.ch|Department of Biochemistry, University of Zürich, Zürich, Switzerland. j.rodrigues@bioc.uzh.ch', 'Switzerland|Switzerland', 0, 'Computational Biology|Escherichia coli|Evolution, Molecular|Gene Regulatory Networks|Genotype|Metabolic Networks and Pathways|Models, Genetic|Phenotype', 'Journal Article', '10.1371/journal.pcbi.1000613', '20019795', 'Genome-scale metabolic networks are highly robust to the elimination of enzyme-coding genes. Their structure can evolve rapidly through mutations that eliminate such genes and through horizontal gene transfer that adds new enzyme-coding genes. Using flux balance analysis we study a vast space of metabolic network genotypes and their relationship to metabolic phenotypes, the ability to sustain life in an environment defined by an available spectrum of carbon sources. Two such networks typically differ in most of their reactions and have few essential reactions in common. Our observations suggest that the robustness of the Escherichia coli metabolic network to mutations is typical of networks with the same phenotype. We also demonstrate that networks with the same phenotype form large sets that can be traversed through single mutations, and that single mutations of different genotypes with the same phenotype can yield very different novel phenotypes. This means that the evolutionary plasticity and robustness of metabolic networks facilitates the evolution of new metabolic abilities. Our approach has broad implications for the evolution of metabolic networks, for our understanding of mutational robustness, for the design of antimetabolic drugs, and for metabolic engineering.'),
(84447, 2009, 'plos', 'Nano-motion dynamics are determined by surface-tethered selectin mechanokinetics and bond formation', 'Schmidt, Brian J|Papin, Jason A|Lawrence, Michael B', 'Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.|Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.|Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.', 'United States|United States|United States', 0, 'Biomechanical Phenomena|Computational Biology|Computer Simulation|Microspheres|Models, Biological|Motion|Nanotechnology|Protein Binding|Reproducibility of Results|Selectins|Surface Properties', 'Journal Article', '10.1371/journal.pcbi.1000612', '20019797', 'The interaction of proteins at cellular interfaces is critical for many biological processes, from intercellular signaling to cell adhesion. For example, the selectin family of adhesion receptors plays a critical role in trafficking during inflammation and immunosurveillance. Quantitative measurements of binding rates between surface-constrained proteins elicit insight into how molecular structural details and post-translational modifications contribute to function. However, nano-scale transport effects can obfuscate measurements in experimental assays. We constructed a biophysical simulation of the motion of a rigid microsphere coated with biomolecular adhesion receptors in shearing flow undergoing thermal motion. The simulation enabled in silico investigation of the effects of kinetic force dependence, molecular deformation, grouping adhesion receptors into clusters, surface-constrained bond formation, and nano-scale vertical transport on outputs that directly map to observable motions. Simulations recreated the jerky, discrete stop-and-go motions observed in P-selectin/PSGL-1 microbead assays with physiologic ligand densities. Motion statistics tied detailed simulated motion data to experimentally reported quantities. New deductions about biomolecular function for P-selectin/PSGL-1 interactions were made. Distributing adhesive forces among P-selectin/PSGL-1 molecules closely grouped in clusters was necessary to achieve bond lifetimes observed in microbead assays. Initial, capturing bond formation effectively occurred across the entire molecular contour length. However, subsequent rebinding events were enhanced by the reduced separation distance following the initial capture. The result demonstrates that vertical transport can contribute to an enhancement in the apparent bond formation rate. A detailed analysis of in silico motions prompted the proposition of wobble autocorrelation as an indicator of two-dimensional function. Insight into two-dimensional bond formation gained from flow cell assays might therefore be important to understand processes involving extended cellular interactions, such as immunological synapse formation. A biologically informative in silico system was created with minimal, high-confidence inputs. Incorporating random effects in surface separation through thermal motion enabled new deductions of the effects of surface-constrained biomolecular function. Important molecular information is embedded in the patterns and statistics of motion.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84448, 2009, 'plos', 'Power-law scaling in the brain surface electric potential', 'Miller, Kai J|Sorensen, Larry B|Ojemann, Jeffrey G|den Nijs, Marcel', 'Department of Physics, University of Washington, Seattle, Washington, USA. kjmiller@u.washington.edu|Department of Physics, University of Washington, Seattle, Washington, USA. kjmiller@u.washington.edu|Department of Physics, University of Washington, Seattle, Washington, USA. kjmiller@u.washington.edu|Department of Physics, University of Washington, Seattle, Washington, USA. kjmiller@u.washington.edu', 'United States|United States|United States|United States', 316, 'Action Potentials|Algorithms|Brain Mapping|Cerebral Cortex|Computational Biology|Computer Simulation|Electroencephalography|Epilepsy|Humans|Poisson Distribution', 'Journal Article', '10.1371/journal.pcbi.1000609', '20019800', 'Recent studies have identified broadband phenomena in the electric potentials produced by the brain. We report the finding of power-law scaling in these signals using subdural electrocorticographic recordings from the surface of human cortex. The power spectral density (PSD) of the electric potential has the power-law form P(f ) approximately Af(-chi) from 80 to 500 Hz. This scaling index, chi = 4.0+/-0.1, is conserved across subjects, area in the cortex, and local neural activity levels. The shape of the PSD does not change with increases in local cortical activity, but the amplitude, A, increases. We observe a knee in the spectra at f(0) approximately 75 Hz, implying the existence of a characteristic time scale tau = (2pif(0))(-1) approximately 2 - 4ms. Below f(0), we explore two-power-law forms of the PSD, and demonstrate that there are activity-related fluctuations in the amplitude of a power-law process lying beneath the alpha/beta rhythms. Finally, we illustrate through simulation how, small-scale, simplified neuronal models could lead to these power-law observations. This suggests a new paradigm of non-oscillatory asynchronous, scale-free, changes in cortical potentials, corresponding to changes in mean population-averaged firing rate, to complement the prevalent synchronous rhythm-based paradigm.'),
(84449, 2009, 'plos', 'Model of transcriptional activation by MarA in Escherichia coli', 'Wall, Michael E|Markowitz, David A|Rosner, Judah L|Martin, Robert G', 'Computer, Computational, and Statistical Sciences Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA. mewall@lanl.gov|Computer, Computational, and Statistical Sciences Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA. mewall@lanl.gov|Computer, Computational, and Statistical Sciences Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA. mewall@lanl.gov|Computer, Computational, and Statistical Sciences Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA. mewall@lanl.gov', 'Mexico|Mexico|Mexico|Mexico', 0, 'Bacterial Proteins|Chi-Square Distribution|Computational Biology|Computer Simulation|DNA-Binding Proteins|DNA-Directed DNA Polymerase|Escherichia coli|Escherichia coli Proteins|Models, Genetic|Promoter Regions, Genetic|Reproducibility of Results|Superoxide Dismutase|Thermodynamics|Transcriptional Activation', 'Journal Article', '10.1371/journal.pcbi.1000614', '20019803', 'The AraC family transcription factor MarA activates approximately 40 genes (the marA/soxS/rob regulon) of the Escherichia coli chromosome resulting in different levels of resistance to a wide array of antibiotics and to superoxides. Activation of marA/soxS/rob regulon promoters occurs in a well-defined order with respect to the level of MarA, however, the order of activation does not parallel the strength of MarA binding to promoter sequences. To understand this lack of correspondence, we developed a computational model of transcriptional activation in which a transcription factor either increases or decreases RNA polymerase binding, and either accelerates or retards post-binding events associated with transcription initiation. We used the model to analyze data characterizing MarA regulation of promoter activity. The model clearly explains the lack of correspondence between the order of activation and the MarA-DNA affinity and indicates that the order of activation can only be predicted using information about the strength of the full MarA-polymerase-DNA interaction. The analysis further suggests that MarA can activate without increasing polymerase binding and that activation can even involve a decrease in polymerase binding, which is opposite to the textbook model of activation by recruitment. These findings are consistent with published chromatin immunoprecipitation assays of interactions between polymerase and the E. coli chromosome. We find that activation involving decreased polymerase binding yields lower latency in gene regulation and therefore might confer a competitive advantage to cells. Our model yields insights into requirements for predicting the order of activation of a regulon and enables us to suggest that activation might involve a decrease in polymerase binding which we expect to be an important theme of gene regulation in E. coli and beyond.'),
(84450, 2009, 'plos', 'Transcriptome and proteome exploration to model translation efficiency and protein stability in Lactococcus lactis', 'Dressaire, Clémentine|Gitton, Christophe|Loubière, Pascal|Monnet, Véronique|Queinnec, Isabelle|Cocaign-Bousquet, Muriel', 'Université de Toulouse, INSA, UPS, INP, LISBP, Toulouse, France.|Université de Toulouse, INSA, UPS, INP, LISBP, Toulouse, France.|Université de Toulouse, INSA, UPS, INP, LISBP, Toulouse, France.|Université de Toulouse, INSA, UPS, INP, LISBP, Toulouse, France.|Université de Toulouse, INSA, UPS, INP, LISBP, Toulouse, France.|Université de Toulouse, INSA, UPS, INP, LISBP, Toulouse, France.', 'France|France|France|France|France|France', 35, 'Amino Acids|Bacterial Proteins|Gene Expression Profiling|Lactococcus lactis|Models, Biological|Protein Stability|Proteome|Proteomics|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000606', '20019804', 'This genome-scale study analysed the various parameters influencing protein levels in cells. To achieve this goal, the model bacterium Lactococcus lactis was grown at steady state in continuous cultures at different growth rates, and proteomic and transcriptomic data were thoroughly compared. Ratios of mRNA to protein were highly variable among proteins but also, for a given gene, between the different growth conditions. The modeling of cellular processes combined with a data fitting modeling approach allowed both translation efficiencies and degradation rates to be estimated for each protein in each growth condition. Estimated translational efficiencies and degradation rates strongly differed between proteins and were tested for their biological significance through statistical correlations with relevant parameters such as codon or amino acid bias. These efficiencies and degradation rates were not constant in all growth conditions and were inversely proportional to the growth rate, indicating a more efficient translation at low growth rate but an antagonistic higher rate of protein degradation. Estimated protein median half-lives ranged from 23 to 224 min, underlying the importance of protein degradation notably at low growth rates. The regulation of intracellular protein level was analysed through regulatory coefficient calculations, revealing a complex control depending on protein and growth conditions. The modeling approach enabled translational efficiencies and protein degradation rates to be estimated, two biological parameters extremely difficult to determine experimentally and generally lacking in bacteria. This method is generic and can now be extended to other environments and/or other micro-organisms.'),
(84451, 2009, 'plos', 'Meta-analysis of inter-species liver co-expression networks elucidates traits associated with common human diseases', 'Wang, Kai|Narayanan, Manikandan|Zhong, Hua|Tompa, Martin|Schadt, Eric E|Zhu, Jun', 'Department of Genetics, Rosetta Inpharmatics, Seattle, Washington, USA.|Department of Genetics, Rosetta Inpharmatics, Seattle, Washington, USA.|Department of Genetics, Rosetta Inpharmatics, Seattle, Washington, USA.|Department of Genetics, Rosetta Inpharmatics, Seattle, Washington, USA.|Department of Genetics, Rosetta Inpharmatics, Seattle, Washington, USA.|Department of Genetics, Rosetta Inpharmatics, Seattle, Washington, USA.', 'United States|United States|United States|United States|United States|United States', 0, 'Animals|Computer Simulation|Diabetes Mellitus|Gene Regulatory Networks|Genetic Predisposition to Disease|Genome-Wide Association Study|Humans|Lipid Metabolism|Liver|Mice|Mice, Transgenic|Models, Biological|Oligonucleotide Array Sequence Analysis|Polymorphism, Single Nucleotide|Rats|Regression Analysis|Signal Transduction|Species Specificity|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000616', '20019805', 'Co-expression networks are routinely used to study human diseases like obesity and diabetes. Systematic comparison of these networks between species has the potential to elucidate common mechanisms that are conserved between human and rodent species, as well as those that are species-specific characterizing evolutionary plasticity. We developed a semi-parametric meta-analysis approach for combining gene-gene co-expression relationships across expression profile datasets from multiple species. The simulation results showed that the semi-parametric method is robust against noise. When applied to human, mouse, and rat liver co-expression networks, our method out-performed existing methods in identifying gene pairs with coherent biological functions. We identified a network conserved across species that highlighted cell-cell signaling, cell-adhesion and sterol biosynthesis as main biological processes represented in genome-wide association study candidate gene sets for blood lipid levels. We further developed a heterogeneity statistic to test for network differences among multiple datasets, and demonstrated that genes with species-specific interactions tend to be under positive selection throughout evolution. Finally, we identified a human-specific sub-network regulated by RXRG, which has been validated to play a different role in hyperlipidemia and Type 2 diabetes between human and mouse. Taken together, our approach represents a novel step forward in integrating gene co-expression networks from multiple large scale datasets to leverage not only common information but also differences that are dataset-specific.'),
(84452, 2009, 'plos', 'Calculating evolutionary dynamics in structured populations', 'Nathanson, Charles G|Tarnita, Corina E|Nowak, Martin A', 'Department of Economics, Harvard University, Cambridge, Massachusetts, USA.|Department of Economics, Harvard University, Cambridge, Massachusetts, USA.|Department of Economics, Harvard University, Cambridge, Massachusetts, USA.', 'United States|United States|United States', 28, 'Algorithms|Computer Simulation|Evolution, Molecular|Models, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000615', '20019806', 'Evolution is shaping the world around us. At the core of every evolutionary process is a population of reproducing individuals. The outcome of an evolutionary process depends on population structure. Here we provide a general formula for calculating evolutionary dynamics in a wide class of structured populations. This class includes the recently introduced games in phenotype space and evolutionary set theory. There can be local interactions for determining the relative fitness of individuals, but we require global updating, which means all individuals compete uniformly for reproduction. We study the competition of two strategies in the context of an evolutionary game and determine which strategy is favored in the limit of weak selection. We derive an intuitive formula for the structure coefficient, sigma, and provide a method for efficient numerical calculation.'),
(84453, 2009, 'plos', 'Distributed dynamical computation in neural circuits with propagating coherent activity patterns', 'Gong, Pulin|van Leeuwen, Cees', 'School of Physics, University of Sydney, Sydney, Australia. gong@physics.usyd.edu.au|School of Physics, University of Sydney, Sydney, Australia. gong@physics.usyd.edu.au', 'Australia|Australia', 0, 'Action Potentials|Algorithms|Brain|Computational Biology|Humans|Models, Neurological|Nerve Net|Pattern Recognition, Automated', 'Journal Article', '10.1371/journal.pcbi.1000611', '20019807', 'Activity in neural circuits is spatiotemporally organized. Its spatial organization consists of multiple, localized coherent patterns, or patchy clusters. These patterns propagate across the circuits over time. This type of collective behavior has ubiquitously been observed, both in spontaneous activity and evoked responses, its function, however, has remained unclear. We construct a spatially extended, spiking neural circuit that generates emergent spatiotemporal activity patterns, thereby capturing some of the complexities of the patterns observed empirically. We elucidate what kind of fundamental function these patterns can serve by showing how they process information. As self-sustained objects, localized coherent patterns can signal information by propagating across the neural circuit. Computational operations occur when these emergent patterns interact, or collide with each other. The ongoing behaviors of these patterns naturally embody both distributed, parallel computation and cascaded logical operations. Such distributed computations enable the system to work in an inherently flexible and efficient way. Our work leads us to propose that propagating coherent activity patterns are the underlying primitives with which neural circuits carry out distributed dynamical computation.'),
(84454, 2009, 'plos', 'Adaptive gain modulation in V1 explains contextual modifications during bisection learning', 'Schäfer, Roland|Vasilaki, Eleni|Senn, Walter', 'Department of Physiology, University of Bern, Bern, Switzerland.|Department of Physiology, University of Bern, Bern, Switzerland.|Department of Physiology, University of Bern, Bern, Switzerland.', 'Switzerland|Switzerland|Switzerland', 0, 'Algorithms|Computational Biology|Learning|Models, Neurological|Normal Distribution|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1000617', '20019808', 'The neuronal processing of visual stimuli in primary visual cortex (V1) can be modified by perceptual training. Training in bisection discrimination, for instance, changes the contextual interactions in V1 elicited by parallel lines. Before training, two parallel lines inhibit their individual V1-responses. After bisection training, inhibition turns into non-symmetric excitation while performing the bisection task. Yet, the receptive field of the V1 neurons evaluated by a single line does not change during task performance. We present a model of recurrent processing in V1 where the neuronal gain can be modulated by a global attentional signal. Perceptual learning mainly consists in strengthening this attentional signal, leading to a more effective gain modulation. The model reproduces both the psychophysical results on bisection learning and the modified contextual interactions observed in V1 during task performance. It makes several predictions, for instance that imagery training should improve the performance, or that a slight stimulus wiggling can strongly affect the representation in V1 while performing the task. We conclude that strengthening a top-down induced gain increase can explain perceptual learning, and that this top-down signal can modify lateral interactions within V1, without significantly changing the classical receptive field of V1 neurons.'),
(84455, 2009, 'plos', 'Order and stochastic dynamics in Drosophila planar cell polarity', 'Burak, Yoram|Shraiman, Boris I', 'Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA.|Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA.', 'United States|United States', 43, 'Animals|Body Patterning|Cell Communication|Cell Polarity|Computer Simulation|Drosophila Proteins|Drosophila melanogaster|Models, Biological|Models, Statistical|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1000628', '20041171', 'Cells in the wing blade of Drosophila melanogaster exhibit an in-plane polarization causing distal orientation of hairs. Establishment of the Planar Cell Polarity (PCP) involves intercellular interactions as well as a global orienting signal. Many of the genetic and molecular components underlying this process have been experimentally identified and a recently advanced system-level model has suggested that the observed mutant phenotypes can be understood in terms of intercellular interactions involving asymmetric localization of membrane bound proteins. Among key open questions in understanding the emergence of ordered polarization is the effect of stochasticity and the role of the global orienting signal. These issues relate closely to our understanding of ferromagnetism in physical systems. Here we pursue this analogy to understand the emergence of PCP order. To this end we develop a semi-phenomenological representation of the underlying molecular processes and define a phase diagram of the model which provides a global view of the dependence of the phenotype on parameters. We show that the dynamics of PCP has two regimes: rapid growth in the amplitude of local polarization followed by a slower process of alignment which progresses from small to large scales. We discuss the response of the tissue to various types of orienting signals and show that global PCP order can be achieved with a weak orienting signal provided that it acts during the early phase of the process. Finally we define and discuss some of the experimental predictions of the model.'),
(84456, 2009, 'plos', 'Introduction to the quantitative analysis of two-dimensional fluorescence microscopy images for cell-based screening', 'Ljosa, Vebjorn|Carpenter, Anne E', 'Imaging Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Imaging Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.', 'United States|United States', 0, 'Algorithms|Artificial Intelligence|Biological Assay|Image Enhancement|Image Interpretation, Computer-Assisted|Microscopy, Fluorescence, Multiphoton|Pattern Recognition, Automated|Reproducibility of Results|Sensitivity and Specificity|Software', 'Journal Article', '10.1371/journal.pcbi.1000603', '20041172', '-'),
(84457, 2009, 'plos', 'Emergent patterns of social affiliation in primates, a model', 'Puga-Gonzalez, Ivan|Hildenbrandt, Hanno|Hemelrijk, Charlotte K', 'Theoretical Biology, Centre for Ecological and Evolutionary Studies, University of Groningen, Groningen, The Netherlands.|Theoretical Biology, Centre for Ecological and Evolutionary Studies, University of Groningen, Groningen, The Netherlands.|Theoretical Biology, Centre for Ecological and Evolutionary Studies, University of Groningen, Groningen, The Netherlands.', 'Netherlands|Netherlands|Netherlands', 43, 'Animals|Computer Simulation|Grooming|Macaca|Models, Biological|Pattern Recognition, Automated|Population Dynamics|Social Behavior|Social Dominance', 'Journal Article', '10.1371/journal.pcbi.1000630', '20041175', 'Many patterns of affiliative behaviour have been described for primates, for instance: reciprocation and exchange of grooming, grooming others of similar rank, reconciliation of fights, and preferential reconciliation with more valuable partners. For these patterns several functions and underlying cognitive processes have been suggested. It is, however, difficult to imagine how animals may combine these diverse considerations in their mind. Although the co-variation hypothesis, by limiting the social possibilities an individual has, constrains the number of cognitive considerations an individual has to take, it does not present an integrated theory of affiliative patterns either. In the present paper, after surveying patterns of affiliation in egalitarian and despotic macaques, we use an individual-based model with a high potential for self-organisation as a starting point for such an integrative approach. In our model, called GrooFiWorld, individuals group and, upon meeting each other, may perform a dominance interaction of which the outcomes of winning and losing are self-reinforcing. Besides, if individuals think they will be defeated, they consider grooming others. Here, the greater their anxiety is, the greater their motivation to groom others. Our model generates patterns similar to many affiliative patterns of empirical data. By merely increasing the intensity of aggression, affiliative patterns in the model change from those resembling egalitarian macaques to those resembling despotic ones. Our model produces such patterns without assuming in the mind of the individual the specific cognitive processes that are usually thought to underlie these patterns (such as recordkeeping of the acts given and received, a tendency to exchange, memory of the former fight, selective attraction to the former opponent, and estimation of the value of a relationship). Our model can be used as a null model to increase our understanding of affiliative behaviour among primates, in particular macaques.'),
(84458, 2009, 'plos', 'Bistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia', 'Selivanov, Vitaly A|Votyakova, Tatyana V|Zeak, Jennifer A|Trucco, Massimo|Roca, Josep|Cascante, Marta', 'Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Institut de Biomedicina at Universitat de Barcelona IBUB and IDIBAPS Hospital Clinic, Barcelona, Catalunya, Spain.|Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Institut de Biomedicina at Universitat de Barcelona IBUB and IDIBAPS Hospital Clinic, Barcelona, Catalunya, Spain.|Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Institut de Biomedicina at Universitat de Barcelona IBUB and IDIBAPS Hospital Clinic, Barcelona, Catalunya, Spain.|Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Institut de Biomedicina at Universitat de Barcelona IBUB and IDIBAPS Hospital Clinic, Barcelona, Catalunya, Spain.|Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Institut de Biomedicina at Universitat de Barcelona IBUB and IDIBAPS Hospital Clinic, Barcelona, Catalunya, Spain.|Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Institut de Biomedicina at Universitat de Barcelona IBUB and IDIBAPS Hospital Clinic, Barcelona, Catalunya, Spain.', 'Spain|Spain|Spain|Spain|Spain|Spain', 43, 'Animals|Cell Hypoxia|Computer Simulation|Electron Transport Complex III|Humans|Mitochondria|Models, Biological|Oxygen|Oxygen Consumption|Reactive Oxygen Species', 'Journal Article', '10.1371/journal.pcbi.1000619', '20041200', 'Increased production of reactive oxygen species (ROS) in mitochondria underlies major systemic diseases, and this clinical problem stimulates a great scientific interest in the mechanism of ROS generation. However, the mechanism of hypoxia-induced change in ROS production is not fully understood. To mathematically analyze this mechanism in details, taking into consideration all the possible redox states formed in the process of electron transport, even for respiratory complex III, a system of hundreds of differential equations must be constructed. Aimed to facilitate such tasks, we developed a new methodology of modeling, which resides in the automated construction of large sets of differential equations. The detailed modeling of electron transport in mitochondria allowed for the identification of two steady state modes of operation (bistability) of respiratory complex III at the same microenvironmental conditions. Various perturbations could induce the transition of respiratory chain from one steady state to another. While normally complex III is in a low ROS producing mode, temporal anoxia could switch it to a high ROS producing state, which persists after the return to normal oxygen supply. This prediction, which we qualitatively validated experimentally, explains the mechanism of anoxia-induced cell damage. Recognition of bistability of complex III operation may enable novel therapeutic strategies for oxidative stress and our method of modeling could be widely used in systems biology studies.'),
(84459, 2009, 'plos', 'Rational mutational analysis of a multidrug MFS transporter CaMdr1p of Candida albicans by employing a membrane environment based computational approach', 'Kapoor, Khyati|Rehan, Mohd|Kaushiki, Ajeeta|Pasrija, Ritu|Lynn, Andrew M|Prasad, Rajendra', 'School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.|School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.|School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.|School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.|School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.|School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.', 'India|India|India|India|India|India', 18, 'ATP Binding Cassette Transporter, Subfamily B|Amino Acid Sequence|Binding Sites|Candida albicans|Cell Membrane|Computer Simulation|DNA Mutational Analysis|Models, Biological|Molecular Sequence Data|Protein Binding|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1000624', '20041202', 'CaMdr1p is a multidrug MFS transporter of pathogenic Candida albicans. An over-expression of the gene encoding this protein is linked to clinically encountered azole resistance. In-depth knowledge of the structure and function of CaMdr1p is necessary for an effective design of modulators or inhibitors of this efflux transporter. Towards this goal, in this study, we have employed a membrane environment based computational approach to predict the functionally critical residues of CaMdr1p. For this, information theoretic scores which are variants of Relative Entropy (Modified Relative Entropy RE(M)) were calculated from Multiple Sequence Alignment (MSA) by separately considering distinct physico-chemical properties of transmembrane (TM) and inter-TM regions. The residues of CaMdr1p with high RE(M) which were predicted to be significantly important were subjected to site-directed mutational analysis. Interestingly, heterologous host Saccharomyces cerevisiae, over-expressing these mutant variants of CaMdr1p wherein these high RE(M) residues were replaced by either alanine or leucine, demonstrated increased susceptibility to tested drugs. The hypersensitivity to drugs was supported by abrogated substrate efflux mediated by mutant variant proteins and was not attributed to their poor expression or surface localization. Additionally, by employing a distance plot from a 3D deduced model of CaMdr1p, we could also predict the role of these functionally critical residues in maintaining apparent inter-helical interactions to provide the desired fold for the proper functioning of CaMdr1p. Residues predicted to be critical for function across the family were also found to be vital from other previously published studies, implying its wider application to other membrane protein families.'),
(84460, 2009, 'plos', 'A stochastic model for microtubule motors describes the in vivo cytoplasmic transport of human adenovirus', 'Gazzola, Mattia|Burckhardt, Christoph J|Bayati, Basil|Engelke, Martin|Greber, Urs F|Koumoutsakos, Petros', 'Chair of Computational Science, ETH Zurich, Zurich, Switzerland.|Chair of Computational Science, ETH Zurich, Zurich, Switzerland.|Chair of Computational Science, ETH Zurich, Zurich, Switzerland.|Chair of Computational Science, ETH Zurich, Zurich, Switzerland.|Chair of Computational Science, ETH Zurich, Zurich, Switzerland.|Chair of Computational Science, ETH Zurich, Zurich, Switzerland.', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 45, 'Adenoviruses, Human|Biological Transport, Active|Computer Simulation|Cytoplasm|HeLa Cells|Humans|Microtubules|Models, Biological|Models, Statistical|Molecular Motor Proteins|Stochastic Processes|Virus Internalization', 'Journal Article', '10.1371/journal.pcbi.1000623', '20041204', 'Cytoplasmic transport of organelles, nucleic acids and proteins on microtubules is usually bidirectional with dynein and kinesin motors mediating the delivery of cargoes in the cytoplasm. Here we combine live cell microscopy, single virus tracking and trajectory segmentation to systematically identify the parameters of a stochastic computational model of cargo transport by molecular motors on microtubules. The model parameters are identified using an evolutionary optimization algorithm to minimize the Kullback-Leibler divergence between the in silico and the in vivo run length and velocity distributions of the viruses on microtubules. The present stochastic model suggests that bidirectional transport of human adenoviruses can be explained without explicit motor coordination. The model enables the prediction of the number of motors active on the viral cargo during microtubule-dependent motions as well as the number of motor binding sites, with the protein hexon as the binding site for the motors.'),
(84461, 2009, 'plos', 'Bayesian integration and non-linear feedback control in a full-body motor task', 'Stevenson, Ian H|Fernandes, Hugo L|Vilares, Iris|Wei, Kunlin|Körding, Konrad P', 'Department of Physical Medicine and Rehabilitation, Northwestern University and Rehabilitation Institute of Chicago, Chicago, Illinois, USA. i-stevenson@northwestern.edu|Department of Physical Medicine and Rehabilitation, Northwestern University and Rehabilitation Institute of Chicago, Chicago, Illinois, USA. i-stevenson@northwestern.edu|Department of Physical Medicine and Rehabilitation, Northwestern University and Rehabilitation Institute of Chicago, Chicago, Illinois, USA. i-stevenson@northwestern.edu|Department of Physical Medicine and Rehabilitation, Northwestern University and Rehabilitation Institute of Chicago, Chicago, Illinois, USA. i-stevenson@northwestern.edu|Department of Physical Medicine and Rehabilitation, Northwestern University and Rehabilitation Institute of Chicago, Chicago, Illinois, USA. i-stevenson@northwestern.edu', 'United States|United States|United States|United States|United States', 33, 'Adult|Bayes Theorem|Computer Simulation|Feedback, Physiological|Female|Humans|Male|Models, Biological|Movement|Nonlinear Dynamics|Postural Balance|Posture|Task Performance and Analysis', 'Journal Article', '10.1371/journal.pcbi.1000629', '20041205', 'A large number of experiments have asked to what degree human reaching movements can be understood as being close to optimal in a statistical sense. However, little is known about whether these principles are relevant for other classes of movements. Here we analyzed movement in a task that is similar to surfing or snowboarding. Human subjects stand on a force plate that measures their center of pressure. This center of pressure affects the acceleration of a cursor that is displayed in a noisy fashion (as a cloud of dots) on a projection screen while the subject is incentivized to keep the cursor close to a fixed position. We find that salient aspects of observed behavior are well-described by optimal control models where a Bayesian estimation model (Kalman filter) is combined with an optimal controller (either a Linear-Quadratic-Regulator or Bang-bang controller). We find evidence that subjects integrate information over time taking into account uncertainty. However, behavior in this continuous steering task appears to be a highly non-linear function of the visual feedback. While the nervous system appears to implement Bayes-like mechanisms for a full-body, dynamic task, it may additionally take into account the specific costs and constraints of the task.'),
(84462, 2009, 'plos', 'Design principles for ligand-sensing, conformation-switching ribozymes', 'Chen, Xi|Ellington, Andrew D', 'Department of Chemistry and Biochemistry, Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, Texas, USA.|Department of Chemistry and Biochemistry, Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, Texas, USA.', 'United States|United States', 35, 'Algorithms|Aptamers, Nucleotide|Base Sequence|Binding Sites|Computer Simulation|Models, Chemical|Models, Molecular|Molecular Sequence Data|Protein Binding|RNA, Catalytic', 'Journal Article', '10.1371/journal.pcbi.1000620', '20041206', 'Nucleic acid sensor elements are proving increasingly useful in biotechnology and biomedical applications. A number of ligand-sensing, conformational-switching ribozymes (also known as allosteric ribozymes or aptazymes) have been generated by some combination of directed evolution or rational design. Such sensor elements typically fuse a molecular recognition domain (aptamer) with a catalytic signal generator (ribozyme). Although the rational design of aptazymes has begun to be explored, the relationships between the thermodynamics of aptazyme conformational changes and aptazyme performance in vitro and in vivo have not been examined in a quantitative framework. We have therefore developed a quantitative and predictive model for aptazymes as biosensors in vitro and as riboswitches in vivo. In the process, we have identified key relationships (or dimensionless parameters) that dictate aptazyme performance, and in consequence, established equations for precisely engineering aptazyme function. In particular, our analysis quantifies the intrinsic trade-off between ligand sensitivity and the dynamic range of activity. We were also able to determine how in vivo parameters, such as mRNA degradation rates, impact the design and function of aptazymes when used as riboswitches. Using this theoretical framework we were able to achieve quantitative agreement between our models and published data. In consequence, we are able to suggest experimental guidelines for quantitatively predicting the performance of aptazyme-based riboswitches. By identifying factors that limit the performance of previously published systems we were able to generate immediately testable hypotheses for their improvement. The robust theoretical framework and identified optimization parameters should now enable the precision design of aptazymes for biotechnological and clinical applications.'),
(84463, 2009, 'plos', 'Burst-time-dependent plasticity robustly guides ON/OFF segregation in the lateral geniculate nucleus', 'Gjorgjieva, Julijana|Toyoizumi, Taro|Eglen, Stephen J', 'Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, United Kingdom. jg447@cam.ac.uk|Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, United Kingdom. jg447@cam.ac.uk|Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, United Kingdom. jg447@cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 23, 'Action Potentials|Animals|Computer Simulation|Geniculate Bodies|Mice|Models, Neurological|Nerve Net|Neural Inhibition|Neuronal Plasticity|Retinal Ganglion Cells|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1000618', '20041207', 'Spontaneous retinal activity (known as waves) remodels synaptic connectivity to the lateral geniculate nucleus (LGN) during development. Analysis of retinal waves recorded with multielectrode arrays in mouse suggested that a cue for the segregation of functionally distinct (ON and OFF) retinal ganglion cells (RGCs) in the LGN may be a desynchronization in their firing, where ON cells precede OFF cells by one second. Using the recorded retinal waves as input, with two different modeling approaches we explore timing-based plasticity rules for the evolution of synaptic weights to identify key features underlying ON/OFF segregation. First, we analytically derive a linear model for the evolution of ON and OFF weights, to understand how synaptic plasticity rules extract input firing properties to guide segregation. Second, we simulate postsynaptic activity with a nonlinear integrate-and-fire model to compare findings with the linear model. We find that spike-time-dependent plasticity, which modifies synaptic weights based on millisecond-long timing and order of pre- and postsynaptic spikes, fails to segregate ON and OFF retinal inputs in the absence of normalization. Implementing homeostatic mechanisms results in segregation, but only with carefully-tuned parameters. Furthermore, extending spike integration timescales to match the second-long input correlation timescales always leads to ON segregation because ON cells fire before OFF cells. We show that burst-time-dependent plasticity can robustly guide ON/OFF segregation in the LGN without normalization, by integrating pre- and postsynaptic bursts irrespective of their firing order and over second-long timescales. We predict that an LGN neuron will become ON- or OFF-responsive based on a local competition of the firing patterns of neighboring RGCs connecting to it. Finally, we demonstrate consistency with ON/OFF segregation in ferret, despite differences in the firing properties of retinal waves. Our model suggests that diverse input statistics of retinal waves can be robustly interpreted by a burst-based rule, which underlies retinogeniculate plasticity across different species.'),
(84464, 2009, 'plos', 'Tradeoff between stability and multispecificity in the design of promiscuous proteins', 'Fromer, Menachem|Shifman, Julia M', 'School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.|School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.', 'Israel|Israel', 38, 'Amino Acid Sequence|Binding Sites|Calmodulin|Computer Simulation|Drug Design|Models, Chemical|Molecular Sequence Data|Protein Binding|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1000627', '20041208', 'Natural proteins often partake in several highly specific protein-protein interactions. They are thus subject to multiple opposing forces during evolutionary selection. To be functional, such multispecific proteins need to be stable in complex with each interaction partner, and, at the same time, to maintain affinity toward all partners. How is this multispecificity acquired through natural evolution? To answer this compelling question, we study a prototypical multispecific protein, calmodulin (CaM), which has evolved to interact with hundreds of target proteins. Starting from high-resolution structures of sixteen CaM-target complexes, we employ state-of-the-art computational methods to predict a hundred CaM sequences best suited for interaction with each individual CaM target. Then, we design CaM sequences most compatible with each possible combination of two, three, and all sixteen targets simultaneously, producing almost 70,000 low energy CaM sequences. By comparing these sequences and their energies, we gain insight into how nature has managed to find the compromise between the need for favorable interaction energies and the need for multispecificity. We observe that designing for more partners simultaneously yields CaM sequences that better match natural sequence profiles, thus emphasizing the importance of such strategies in nature. Furthermore, we show that the CaM binding interface can be nicely partitioned into positions that are critical for the affinity of all CaM-target complexes and those that are molded to provide interaction specificity. We reveal several basic categories of sequence-level tradeoffs that enable the compromise necessary for the promiscuity of this protein. We also thoroughly quantify the tradeoff between interaction energetics and multispecificity and find that facilitating seemingly competing interactions requires only a small deviation from optimal energies. We conclude that multispecific proteins have been subjected to a rigorous optimization process that has fine-tuned their sequences for interactions with a precise set of targets, thus conferring their multiple cellular functions.'),
(84465, 2009, 'plos', 'The presence of VEGF receptors on the luminal surface of endothelial cells affects VEGF distribution and VEGF signaling', 'Stefanini, Marianne O|Wu, Florence T H|Mac Gabhann, Feilim|Popel, Aleksander S', 'Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. stefanini@jhmi.edu|Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. stefanini@jhmi.edu|Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. stefanini@jhmi.edu|Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. stefanini@jhmi.edu', 'United States|United States|United States|United States', 39, 'Animals|Cell Membrane|Computer Simulation|Endothelial Cells|Humans|Models, Biological|Receptors, Vascular Endothelial Growth Factor|Signal Transduction|Tissue Distribution|Vascular Endothelial Growth Factor A', 'Journal Article', '10.1371/journal.pcbi.1000622', '20041209', 'Vascular endothelial growth factor (VEGF) is a potent cytokine that binds to specific receptors on the endothelial cells lining blood vessels. The signaling cascade triggered eventually leads to the formation of new capillaries, a process called angiogenesis. Distributions of VEGF receptors and VEGF ligands are therefore crucial determinants of angiogenic events and, to our knowledge, no quantification of abluminal vs. luminal receptors has been performed. We formulate a molecular-based compartment model to investigate the VEGF distribution in blood and tissue in humans and show that such quantification would lead to new insights on angiogenesis and VEGF-dependent diseases. Our multiscale model includes two major isoforms of VEGF (VEGF(121) and VEGF(165)), as well as their receptors (VEGFR1 and VEGFR2) and the non-signaling co-receptor neuropilin-1 (NRP1). VEGF can be transported between tissue and blood via transendothelial permeability and the lymphatics. VEGF receptors are located on both the luminal and abluminal sides of the endothelial cells. In this study, we analyze the effects of the VEGF receptor localization on the endothelial cells as well as of the lymphatic transport. We show that the VEGF distribution is affected by the luminal receptor density. We predict that the receptor signaling occurs mostly on the abluminal endothelial surface, assuming that VEGF is secreted by parenchymal cells. However, for a low abluminal but high luminal receptor density, VEGF binds predominantly to VEGFR1 on the abluminal surface and VEGFR2 on the luminal surface. Such findings would be pertinent to pathological conditions and therapies related to VEGF receptor imbalance and overexpression on the endothelial cells and will hopefully encourage experimental receptor quantification for both luminal and abluminal surfaces on endothelial cells.'),
(84466, 2009, 'plos', 'Decomposition of gene expression state space trajectories', 'Mar, Jessica C|Quackenbush, John', 'Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.|Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.', 'United States|United States', 31, 'Animals|Cell Differentiation|Cells, Cultured|Computer Simulation|Gene Expression Regulation|Granulocyte Precursor Cells|Models, Biological|Neutrophils|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000626', '20041215', 'Representing and analyzing complex networks remains a roadblock to creating dynamic network models of biological processes and pathways. The study of cell fate transitions can reveal much about the transcriptional regulatory programs that underlie these phenotypic changes and give rise to the coordinated patterns in expression changes that we observe. The application of gene expression state space trajectories to capture cell fate transitions at the genome-wide level is one approach currently used in the literature. In this paper, we analyze the gene expression dataset of Huang et al. (2005) which follows the differentiation of promyelocytes into neutrophil-like cells in the presence of inducers dimethyl sulfoxide and all-trans retinoic acid. Huang et al. (2005) build on the work of Kauffman (2004) who raised the attractor hypothesis, stating that cells exist in an expression landscape and their expression trajectories converge towards attractive sites in this landscape. We propose an alternative interpretation that explains this convergent behavior by recognizing that there are two types of processes participating in these cell fate transitions-core processes that include the specific differentiation pathways of promyelocytes to neutrophils, and transient processes that capture those pathways and responses specific to the inducer. Using functional enrichment analyses, specific biological examples and an analysis of the trajectories and their core and transient components we provide a validation of our hypothesis using the Huang et al. (2005) dataset.'),
(84467, 2009, 'plos', 'Biomedical text mining and its applications', 'Rodriguez-Esteban, Raul', 'Pfizer Research Technology Center, Cambridge, Massachusetts, USA. raul.rodriguez-esteban@pfizer.com', 'United States', 63, 'Biomedical Research|Data Mining|Internet|Natural Language Processing|Search Engine|Software', 'Journal Article', '10.1371/journal.pcbi.1000597', '20041219', '-'),
(84468, 2009, 'plos', 'A quick guide for developing effective bioinformatics programming skills', 'Dudley, Joel T|Butte, Atul J', 'Program in Biomedical Informatics, Stanford University School of Medicine, Stanford, California, USA. jdudley@stanford.edu|Program in Biomedical Informatics, Stanford University School of Medicine, Stanford, California, USA. jdudley@stanford.edu', 'United States|United States', 37, 'Computational Biology|Professional Competence|Programming Languages|Software|Software Design|United States', 'Journal Article', '10.1371/journal.pcbi.1000589', '20041221', '-'),
(84469, 2009, 'plos', 'Hyperbolic planforms in relation to visual edges and textures perception', 'Chossat, Pascal|Faugeras, Olivier', 'Department of Mathematics, University of Nice Sophia-Antipolis, JAD Laboratory and CNRS, Nice, France.|Department of Mathematics, University of Nice Sophia-Antipolis, JAD Laboratory and CNRS, Nice, France.', 'France|France', 29, 'Animals|Computer Simulation|Humans|Models, Neurological|Nerve Net|Pattern Recognition, Visual|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1000625', '20046839', 'We propose to use bifurcation theory and pattern formation as theoretical probes for various hypotheses about the neural organization of the brain. This allows us to make predictions about the kinds of patterns that should be observed in the activity of real brains through, e.g., optical imaging, and opens the door to the design of experiments to test these hypotheses. We study the specific problem of visual edges and textures perception and suggest that these features may be represented at the population level in the visual cortex as a specific second-order tensor, the structure tensor, perhaps within a hypercolumn. We then extend the classical ring model to this case and show that its natural framework is the non-Euclidean hyperbolic geometry. This brings in the beautiful structure of its group of isometries and certain of its subgroups which have a direct interpretation in terms of the organization of the neural populations that are assumed to encode the structure tensor. By studying the bifurcations of the solutions of the structure tensor equations, the analog of the classical Wilson and Cowan equations, under the assumption of invariance with respect to the action of these subgroups, we predict the appearance of characteristic patterns. These patterns can be described by what we call hyperbolic or H-planforms that are reminiscent of Euclidean planar waves and of the planforms that were used in previous work to account for some visual hallucinations. If these patterns could be observed through brain imaging techniques they would reveal the built-in or acquired invariance of the neural organization to the action of the corresponding subgroups.');
