INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85660, 2012, 'plos', 'Determinants of brain cell metabolic phenotypes and energy substrate utilization unraveled with a modeling approach', 'Neves, Aitana|Costalat, Robert|Pellerin, Luc', 'Département de Physiologie, Université de Lausanne, Lausanne, Switzerland.|Département de Physiologie, Université de Lausanne, Lausanne, Switzerland.|Département de Physiologie, Université de Lausanne, Lausanne, Switzerland.', 'Switzerland|Switzerland|Switzerland', 13, 'Animals|Brain|Computer Simulation|Energy Metabolism|Humans|Lactic Acid|Models, Neurological|NAD|Neurons|Pyruvate Dehydrogenase Complex', 'Journal Article', '10.1371/journal.pcbi.1002686', '23028284', 'Although all brain cells bear in principle a comparable potential in terms of energetics, in reality they exhibit different metabolic profiles. The specific biochemical characteristics explaining such disparities and their relative importance are largely unknown. Using a modeling approach, we show that modifying the kinetic parameters of pyruvate dehydrogenase and mitochondrial NADH shuttling within a realistic interval can yield a striking switch in lactate flux direction. In this context, cells having essentially an oxidative profile exhibit pronounced extracellular lactate uptake and consumption. However, they can be turned into cells with prominent aerobic glycolysis by selectively reducing the aforementioned parameters. In the case of primarily oxidative cells, we also examined the role of glycolysis and lactate transport in providing pyruvate to mitochondria in order to sustain oxidative phosphorylation. The results show that changes in lactate transport capacity and extracellular lactate concentration within the range described experimentally can sustain enhanced oxidative metabolism upon activation. Such a demonstration provides key elements to understand why certain brain cell types constitutively adopt a particular metabolic profile and how specific features can be altered under different physiological and pathological conditions in order to face evolving energy demands.'),
(85661, 2012, 'plos', 'Inferring correlation networks from genomic survey data', 'Friedman, Jonathan|Alm, Eric J', 'Computational & Systems Biology Initiative, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Computational & Systems Biology Initiative, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.', 'United States|United States', 0, 'Chromosome Mapping|Computer Simulation|Genetics, Population|Genome, Bacterial|Humans|Microbial Consortia|Models, Genetic|Recombination, Genetic|Statistics as Topic', 'Journal Article', '10.1371/journal.pcbi.1002687', '23028285', 'High-throughput sequencing based techniques, such as 16S rRNA gene profiling, have the potential to elucidate the complex inner workings of natural microbial communities - be they from the worlds oceans or the human gut. A key step in exploring such data is the identification of dependencies between members of these communities, which is commonly achieved by correlation analysis. However, it has been known since the days of Karl Pearson that the analysis of the type of data generated by such techniques (referred to as compositional data) can produce unreliable results since the observed data take the form of relative fractions of genes or species, rather than their absolute abundances. Using simulated and real data from the Human Microbiome Project, we show that such compositional effects can be widespread and severe: in some real data sets many of the correlations among taxa can be artifactual, and true correlations may even appear with opposite sign. Additionally, we show that community diversity is the key factor that modulates the acuteness of such compositional effects, and develop a new approach, called SparCC (available at https://bitbucket.org/yonatanf/sparcc), which is capable of estimating correlation values from compositional data. To illustrate a potential application of SparCC, we infer a rich ecological network connecting hundreds of interacting species across 18 sites on the human body. Using the SparCC network as a reference, we estimated that the standard approach yields 3 spurious species-species interactions for each true interaction and misses 60% of the true interactions in the human microbiome data, and, as predicted, most of the erroneous links are found in the samples with the lowest diversity.'),
(85662, 2012, 'plos', 'Modeling phenotypic metabolic adaptations of Mycobacterium tuberculosis H37Rv under hypoxia', 'Fang, Xin|Wallqvist, Anders|Reifman, Jaques', 'DoD Biotechnology High-Performance-Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland, USA.|DoD Biotechnology High-Performance-Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland, USA.|DoD Biotechnology High-Performance-Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland, USA.', 'United States|United States|United States', 42, 'Adaptation, Physiological|Bacterial Proteins|Computer Simulation|Models, Biological|Mycobacterium tuberculosis|Oxygen|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002688', '23028286', 'The ability to adapt to different conditions is key for Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), to successfully infect human hosts. Adaptations allow the organism to evade the host immune responses during acute infections and persist for an extended period of time during the latent infectious stage. In latently infected individuals, estimated to include one-third of the human population, the organism exists in a variety of metabolic states, which impedes the development of a simple strategy for controlling or eradicating this disease. Direct knowledge of the metabolic states of M. tuberculosis in patients would aid in the management of the disease as well as in forming the basis for developing new drugs and designing more efficacious drug cocktails. Here, we propose an in silico approach to create state-specific models based on readily available gene expression data. The coupling of differential gene expression data with a metabolic network model allowed us to characterize the metabolic adaptations of M. tuberculosis H37Rv to hypoxia. Given the microarray data for the alterations in gene expression, our model predicted reduced oxygen uptake, ATP production changes, and a global change from an oxidative to a reductive tricarboxylic acid (TCA) program. Alterations in the biomass composition indicated an increase in the cell wall metabolites required for cell-wall growth, as well as heightened accumulation of triacylglycerol in preparation for a low-nutrient, low metabolic activity life style. In contrast, the gene expression program in the deletion mutant of dosR, which encodes the immediate hypoxic response regulator, failed to adapt to low-oxygen stress. Our predictions were compatible with recent experimental observations of M. tuberculosis activity under hypoxic and anaerobic conditions. Importantly, alterations in the flow and accumulation of a particular metabolite were not necessarily directly linked to differential gene expression of the enzymes catalyzing the related metabolic reactions.'),
(85663, 2012, 'plos', 'Spike-timing dependence of structural plasticity explains cooperative synapse formation in the neocortex', 'Deger, Moritz|Helias, Moritz|Rotter, Stefan|Diesmann, Markus', 'Bernstein Center Freiburg, Albert-Ludwig University, Freiburg, Germany. deger@bcf.uni-freiburg.de|Bernstein Center Freiburg, Albert-Ludwig University, Freiburg, Germany. deger@bcf.uni-freiburg.de|Bernstein Center Freiburg, Albert-Ludwig University, Freiburg, Germany. deger@bcf.uni-freiburg.de|Bernstein Center Freiburg, Albert-Ludwig University, Freiburg, Germany. deger@bcf.uni-freiburg.de', 'Germany|Germany|Germany|Germany', 25, 'Action Potentials|Animals|Computer Simulation|Connectome|Humans|Models, Neurological|Neocortex|Nerve Net|Neuronal Plasticity|Synapses', 'Journal Article', '10.1371/journal.pcbi.1002689', '23028287', 'Structural plasticity governs the long-term development of synaptic connections in the neocortex. While the underlying processes at the synapses are not fully understood, there is strong evidence that a process of random, independent formation and pruning of excitatory synapses can be ruled out. Instead, there must be some cooperation between the synaptic contacts connecting a single pre- and postsynaptic neuron pair. So far, the mechanism of cooperation is not known. Here we demonstrate that local correlation detection at the postsynaptic dendritic spine suffices to explain the synaptic cooperation effect, without assuming any hypothetical direct interaction pathway between the synaptic contacts. Candidate biomolecular mechanisms for dendritic correlation detection have been identified previously, as well as for structural plasticity based thereon. By analyzing and fitting of a simple model, we show that spike-timing correlation dependent structural plasticity, without additional mechanisms of cross-synapse interaction, can reproduce the experimentally observed distributions of numbers of synaptic contacts between pairs of neurons in the neocortex. Furthermore, the model yields a first explanation for the existence of both transient and persistent dendritic spines and allows to make predictions for future experiments.'),
(85664, 2012, 'plos', 'Enhancing the prioritization of disease-causing genes through tissue specific protein interaction networks', 'Magger, Oded|Waldman, Yedael Y|Ruppin, Eytan|Sharan, Roded', 'Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel. OdedMagger@gmail.com|Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel. OdedMagger@gmail.com|Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel. OdedMagger@gmail.com|Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel. OdedMagger@gmail.com', 'Israel|Israel|Israel|Israel', 95, 'Computer Simulation|Genetic Predisposition to Disease|Humans|Models, Biological|Protein Interaction Mapping|Proteome|Signal Transduction|Tissue Distribution', 'Journal Article', '10.1371/journal.pcbi.1002690', '23028288', 'The prioritization of candidate disease-causing genes is a fundamental challenge in the post-genomic era. Current state of the art methods exploit a protein-protein interaction (PPI) network for this task. They are based on the observation that genes causing phenotypically-similar diseases tend to lie close to one another in a PPI network. However, to date, these methods have used a static picture of human PPIs, while diseases impact specific tissues in which the PPI networks may be dramatically different. Here, for the first time, we perform a large-scale assessment of the contribution of tissue-specific information to gene prioritization. By integrating tissue-specific gene expression data with PPI information, we construct tissue-specific PPI networks for 60 tissues and investigate their prioritization power. We find that tissue-specific PPI networks considerably improve the prioritization results compared to those obtained using a generic PPI network. Furthermore, they allow predicting novel disease-tissue associations, pointing to sub-clinical tissue effects that may escape early detection.'),
(85665, 2012, 'plos', 'Spike-based decision learning of Nash equilibria in two-player games', 'Friedrich, Johannes|Senn, Walter', 'Department of Physiology and Center for Cognition, Learning and Memory, University of Bern, Switzerland.|Department of Physiology and Center for Cognition, Learning and Memory, University of Bern, Switzerland.', 'Switzerland|Switzerland', 5, 'Action Potentials|Brain|Competitive Behavior|Computer Simulation|Decision Making|Game Theory|Humans|Models, Neurological|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.1002691', '23028289', 'Humans and animals face decision tasks in an uncertain multi-agent environment where an agents strategy may change in time due to the co-adaptation of others strategies. The neuronal substrate and the computational algorithms underlying such adaptive decision making, however, is largely unknown. We propose a population coding model of spiking neurons with a policy gradient procedure that successfully acquires optimal strategies for classical game-theoretical tasks. The suggested population reinforcement learning reproduces data from human behavioral experiments for the blackjack and the inspector game. It performs optimally according to a pure (deterministic) and mixed (stochastic) Nash equilibrium, respectively. In contrast, temporal-difference(TD)-learning, covariance-learning, and basic reinforcement learning fail to perform optimally for the stochastic strategy. Spike-based population reinforcement learning, shown to follow the stochastic reward gradient, is therefore a viable candidate to explain automated decision learning of a Nash equilibrium in two-player games.'),
(85666, 2012, 'plos', 'Convergent transmission of RNAi guide-target mismatch information across Argonaute internal allosteric network', 'Joseph, Thomas T|Osman, Roman', 'Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York, USA.|Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York, USA.', 'United States|United States', 8, 'Argonaute Proteins|Binding Sites|Computer Simulation|MicroRNAs|Models, Genetic|Protein Binding|Protein Interaction Mapping|RNA Interference|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002693', '23028290', 'In RNA interference, a guide strand derived from a short dsRNA such as a microRNA (miRNA) is loaded into Argonaute, the central protein in the RNA Induced Silencing Complex (RISC) that silences messenger RNAs on a sequence-specific basis. The positions of any mismatched base pairs in an miRNA determine which Argonaute subtype is used. Subsequently, the Argonaute-guide complex binds and silences complementary target mRNAs, certain Argonautes cleave the target. Mismatches between guide strand and the target mRNA decrease cleavage efficiency. Thus, loading and silencing both require that signals about the presence of a mismatched base pair are communicated from the mismatch site to effector sites. These effector sites include the active site, to prevent target cleavage, the binding groove, to modify nucleic acid binding affinity, and surface allosteric sites, to control recruitment of additional proteins to form the RISC. To examine how such signals may be propagated, we analyzed the network of internal allosteric pathways in Argonaute exhibited through correlations of residue-residue interactions. The emerging network can be described as a set of pathways emanating from the core of the protein near the active site, distributed into the bulk of the protein, and converging upon a distributed cluster of surface residues. Nucleotides in the guide strand seed region have a stronger relationship with the protein than other nucleotides, concordant with their importance in sequence selectivity. Finally, any of several seed region guide-target mismatches cause certain Argonaute residues to have modified correlations with the rest of the protein. This arises from the aggregation of relatively small interaction correlation changes distributed across a large subset of residues. These residues are in effector sites: the active site, binding groove, and surface, implying that direct functional consequences of guide-target mismatches are mediated through the cumulative effects of a large number of internal allosteric pathways.'),
(85667, 2012, 'plos', 'Tissue-specific functional networks for prioritizing phenotype and disease genes', 'Guan, Yuanfang|Gorenshteyn, Dmitriy|Burmeister, Margit|Wong, Aaron K|Schimenti, John C|Handel, Mary Ann|Bult, Carol J|Hibbs, Matthew A|Troyanskaya, Olga G', 'Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States|United States', 67, 'Animals|Computer Simulation|Genetic Predisposition to Disease|Humans|Mice|Models, Biological|Organ Specificity|Protein Interaction Mapping|Proteome|Signal Transduction|Tissue Distribution', 'Journal Article', '10.1371/journal.pcbi.1002694', '23028291', 'Integrated analyses of functional genomics data have enormous potential for identifying phenotype-associated genes. Tissue-specificity is an important aspect of many genetic diseases, reflecting the potentially different roles of proteins and pathways in diverse cell lineages. Accounting for tissue specificity in global integration of functional genomics data is challenging, as functionality and functional relationships are often not resolved for specific tissue types. We address this challenge by generating tissue-specific functional networks, which can effectively represent the diversity of protein function for more accurate identification of phenotype-associated genes in the laboratory mouse. Specifically, we created 107 tissue-specific functional relationship networks through integration of genomic data utilizing knowledge of tissue-specific gene expression patterns. Cross-network comparison revealed significantly changed genes enriched for functions related to specific tissue development. We then utilized these tissue-specific networks to predict genes associated with different phenotypes. Our results demonstrate that prediction performance is significantly improved through using the tissue-specific networks as compared to the global functional network. We used a testis-specific functional relationship network to predict genes associated with male fertility and spermatogenesis phenotypes, and experimentally confirmed one top prediction, Mbyl1. We then focused on a less-common genetic disease, ataxia, and identified candidates uniquely predicted by the cerebellum network, which are supported by both literature and experimental evidence. Our systems-level, tissue-specific scheme advances over traditional global integration and analyses and establishes a prototype to address the tissue-specific effects of genetic perturbations, diseases and drugs.'),
(85668, 2012, 'plos', 'Substrate-specific reorganization of the conformational ensemble of CSK implicates novel modes of kinase function', 'Jamros, Michael A|Oliveira, Leandro C|Whitford, Paul C|Onuchic, José N|Adams, Joseph A|Jennings, Patricia A', 'Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.|Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.|Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.|Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.|Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.|Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.', 'United States|United States|United States|United States|United States|United States', 10, 'Adenosine Triphosphate|Computer Simulation|Enzyme Activation|Models, Chemical|Molecular Dynamics Simulation|Protein Conformation|Protein Structure, Tertiary|Structure-Activity Relationship|Substrate Specificity|src-Family Kinases', 'Journal Article', '10.1371/journal.pcbi.1002695', '23028292', 'Protein kinases use ATP as a phosphoryl donor for the posttranslational modification of signaling targets. It is generally thought that the binding of this nucleotide induces conformational changes leading to closed, more compact forms of the kinase domain that ideally orient active-site residues for efficient catalysis. The kinase domain is oftentimes flanked by additional ligand binding domains that up- or down-regulate catalytic function. C-terminal Src kinase (Csk) is a multidomain tyrosine kinase that is up-regulated by N-terminal SH2 and SH3 domains. Although the X-ray structure of Csk suggests the enzyme is compact, X-ray scattering studies indicate that the enzyme possesses both compact and open conformational forms in solution. Here, we investigated whether interactions with the ATP analog AMP-PNP and ADP can shift the conformational ensemble of Csk in solution using a combination of small angle x-ray scattering and molecular dynamics simulations. We find that binding of AMP-PNP shifts the ensemble towards more extended rather than more compact conformations. Binding of ADP further shifts the ensemble towards extended conformations, including highly extended conformations not adopted by the apo protein, nor by the AMP-PNP bound protein. These ensembles indicate that any compaction of the kinase domain induced by nucleotide binding does not extend to the overall multi-domain architecture. Instead, assembly of an ATP-bound kinase domain generates further extended forms of Csk that may have relevance for kinase scaffolding and Src regulation in the cell.'),
(85669, 2012, 'plos', 'Modeling the seasonal adaptation of circadian clocks by changes in the network structure of the suprachiasmatic nucleus', 'Bodenstein, Christian|Gosak, Marko|Schuster, Stefan|Marhl, Marko|Perc, Matjaž', 'Department of Bioinformatics, Friedrich Schiller University Jena, Jena, Germany.|Department of Bioinformatics, Friedrich Schiller University Jena, Jena, Germany.|Department of Bioinformatics, Friedrich Schiller University Jena, Jena, Germany.|Department of Bioinformatics, Friedrich Schiller University Jena, Jena, Germany.|Department of Bioinformatics, Friedrich Schiller University Jena, Jena, Germany.', 'Germany|Germany|Germany|Germany|Germany', 33, 'Adaptation, Physiological|Biological Clocks|Circadian Clocks|Computer Simulation|Humans|Models, Neurological|Nerve Net|Neuronal Plasticity|Oscillometry|Seasons|Suprachiasmatic Nucleus', 'Journal Article', '10.1371/journal.pcbi.1002697', '23028293', 'The dynamics of circadian rhythms needs to be adapted to day length changes between summer and winter. It has been observed experimentally, however, that the dynamics of individual neurons of the suprachiasmatic nucleus (SCN) does not change as the seasons change. Rather, the seasonal adaptation of the circadian clock is hypothesized to be a consequence of changes in the intercellular dynamics, which leads to a phase distribution of electrical activity of SCN neurons that is narrower in winter and broader during summer. Yet to understand this complex intercellular dynamics, a more thorough understanding of the impact of the network structure formed by the SCN neurons is needed. To that effect, we propose a mathematical model for the dynamics of the SCN neuronal architecture in which the structure of the network plays a pivotal role. Using our model we show that the fraction of long-range cell-to-cell connections and the seasonal changes in the daily rhythms may be tightly related. In particular, simulations of the proposed mathematical model indicate that the fraction of long-range connections between the cells adjusts the phase distribution and consequently the length of the behavioral activity as follows: dense long-range connections during winter lead to a narrow activity phase, while rare long-range connections during summer lead to a broad activity phase. Our model is also able to account for the experimental observations indicating a larger light-induced phase-shift of the circadian clock during winter, which we show to be a consequence of higher synchronization between neurons. Our model thus provides evidence that the variations in the seasonal dynamics of circadian clocks can in part also be understood and regulated by the plasticity of the SCN network structure.'),
(85670, 2012, 'plos', 'Risk-sensitivity in Bayesian sensorimotor integration', 'Grau-Moya, Jordi|Ortega, Pedro A|Braun, Daniel A', 'Max Planck Institute for Biological Cybernetics, Tübingen, Germany. jordi.grau@tuebingen.mpg.de|Max Planck Institute for Biological Cybernetics, Tübingen, Germany. jordi.grau@tuebingen.mpg.de|Max Planck Institute for Biological Cybernetics, Tübingen, Germany. jordi.grau@tuebingen.mpg.de', 'Germany|Germany|Germany', 10, 'Bayes Theorem|Brain|Computer Simulation|Cues|Decision Making|Feedback, Sensory|Humans|Models, Neurological|Models, Statistical|Pattern Recognition, Visual|Risk Assessment', 'Journal Article', '10.1371/journal.pcbi.1002698', '23028294', 'Information processing in the nervous system during sensorimotor tasks with inherent uncertainty has been shown to be consistent with Bayesian integration. Bayes optimal decision-makers are, however, risk-neutral in the sense that they weigh all possibilities based on prior expectation and sensory evidence when they choose the action with highest expected value. In contrast, risk-sensitive decision-makers are sensitive to model uncertainty and bias their decision-making processes when they do inference over unobserved variables. In particular, they allow deviations from their probabilistic model in cases where this model makes imprecise predictions. Here we test for risk-sensitivity in a sensorimotor integration task where subjects exhibit Bayesian information integration when they infer the position of a target from noisy sensory feedback. When introducing a cost associated with subjects response, we found that subjects exhibited a characteristic bias towards low cost responses when their uncertainty was high. This result is in accordance with risk-sensitive decision-making processes that allow for deviations from Bayes optimal decision-making in the face of uncertainty. Our results suggest that both Bayesian integration and risk-sensitivity are important factors to understand sensorimotor integration in a quantitative fashion.'),
(85671, 2012, 'plos', 'Multistationary and oscillatory modes of free radicals generation by the mitochondrial respiratory chain revealed by a bifurcation analysis', 'Selivanov, Vitaly A|Cascante, Marta|Friedman, Mark|Schumaker, Mark F|Trucco, Massimo|Votyakova, Tatyana V', 'Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain. selivanov@ub.edu|Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain. selivanov@ub.edu|Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain. selivanov@ub.edu|Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain. selivanov@ub.edu|Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain. selivanov@ub.edu|Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain. selivanov@ub.edu', 'Spain|Spain|Spain|Spain|Spain|Spain', 15, 'Binding Sites|Biological Clocks|Computer Simulation|Electron Transport|Electron Transport Chain Complex Proteins|Free Radicals|Mitochondria|Mitochondrial Proteins|Models, Chemical|Models, Molecular|Oscillometry|Protein Binding|Reactive Oxygen Species', 'Journal Article', '10.1371/journal.pcbi.1002700', '23028295', 'The mitochondrial electron transport chain transforms energy satisfying cellular demand and generates reactive oxygen species (ROS) that act as metabolic signals or destructive factors. Therefore, knowledge of the possible modes and bifurcations of electron transport that affect ROS signaling provides insight into the interrelationship of mitochondrial respiration with cellular metabolism. Here, a bifurcation analysis of a sequence of the electron transport chain models of increasing complexity was used to analyze the contribution of individual components to the modes of respiratory chain behavior. Our algorithm constructed models as large systems of ordinary differential equations describing the time evolution of the distribution of redox states of the respiratory complexes. The most complete model of the respiratory chain and linked metabolic reactions predicted that condensed mitochondria produce more ROS at low succinate concentration and less ROS at high succinate levels than swelled mitochondria. This prediction was validated by measuring ROS production under various swelling conditions. A numerical bifurcation analysis revealed qualitatively different types of multistationary behavior and sustained oscillations in the parameter space near a region that was previously found to describe the behavior of isolated mitochondria. The oscillations in transmembrane potential and ROS generation, observed in living cells were reproduced in the model that includes interaction of respiratory complexes with the reactions of TCA cycle. Whereas multistationarity is an internal characteristic of the respiratory chain, the functional link of respiration with central metabolism creates oscillations, which can be understood as a means of auto-regulation of cell metabolism.'),
(85672, 2012, 'plos', 'The p7 protein of hepatitis C virus forms structurally plastic, minimalist ion channels', 'Chandler, Danielle E|Penin, François|Schulten, Klaus|Chipot, Christophe', 'Department of Physics and Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.|Department of Physics and Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.|Department of Physics and Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.|Department of Physics and Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.', 'United States|United States|United States|United States', 49, 'Computer Simulation|Dimerization|Elastic Modulus|Ion Channels|Models, Chemical|Molecular Dynamics Simulation|Porosity|Protein Conformation|Viral Proteins', 'Journal Article', '10.1371/journal.pcbi.1002702', '23028296', 'Hepatitis C virus (HCV) p7 is a membrane-associated oligomeric protein harboring ion channel activity. It is essential for effective assembly and release of infectious HCV particles and an attractive target for antiviral intervention. Yet, the self-assembly and molecular mechanism of p7 ion channelling are currently only partially understood. Using molecular dynamics simulations (aggregate time 1.2 µs), we show that p7 can form stable oligomers of four to seven subunits, with a bias towards six or seven subunits, and suggest that p7 self-assembles in a sequential manner, with tetrameric and pentameric complexes forming as intermediate states leading to the final hexameric or heptameric assembly. We describe a model of a hexameric p7 complex, which forms a transiently-open channel capable of conducting ions in simulation. We investigate the ability of the hexameric model to flexibly rearrange to adapt to the local lipid environment, and demonstrate how this model can be reconciled with low-resolution electron microscopy data. In the light of these results, a view of p7 oligomerization is proposed, wherein hexameric and heptameric complexes may coexist, forming minimalist, yet robust functional ion channels. In the absence of a high-resolution p7 structure, the models presented in this paper can prove valuable as a substitute structure in future studies of p7 function, or in the search for p7-inhibiting drugs.'),
(85673, 2012, 'plos', 'Coupling between catalytic loop motions and enzyme global dynamics', 'Kurkcuoglu, Zeynep|Bakan, Ahmet|Kocaman, Duygu|Bahar, Ivet|Doruker, Pemra', 'Department of Chemical Engineering and Polymer Research Center, Bogazici University, Bebek, Istanbul, Turkey.|Department of Chemical Engineering and Polymer Research Center, Bogazici University, Bebek, Istanbul, Turkey.|Department of Chemical Engineering and Polymer Research Center, Bogazici University, Bebek, Istanbul, Turkey.|Department of Chemical Engineering and Polymer Research Center, Bogazici University, Bebek, Istanbul, Turkey.|Department of Chemical Engineering and Polymer Research Center, Bogazici University, Bebek, Istanbul, Turkey.', 'Turkey|Turkey|Turkey|Turkey|Turkey', 32, 'Catalysis|Computer Simulation|Enzyme Activation|Enzyme Stability|Enzymes|Models, Chemical|Models, Molecular|Motion|Protein Conformation|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1002705', '23028297', 'Catalytic loop motions facilitate substrate recognition and binding in many enzymes. While these motions appear to be highly flexible, their functional significance suggests that structure-encoded preferences may play a role in selecting particular mechanisms of motions. We performed an extensive study on a set of enzymes to assess whether the collective/global dynamics, as predicted by elastic network models (ENMs), facilitates or even defines the local motions undergone by functional loops. Our dataset includes a total of 117 crystal structures for ten enzymes of different sizes and oligomerization states. Each enzyme contains a specific functional/catalytic loop (10-21 residues long) that closes over the active site during catalysis. Principal component analysis (PCA) of the available crystal structures (including apo and ligand-bound forms) for each enzyme revealed the dominant conformational changes taking place in these loops upon substrate binding. These experimentally observed loop reconfigurations are shown to be predominantly driven by energetically favored modes of motion intrinsically accessible to the enzyme in the absence of its substrate. The analysis suggests that robust global modes cooperatively defined by the overall enzyme architecture also entail local components that assist in suitable opening/closure of the catalytic loop over the active site.'),
(85674, 2012, 'plos', 'Why open drug discovery needs four simple rules for licensing data and models', 'Williams, Antony J|Wilbanks, John|Ekins, Sean', 'Royal Society of Chemistry, Wake Forest, North Carolina, USA. tony27587@gmail.com|Royal Society of Chemistry, Wake Forest, North Carolina, USA. tony27587@gmail.com|Royal Society of Chemistry, Wake Forest, North Carolina, USA. tony27587@gmail.com', 'United States|United States|United States', 15, 'Algorithms|Database Management Systems|Databases, Pharmaceutical|Drug Discovery|Information Dissemination|Licensure|Models, Theoretical|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1002706', '23028298', 'When we look at the rapid growth of scientific databases on the Internet in the past decade, we tend to take the accessibility and provenance of the data for granted. As we see a future of increased database integration, the licensing of the data may be a hurdle that hampers progress and usability. We have formulated four rules for licensing data for open drug discovery, which we propose as a starting point for consideration by databases and for their ultimate adoption. This work could also be extended to the computational models derived from such data. We suggest that scientists in the future will need to consider data licensing before they embark upon re-using such content in databases they construct themselves.'),
(85675, 2012, 'plos', 'Ten simple rules to commercialize scientific research', 'Fletcher, Anthony C|Bourne, Philip E', 'Royal Society of Chemistry, Wake Forest, North Carolina, USA. tony27587@gmail.com|Royal Society of Chemistry, Wake Forest, North Carolina, USA. tony27587@gmail.com', 'United States|United States', 5, 'Algorithms|Industry|Models, Organizational|Science|Translational Medical Research', 'Editorial', '10.1371/journal.pcbi.1002712', '23028299', '-'),
(85676, 2012, 'plos', 'Confidence-based somatic mutation evaluation and prioritization', 'Löwer, Martin|Renard, Bernhard Y|de Graaf, Jos|Wagner, Meike|Paret, Claudia|Kneip, Christoph|Türeci, Ozlem|Diken, Mustafa|Britten, Cedrik|Kreiter, Sebastian|Koslowski, Michael|Castle, John C|Sahin, Ugur', 'TRON - Translational Oncology at Johannes Gutenberg University of Mainz Medicine, Mainz, Germany.|TRON - Translational Oncology at Johannes Gutenberg University of Mainz Medicine, Mainz, Germany.|TRON - Translational Oncology at Johannes Gutenberg University of Mainz Medicine, Mainz, Germany.|TRON - Translational Oncology at Johannes Gutenberg University of Mainz Medicine, Mainz, Germany.|TRON - Translational Oncology at Johannes Gutenberg University of Mainz Medicine, Mainz, Germany.|TRON - Translational Oncology at Johannes Gutenberg University of Mainz Medicine, Mainz, Germany.|TRON - Translational Oncology at Johannes Gutenberg University of Mainz Medicine, Mainz, Germany.|TRON - Translational Oncology at Johannes Gutenberg University of Mainz Medicine, Mainz, Germany.|TRON - Translational Oncology at Johannes Gutenberg University of Mainz Medicine, Mainz, Germany.|TRON - Translational Oncology at Johannes Gutenberg University of Mainz Medicine, Mainz, Germany.|TRON - Translational Oncology at Johannes Gutenberg University of Mainz Medicine, Mainz, Germany.|TRON - Translational Oncology at Johannes Gutenberg University of Mainz Medicine, Mainz, Germany.|TRON - Translational Oncology at Johannes Gutenberg University of Mainz Medicine, Mainz, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germ', 25, 'Animals|Artifacts|DNA Mutational Analysis|DNA, Neoplasm|Exome|False Positive Reactions|Melanoma|Mice|Mice, Inbred C57BL|Mutation|Reproducibility of Results|Sensitivity and Specificity|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1002714', '23028300', 'Next generation sequencing (NGS) has enabled high throughput discovery of somatic mutations. Detection depends on experimental design, lab platforms, parameters and analysis algorithms. However, NGS-based somatic mutation detection is prone to erroneous calls, with reported validation rates near 54% and congruence between algorithms less than 50%. Here, we developed an algorithm to assign a single statistic, a false discovery rate (FDR), to each somatic mutation identified by NGS. This FDR confidence value accurately discriminates true mutations from erroneous calls. Using sequencing data generated from triplicate exome profiling of C57BL/6 mice and B16-F10 melanoma cells, we used the existing algorithms GATK, SAMtools and SomaticSNiPer to identify somatic mutations. For each identified mutation, our algorithm assigned an FDR. We selected 139 mutations for validation, including 50 somatic mutations assigned a low FDR (high confidence) and 44 mutations assigned a high FDR (low confidence). All of the high confidence somatic mutations validated (50 of 50), none of the 44 low confidence somatic mutations validated, and 15 of 45 mutations with an intermediate FDR validated. Furthermore, the assignment of a single FDR to individual mutations enables statistical comparisons of lab and computation methodologies, including ROC curves and AUC metrics. Using the HiSeq 2000, single end 50 nt reads from replicates generate the highest confidence somatic mutation call set.'),
(85677, 2012, 'plos', 'The mechanistic basis of Myxococcus xanthus rippling behavior and its physiological role during predation', 'Zhang, Haiyang|Vaksman, Zalman|Litwin, Douglas B|Shi, Peng|Kaplan, Heidi B|Igoshin, Oleg A', 'Department of Bioengineering, Rice University, Houston, Texas, USA.|Department of Bioengineering, Rice University, Houston, Texas, USA.|Department of Bioengineering, Rice University, Houston, Texas, USA.|Department of Bioengineering, Rice University, Houston, Texas, USA.|Department of Bioengineering, Rice University, Houston, Texas, USA.|Department of Bioengineering, Rice University, Houston, Texas, USA.', 'United States|United States|United States|United States|United States|United States', 23, 'Animals|Cell Communication|Cell Movement|Cell Polarity|Computer Simulation|Mechanotransduction, Cellular|Models, Biological|Myxococcus xanthus|Predatory Behavior', 'Journal Article', '10.1371/journal.pcbi.1002715', '23028301', 'Myxococcus xanthus cells self-organize into periodic bands of traveling waves, termed ripples, during multicellular fruiting body development and predation on other bacteria. To investigate the mechanistic basis of rippling behavior and its physiological role during predation by this Gram-negative soil bacterium, we have used an approach that combines mathematical modeling with experimental observations. Specifically, we developed an agent-based model (ABM) to simulate rippling behavior that employs a new signaling mechanism to trigger cellular reversals. The ABM has demonstrated that three ingredients are sufficient to generate rippling behavior: (i) side-to-side signaling between two cells that causes one of the cells to reverse, (ii) a minimal refractory time period after each reversal during which cells cannot reverse again, and (iii) physical interactions that cause the cells to locally align. To explain why rippling behavior appears as a consequence of the presence of prey, we postulate that prey-associated macromolecules indirectly induce ripples by stimulating side-to-side contact-mediated signaling. In parallel to the simulations, M. xanthus predatory rippling behavior was experimentally observed and analyzed using time-lapse microscopy. A formalized relationship between the wavelength, reversal time, and cell velocity has been predicted by the simulations and confirmed by the experimental data. Furthermore, the results suggest that the physiological role of rippling behavior during M. xanthus predation is to increase the rate of spreading over prey cells due to increased side-to-side contact-mediated signaling and to allow predatory cells to remain on the prey longer as a result of more periodic cell motility.'),
(85678, 2012, 'plos', 'How entorhinal grid cells may learn multiple spatial scales from a dorsoventral gradient of cell response rates in a self-organizing map', 'Grossberg, Stephen|Pilly, Praveen K', 'Center for Adaptive Systems, Graduate Program in Cognitive and Neural Systems, and Center for Computational Neuroscience and Neural Technology, Boston University, Boston, Massachusetts, United States of America. steve@bu.edu|Center for Adaptive Systems, Graduate Program in Cognitive and Neural Systems, and Center for Computational Neuroscience and Neural Technology, Boston University, Boston, Massachusetts, United States of America. steve@bu.edu', 'United States|United States', 0, 'Animals|Computational Biology|Entorhinal Cortex|Hippocampus|Membrane Potentials|Models, Neurological|Neural Networks (Computer)|Rats|Space Perception|Time Perception', 'Journal Article', '10.1371/journal.pcbi.1002648', '23055909', 'Place cells in the hippocampus of higher mammals are critical for spatial navigation. Recent modeling clarifies how this may be achieved by how grid cells in the medial entorhinal cortex (MEC) input to place cells. Grid cells exhibit hexagonal grid firing patterns across space in multiple spatial scales along the MEC dorsoventral axis. Signals from grid cells of multiple scales combine adaptively to activate place cells that represent much larger spaces than grid cells. But how do grid cells learn to fire at multiple positions that form a hexagonal grid, and with spatial scales that increase along the dorsoventral axis? In vitro recordings of medial entorhinal layer II stellate cells have revealed subthreshold membrane potential oscillations (MPOs) whose temporal periods, and time constants of excitatory postsynaptic potentials (EPSPs), both increase along this axis. Slower (faster) subthreshold MPOs and slower (faster) EPSPs correlate with larger (smaller) grid spacings and field widths. A self-organizing map neural model explains how the anatomical gradient of grid spatial scales can be learned by cells that respond more slowly along the gradient to their inputs from stripe cells of multiple scales, which perform linear velocity path integration. The model cells also exhibit MPO frequencies that covary with their response rates. The gradient in intrinsic rhythmicity is thus not compelling evidence for oscillatory interference as a mechanism of grid cell firing. A response rate gradient combined with input stripe cells that have normalized receptive fields can reproduce all known spatial and temporal properties of grid cells along the MEC dorsoventral axis. This spatial gradient mechanism is homologous to a gradient mechanism for temporal learning in the lateral entorhinal cortex and its hippocampal projections. Spatial and temporal representations may hereby arise from homologous mechanisms, thereby embodying a mechanistic neural relativity that may clarify how episodic memories are learned.'),
(85679, 2012, 'plos', 'Prediction and dissection of widely-varying association rate constants of actin-binding proteins', 'Pang, Xiaodong|Zhou, Kenneth H|Qin, Sanbo|Zhou, Huan-Xiang', 'Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, United States of America.|Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, United States of America.|Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, United States of America.|Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, United States of America.', 'United States|United States|United States|United States', 10, 'Actins|Amino Acid Sequence|Binding Sites|Computational Biology|Diffusion|Kinetics|Microfilament Proteins|Models, Molecular|Molecular Sequence Data|Polymerization|Protein Binding|Protein Conformation|Protein Multimerization|Static Electricity', 'Journal Article', '10.1371/journal.pcbi.1002696', '23055910', 'Actin is an abundant protein that constitutes a main component of the eukaryotic cytoskeleton. Its polymerization and depolymerization are regulated by a variety of actin-binding proteins. Their functions range from nucleation of actin polymerization to sequestering G-actin in 1xe2x88xb61 complexes. The kinetics of forming these complexes, with rate constants varying at least three orders of magnitude, is critical to the distinct regulatory functions. Previously we have developed a transient-complex theory for computing protein association mechanisms and association rate constants. The transient complex refers to an intermediate in which the two associating proteins have near-native separation and relative orientation but have yet to form short-range specific interactions of the native complex. The association rate constant is predicted as k(a)xe2x80x8a=xe2x80x8ak(a0) e(-xcex94G(el*)/k(B)T), where k(a0) is the basal rate constant for reaching the transient complex by free diffusion, and the Boltzmann factor captures the bias of long-range electrostatic interactions. Here we applied the transient-complex theory to study the association kinetics of seven actin-binding proteins with G-actin. These proteins exhibit three classes of association mechanisms, due to their different molecular shapes and flexibility. The 1000-fold k(a) variations among them can mostly be attributed to disparate electrostatic contributions. The basal rate constants also showed variations, resulting from the different shapes and sizes of the interfaces formed by the seven actin-binding proteins with G-actin. This study demonstrates the various ways that actin-binding proteins use physical properties to tune their association mechanisms and rate constants to suit distinct regulatory functions.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85680, 2012, 'plos', 'Ubiquitin dynamics in complexes reveal molecular recognition mechanisms beyond induced fit and conformational selection', 'Peters, Jan H|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|Least-Squares Analysis|Molecular Dynamics Simulation|Principal Component Analysis|Protein Binding|Protein Conformation|Ubiquitin', 'Journal Article', '10.1371/journal.pcbi.1002704', '23055911', 'Protein-protein interactions play an important role in all biological processes. However, the principles underlying these interactions are only beginning to be understood. Ubiquitin is a small signalling protein that is covalently attached to different proteins to mark them for degradation, regulate transport and other functions. As such, it interacts with and is recognised by a multitude of other proteins. We have conducted molecular dynamics simulations of ubiquitin in complex with 11 different binding partners on a microsecond timescale and compared them with ensembles of unbound ubiquitin to investigate the principles of their interaction and determine the influence of complex formation on the dynamic properties of this protein. Along the main mode of fluctuation of ubiquitin, binding in most cases reduces the conformational space available to ubiquitin to a subspace of that covered by unbound ubiquitin. This behaviour can be well explained using the model of conformational selection. For lower amplitude collective modes, a spectrum of zero to almost complete coverage of bound by unbound ensembles was observed. The significant differences between bound and unbound structures are exclusively situated at the binding interface. Overall, the findings correspond neither to a complete conformational selection nor induced fit scenario. Instead, we introduce a model of conformational restriction, extension and shift, which describes the full range of observed effects.'),
(85681, 2012, 'plos', 'Disease-associated mutations disrupt functionally important regions of intrinsic protein disorder', 'Vacic, Vladimir|Markwick, Phineus R L|Oldfield, Christopher J|Zhao, Xiaoyue|Haynes, Chad|Uversky, Vladimir N|Iakoucheva, Lilia M', 'Department of Computer Science, Columbia University, New York, New York, United States of America.|Department of Computer Science, Columbia University, New York, New York, United States of America.|Department of Computer Science, Columbia University, New York, New York, United States of America.|Department of Computer Science, Columbia University, New York, New York, United States of America.|Department of Computer Science, Columbia University, New York, New York, United States of America.|Department of Computer Science, Columbia University, New York, New York, United States of America.|Department of Computer Science, Columbia University, New York, New York, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 73, 'Arginine|Cluster Analysis|Computational Biology|Disease|Humans|Models, Genetic|Molecular Dynamics Simulation|Mutation|Protein Conformation|Proteins|Sequence Analysis, DNA|Transcription Factors|Tumor Suppressor Proteins', 'Journal Article', '10.1371/journal.pcbi.1002709', '23055912', 'The effects of disease mutations on protein structure and function have been extensively investigated, and many predictors of the functional impact of single amino acid substitutions are publicly available. The majority of these predictors are based on protein structure and evolutionary conservation, following the assumption that disease mutations predominantly affect folded and conserved protein regions. However, the prevalence of the intrinsically disordered proteins (IDPs) and regions (IDRs) in the human proteome together with their lack of fixed structure and low sequence conservation raise a question about the impact of disease mutations in IDRs. Here, we investigate annotated missense disease mutations and show that 21.7% of them are located within such intrinsically disordered regions. We further demonstrate that 20% of disease mutations in IDRs cause local disorder-to-order transitions, which represents a 1.7-2.7 fold increase compared to annotated polymorphisms and neutral evolutionary substitutions, respectively. Secondary structure predictions show elevated rates of transition from helices and strands into loops and vice versa in the disease mutations dataset. Disease disorder-to-order mutations also influence predicted molecular recognition features (MoRFs) more often than the control mutations. The repertoire of disorder-to-order transition mutations is limited, with five most frequent mutations (Rxe2x86x92W, Rxe2x86x92C, Exe2x86x92K, Rxe2x86x92H, Rxe2x86x92Q) collectively accounting for 44% of all deleterious disorder-to-order transitions. As a proof of concept, we performed accelerated molecular dynamics simulations on a deleterious disorder-to-order transition mutation of tumor protein p63 and, in agreement with our predictions, observed an increased xcexb1-helical propensity of the region harboring the mutation. Our findings highlight the importance of mutations in IDRs and refine the traditional structure-centric view of disease mutations. The results of this study offer a new perspective on the role of mutations in disease, with implications for improving predictors of the functional impact of missense mutations.'),
(85682, 2012, 'plos', 'Molecular mechanism for the dual alcohol modulation of Cys-loop receptors', 'Murail, Samuel|Howard, Rebecca J|Broemstrup, Torben|Bertaccini, Edward J|Harris, R Adron|Trudell, James R|Lindahl, Erik', 'Science for Life Laboratory, KTH Royal Institute of Technology & Stockholm University, Stockholm, Sweden.|Science for Life Laboratory, KTH Royal Institute of Technology & Stockholm University, Stockholm, Sweden.|Science for Life Laboratory, KTH Royal Institute of Technology & Stockholm University, Stockholm, Sweden.|Science for Life Laboratory, KTH Royal Institute of Technology & Stockholm University, Stockholm, Sweden.|Science for Life Laboratory, KTH Royal Institute of Technology & Stockholm University, Stockholm, Sweden.|Science for Life Laboratory, KTH Royal Institute of Technology & Stockholm University, Stockholm, Sweden.|Science for Life Laboratory, KTH Royal Institute of Technology & Stockholm University, Stockholm, Sweden.', 'Sweden|Sweden|Sweden|Sweden|Sweden|Sweden|Sweden', 33, 'Caenorhabditis elegans Proteins|Chloride Channels|Cysteine Loop Ligand-Gated Ion Channel Receptors|Ethanol|Lipid Bilayers|Models, Biological|Molecular Dynamics Simulation|Mutation|Phosphatidylcholines|Protein Binding|Protein Conformation|Reproducibility of Results|Water', 'Journal Article', '10.1371/journal.pcbi.1002710', '23055913', 'Cys-loop receptors constitute a superfamily of pentameric ligand-gated ion channels (pLGICs), including receptors for acetylcholine, serotonin, glycine and xcexb3-aminobutyric acid. Several bacterial homologues have been identified that are excellent models for understanding allosteric binding of alcohols and anesthetics in human Cys-loop receptors. Recently, we showed that a single point mutation on a prokaryotic homologue (GLIC) could transform it from a channel weakly potentiated by ethanol into a highly ethanol-sensitive channel. Here, we have employed molecular simulations to study ethanol binding to GLIC, and to elucidate the role of the ethanol-enhancing mutation in GLIC modulation. By performing 1-xc2xb5s simulations with and without ethanol on wild-type and mutated GLIC, we observed spontaneous binding in both intra-subunit and inter-subunit transmembrane cavities. In contrast to the glycine receptor GlyR, in which we previously observed ethanol binding primarily in an inter-subunit cavity, ethanol primarily occupied an intra-subunit cavity in wild-type GLIC. However, the highly ethanol-sensitive GLIC mutation significantly enhanced ethanol binding in the inter-subunit cavity. These results demonstrate dramatic effects of the F(14)A mutation on the distribution of ligands, and are consistent with a two-site model of pLGIC inhibition and potentiation.'),
(85683, 2012, 'plos', 'Coding and decoding with adapting neurons: a population approach to the peri-stimulus time histogram', 'Naud, Richard|Gerstner, Wulfram', 'School of Computer and Communication Sciences and School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne-EPFL, Lausanne, Switzerland.|School of Computer and Communication Sciences and School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne-EPFL, Lausanne, Switzerland.', 'Switzerland|Switzerland', 24, 'Action Potentials|Animals|Computer Simulation|Electric Stimulation|Mammals|Models, Neurological|Nerve Net|Neurons', 'Journal Article', '10.1371/journal.pcbi.1002711', '23055914', 'The response of a neuron to a time-dependent stimulus, as measured in a Peri-Stimulus-Time-Histogram (PSTH), exhibits an intricate temporal structure that reflects potential temporal coding principles. Here we analyze the encoding and decoding of PSTHs for spiking neurons with arbitrary refractoriness and adaptation. As a modeling framework, we use the spike response model, also known as the generalized linear neuron model. Because of refractoriness, the effect of the most recent spike on the spiking probability a few milliseconds later is very strong. The influence of the last spike needs therefore to be described with high precision, while the rest of the neuronal spiking history merely introduces an average self-inhibition or adaptation that depends on the expected number of past spikes but not on the exact spike timings. Based on these insights, we derive a quasi-renewal equation which is shown to yield an excellent description of the firing rate of adapting neurons. We explore the domain of validity of the quasi-renewal equation and compare it with other rate equations for populations of spiking neurons. The problem of decoding the stimulus from the population response (or PSTH) is addressed analogously. We find that for small levels of activity and weak adaptation, a simple accumulator of the past activity is sufficient to decode the original input, but when refractory effects become large decoding becomes a non-linear function of the past activity. The results presented here can be applied to the mean-field analysis of coupled neuron networks, but also to arbitrary point processes with negative self-interaction.'),
(85684, 2012, 'plos', 'Random field model reveals structure of the protein recombinational landscape', 'Romero, Philip A|Arnold, Frances H', 'Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America.|Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America.', 'United States|United States', 7, 'Amino Acid Sequence|Databases, Protein|Evolution, Molecular|Genotype|Models, Chemical|Models, Molecular|Mutation|Phenotype|Protein Conformation|Proteins|Recombination, Genetic|Sequence Homology, Amino Acid|beta-Lactamases', 'Journal Article', '10.1371/journal.pcbi.1002713', '23055915', 'We are interested in how intragenic recombination contributes to the evolution of proteins and how this mechanism complements and enhances the diversity generated by random mutation. Experiments have revealed that proteins are highly tolerant to recombination with homologous sequences (mutation by recombination is conservative), more surprisingly, they have also shown that homologous sequence fragments make largely additive contributions to biophysical properties such as stability. Here, we develop a random field model to describe the statistical features of the subset of protein space accessible by recombination, which we refer to as the recombinational landscape. This model shows quantitative agreement with experimental results compiled from eight libraries of proteins that were generated by recombining gene fragments from homologous proteins. The model reveals a recombinational landscape that is highly enriched in functional sequences, with properties dominated by a large-scale additive structure. It also quantifies the relative contributions of parent sequence identity, crossover locations, and protein fold to the tolerance of proteins to recombination. Intragenic recombination explores a unique subset of sequence space that promotes rapid molecular diversification and functional adaptation.'),
(85685, 2012, 'plos', 'A model of reward- and effort-based optimal decision making and motor control', 'Rigoux, Lionel|Guigon, Emmanuel', 'UPMC Univ Paris 06, UMR 7222, ISIR, Paris, France.|UPMC Univ Paris 06, UMR 7222, ISIR, Paris, France.', 'France|France', 55, 'Algorithms|Animals|Computational Biology|Computer Simulation|Decision Making|Humans|Models, Neurological|Motor Activity|Motor Cortex|Rats|Reward', 'Journal Article', '10.1371/journal.pcbi.1002716', '23055916', 'Costs (e.g. energetic expenditure) and benefits (e.g. food) are central determinants of behavior. In ecology and economics, they are combined to form a utility function which is maximized to guide choices. This principle is widely used in neuroscience as a normative model of decision and action, but current versions of this model fail to consider how decisions are actually converted into actions (i.e. the formation of trajectories). Here, we describe an approach where decision making and motor control are optimal, iterative processes derived from the maximization of the discounted, weighted difference between expected rewards and foreseeable motor efforts. The model accounts for decision making in cost/benefit situations, and detailed characteristics of control and goal tracking in realistic motor tasks. As a normative construction, the model is relevant to address the neural bases and pathological aspects of decision making and motor control.'),
(85686, 2012, 'plos', 'Connecting macroscopic observables and microscopic assembly events in amyloid formation using coarse grained simulations', 'Bieler, Noah S|Knowles, Tuomas P J|Frenkel, Daan|Vácha, Robert', 'Laboratory for Physical Chemistry, ETH Zürich, Zurich, Switzerland.|Laboratory for Physical Chemistry, ETH Zürich, Zurich, Switzerland.|Laboratory for Physical Chemistry, ETH Zürich, Zurich, Switzerland.|Laboratory for Physical Chemistry, ETH Zürich, Zurich, Switzerland.', 'Switzerland|Switzerland|Switzerland|Switzerland', 48, 'Amyloid|Amyloid beta-Peptides|Humans|Kinetics|Molecular Dynamics Simulation|Monte Carlo Method|Reproducibility of Results|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002692', '23071427', 'The pre-fibrillar stages of amyloid formation have been implicated in cellular toxicity, but have proved to be challenging to study directly in experiments and simulations. Rational strategies to suppress the formation of toxic amyloid oligomers require a better understanding of the mechanisms by which they are generated. We report Dynamical Monte Carlo simulations that allow us to study the early stages of amyloid formation. We use a generic, coarse-grained model of an amyloidogenic peptide that has two internal states: the first one representing the soluble random coil structure and the second one the [Formula: see text]-sheet conformation. We find that this system exhibits a propensity towards fibrillar self-assembly following the formation of a critical nucleus. Our calculations establish connections between the early nucleation events and the kinetic information available in the later stages of the aggregation process that are commonly probed in experiments. We analyze the kinetic behaviour in our simulations within the framework of the theory of classical nucleated polymerisation, and are able to connect the structural events at the early stages in amyloid growth with the resulting macroscopic observables such as the effective nucleus size. Furthermore, the free-energy landscapes that emerge from these simulations allow us to identify pertinent properties of the monomeric state that could be targeted to suppress oligomer formation.'),
(85687, 2012, 'plos', 'Discovering relations between mind, brain, and mental disorders using topic mapping', 'Poldrack, Russell A|Mumford, Jeanette A|Schonberg, Tom|Kalar, Donald|Barman, Bishal|Yarkoni, Tal', 'Imaging Research Center and Departments of Psychology and Neurobiology, University of Texas, Austin, Texas, United States of America. poldrack@mail.utexas.edu|Imaging Research Center and Departments of Psychology and Neurobiology, University of Texas, Austin, Texas, United States of America. poldrack@mail.utexas.edu|Imaging Research Center and Departments of Psychology and Neurobiology, University of Texas, Austin, Texas, United States of America. poldrack@mail.utexas.edu|Imaging Research Center and Departments of Psychology and Neurobiology, University of Texas, Austin, Texas, United States of America. poldrack@mail.utexas.edu|Imaging Research Center and Departments of Psychology and Neurobiology, University of Texas, Austin, Texas, United States of America. poldrack@mail.utexas.edu|Imaging Research Center and Departments of Psychology and Neurobiology, University of Texas, Austin, Texas, United States of America. poldrack@mail.utexas.edu', 'United States|United States|United States|United States|United States|United States', 58, 'Adult|Brain|Brain Mapping|Cluster Analysis|Cognition|Computational Biology|Data Mining|Humans|Mental Disorders|Mental Processes|Models, Neurological|Phenotype|Random Allocation', 'Journal Article', '10.1371/journal.pcbi.1002707', '23071428', 'Neuroimaging research has largely focused on the identification of associations between brain activation and specific mental functions. Here we show that data mining techniques applied to a large database of neuroimaging results can be used to identify the conceptual structure of mental functions and their mapping to brain systems. This analysis confirms many current ideas regarding the neural organization of cognition, but also provides some new insights into the roles of particular brain systems in mental function. We further show that the same methods can be used to identify the relations between mental disorders. Finally, we show that these two approaches can be combined to empirically identify novel relations between mental disorders and mental functions via their common involvement of particular brain networks. This approach has the potential to discover novel endophenotypes for neuropsychiatric disorders and to better characterize the structure of these disorders and the relations between them.'),
(85688, 2012, 'plos', 'Analysis of slow (theta) oscillations as a potential temporal reference frame for information coding in sensory cortices', 'Kayser, Christoph|Ince, Robin A A|Panzeri, Stefano', 'Max Planck Institute for Biological Cybernetics, Tübingen, Germany. christoph.kayser@tuebingen.mpg.de|Max Planck Institute for Biological Cybernetics, Tübingen, Germany. christoph.kayser@tuebingen.mpg.de|Max Planck Institute for Biological Cybernetics, Tübingen, Germany. christoph.kayser@tuebingen.mpg.de', 'Germany|Germany|Germany', 63, 'Action Potentials|Animals|Auditory Cortex|Computational Biology|Macaca mulatta|Models, Neurological|Signal Processing, Computer-Assisted|Theta Rhythm|Time Factors|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1002717', '23071429', 'While sensory neurons carry behaviorally relevant information in responses that often extend over hundreds of milliseconds, the key units of neural information likely consist of much shorter and temporally precise spike patterns. The mechanisms and temporal reference frames by which sensory networks partition responses into these shorter units of information remain unknown. One hypothesis holds that slow oscillations provide a network-intrinsic reference to temporally partitioned spike trains without exploiting the millisecond-precise alignment of spikes to sensory stimuli. We tested this hypothesis on neural responses recorded in visual and auditory cortices of macaque monkeys in response to natural stimuli. Comparing different schemes for response partitioning revealed that theta band oscillations provide a temporal reference that permits extracting significantly more information than can be obtained from spike counts, and sometimes almost as much information as obtained by partitioning spike trains using precisely stimulus-locked time bins. We further tested the robustness of these partitioning schemes to temporal uncertainty in the decoding process and to noise in the sensory input. This revealed that partitioning using an oscillatory reference provides greater robustness than partitioning using precisely stimulus-locked time bins. Overall, these results provide a computational proof of concept for the hypothesis that slow rhythmic network activity may serve as internal reference frame for information coding in sensory cortices and they foster the notion that slow oscillations serve as key elements for the computations underlying perception.'),
(85689, 2012, 'plos', 'Very slow search and reach: failure to maximize expected gain in an eye-hand coordination task', 'Zhang, Hang|Morvan, Camille|Etezad-Heydari, Louis-Alexandre|Maloney, Laurence T', 'Department of Psychology, New York University, New York, New York, United States of America. hang.zhang@nyu.edu|Department of Psychology, New York University, New York, New York, United States of America. hang.zhang@nyu.edu|Department of Psychology, New York University, New York, New York, United States of America. hang.zhang@nyu.edu|Department of Psychology, New York University, New York, New York, United States of America. hang.zhang@nyu.edu', 'United States|United States|United States|United States', 3, 'Algorithms|Computational Biology|Eye Movements|Female|Hand|Humans|Male|Models, Biological|Psychomotor Performance|Reward', 'Journal Article', '10.1371/journal.pcbi.1002718', '23071430', 'We examined an eye-hand coordination task where optimal visual search and hand movement strategies were inter-related. Observers were asked to find and touch a target among five distractors on a touch screen. Their reward for touching the target was reduced by an amount proportional to how long they took to locate and reach to it. Coordinating the eye and the hand appropriately would markedly reduce the search-reach time. Using statistical decision theory we derived the sequence of interrelated eye and hand movements that would maximize expected gain and we predicted how hand movements should change as the eye gathered further information about target location. We recorded human observers eye movements and hand movements and compared them with the optimal strategy that would have maximized expected gain. We found that most observers failed to adopt the optimal search-reach strategy. We analyze and describe the strategies they did adopt.'),
(85690, 2012, 'plos', 'Functional modules, structural topology, and optimal activity in metabolic networks', 'Resendis-Antonio, Osbaldo|Hernández, Magdalena|Mora, Yolanda|Encarnación, Sergio', 'Centro de Ciencias Genómicas-UNAM, Col. Chamilpa, Cuernavaca, Morelos, México. resendis@ccg.unam.mx|Centro de Ciencias Genómicas-UNAM, Col. Chamilpa, Cuernavaca, Morelos, México. resendis@ccg.unam.mx|Centro de Ciencias Genómicas-UNAM, Col. Chamilpa, Cuernavaca, Morelos, México. resendis@ccg.unam.mx|Centro de Ciencias Genómicas-UNAM, Col. Chamilpa, Cuernavaca, Morelos, México. resendis@ccg.unam.mx', '-|-|-|-', 16, 'Carbon|Metabolic Networks and Pathways|Metabolome|Metabolomics|Models, Biological|Nitrogen Fixation|Phaseolus|Phenotype|Proteome|Rhizobium etli|Symbiosis|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002720', '23071431', 'Modular organization in biological networks has been suggested as a natural mechanism by which a cell coordinates its metabolic strategies for evolving and responding to environmental perturbations. To understand how this occurs, there is a need for developing computational schemes that contribute to integration of genomic-scale information and assist investigators in formulating biological hypotheses in a quantitative and systematic fashion. In this work, we combined metabolome data and constraint-based modeling to elucidate the relationships among structural modules, functional organization, and the optimal metabolic phenotype of Rhizobium etli, a bacterium that fixes nitrogen in symbiosis with Phaseolus vulgaris. To experimentally characterize the metabolic phenotype of this microorganism, we obtained the metabolic profile of 220 metabolites at two physiological stages: under free-living conditions, and during nitrogen fixation with P. vulgaris. By integrating these data into a constraint-based model, we built a refined computational platform with the capability to survey the metabolic activity underlying nitrogen fixation in R. etli. Topological analysis of the metabolic reconstruction led us to identify modular structures with functional activities. Consistent with modular activity in metabolism, we found that most of the metabolites experimentally detected in each module simultaneously increased their relative abundances during nitrogen fixation. In this work, we explore the relationships among topology, biological function, and optimal activity in the metabolism of R. etli through an integrative analysis based on modeling and metabolome data. Our findings suggest that the metabolic activity during nitrogen fixation is supported by interacting structural modules that correlate with three functional classifications: nucleic acids, peptides, and lipids. More fundamentally, we supply evidence that such modular organization during functional nitrogen fixation is a robust property under different environmental conditions.'),
(85691, 2012, 'plos', 'Modeling dynamic regulatory processes in stroke', 'McDermott, Jason E|Jarman, Kenneth|Taylor, Ronald|Lancaster, Mary|Shankaran, Harish|Vartanian, Keri B|Stevens, Susan L|Stenzel-Poore, Mary P|Sanfilippo, Antonio', 'Pacific Northwest National Laboratory, Richland, Washington, United States of America. Jason.McDermott@pnnl.gov|Pacific Northwest National Laboratory, Richland, Washington, United States of America. Jason.McDermott@pnnl.gov|Pacific Northwest National Laboratory, Richland, Washington, United States of America. Jason.McDermott@pnnl.gov|Pacific Northwest National Laboratory, Richland, Washington, United States of America. Jason.McDermott@pnnl.gov|Pacific Northwest National Laboratory, Richland, Washington, United States of America. Jason.McDermott@pnnl.gov|Pacific Northwest National Laboratory, Richland, Washington, United States of America. Jason.McDermott@pnnl.gov|Pacific Northwest National Laboratory, Richland, Washington, United States of America. Jason.McDermott@pnnl.gov|Pacific Northwest National Laboratory, Richland, Washington, United States of America. Jason.McDermott@pnnl.gov|Pacific Northwest National Laboratory, Richland, Washington, United States of America. Jason.McDermott@pnnl.gov', 'United States|United States|United States|United States|United States|United States|United States|Un', 1, 'Algorithms|Animals|Brain Ischemia|Computer Simulation|Gene Expression Profiling|Gene Expression Regulation|Gene Regulatory Networks|Mice|Mice, Inbred C57BL|Models, Genetic|Multigene Family|Reproducibility of Results|Stroke|Transcriptome', 'Journal Article', '10.1371/journal.pcbi.1002722', '23071432', 'The ability to examine the behavior of biological systems in silico has the potential to greatly accelerate the pace of discovery in diseases, such as stroke, where in vivo analysis is time intensive and costly. In this paper we describe an approach for in silico examination of responses of the blood transcriptome to neuroprotective agents and subsequent stroke through the development of dynamic models of the regulatory processes observed in the experimental gene expression data. First, we identified functional gene clusters from these data. Next, we derived ordinary differential equations (ODEs) from the data relating these functional clusters to each other in terms of their regulatory influence on one another. Dynamic models were developed by coupling these ODEs into a model that simulates the expression of regulated functional clusters. By changing the magnitude of gene expression in the initial input state it was possible to assess the behavior of the networks through time under varying conditions since the dynamic model only requires an initial starting state, and does not require measurement of regulatory influences at each time point in order to make accurate predictions. We discuss the implications of our models on neuroprotection in stroke, explore the limitations of the approach, and report that an optimized dynamic model can provide accurate predictions of overall system behavior under several different neuroprotective paradigms.'),
(85692, 2012, 'plos', 'MOSAIC: a multiscale model of osteogenesis and sprouting angiogenesis with lateral inhibition of endothelial cells', 'Carlier, Aurélie|Geris, Liesbet|Bentley, Katie|Carmeliet, Geert|Carmeliet, Peter|Van Oosterwyck, Hans', 'Biomechanics Section, KU Leuven, Leuven, Belgium.|Biomechanics Section, KU Leuven, Leuven, Belgium.|Biomechanics Section, KU Leuven, Leuven, Belgium.|Biomechanics Section, KU Leuven, Leuven, Belgium.|Biomechanics Section, KU Leuven, Leuven, Belgium.|Biomechanics Section, KU Leuven, Leuven, Belgium.', 'Belgium|Belgium|Belgium|Belgium|Belgium|Belgium', 48, 'Animals|Bony Callus|Computational Biology|Computer Simulation|Endothelial Cells|Fracture Healing|Intracellular Signaling Peptides and Proteins|Membrane Proteins|Mice|Models, Biological|Neovascularization, Physiologic|Osteogenesis|Rats|Receptor, Notch1|Signal Transduction|Vascular Endothelial Growth Factor Receptor-2', 'Journal Article', '10.1371/journal.pcbi.1002724', '23071433', 'The healing of a fracture depends largely on the development of a new blood vessel network (angiogenesis) in the callus. During angiogenesis tip cells lead the developing sprout in response to extracellular signals, amongst which vascular endothelial growth factor (VEGF) is critical. In order to ensure a correct development of the vasculature, the balance between stalk and tip cell phenotypes must be tightly controlled, which is primarily achieved by the Dll4-Notch1 signaling pathway. This study presents a novel multiscale model of osteogenesis and sprouting angiogenesis, incorporating lateral inhibition of endothelial cells (further denoted MOSAIC model) through Dll4-Notch1 signaling, and applies it to fracture healing. The MOSAIC model correctly predicted the bone regeneration process and recapitulated many experimentally observed aspects of tip cell selection: the salt and pepper pattern seen for cell fates, an increased tip cell density due to the loss of Dll4 and an excessive number of tip cells in high VEGF environments. When VEGF concentration was even further increased, the MOSAIC model predicted the absence of a vascular network and fracture healing, thereby leading to a non-union, which is a direct consequence of the mutual inhibition of neighboring cells through Dll4-Notch1 signaling. This result was not retrieved for a more phenomenological model that only considers extracellular signals for tip cell migration, which illustrates the importance of implementing the actual signaling pathway rather than phenomenological rules. Finally, the MOSAIC model demonstrated the importance of a proper criterion for tip cell selection and the need for experimental data to further explore this. In conclusion, this study demonstrates that the MOSAIC model creates enhanced capabilities for investigating the influence of molecular mechanisms on angiogenesis and its relation to bone formation in a more mechanistic way and across different time and spatial scales.'),
(85693, 2012, 'plos', 'Multiple spike time patterns occur at bifurcation points of membrane potential dynamics', 'Toups, J Vincent|Fellous, Jean-Marc|Thomas, Peter J|Sejnowski, Terrence J|Tiesinga, Paul H', 'Computational Neurophysics Laboratory, Department of Physics & Astronomy, University of North Carolina, Chapel Hill, NC, USA.|Computational Neurophysics Laboratory, Department of Physics & Astronomy, University of North Carolina, Chapel Hill, NC, USA.|Computational Neurophysics Laboratory, Department of Physics & Astronomy, University of North Carolina, Chapel Hill, NC, USA.|Computational Neurophysics Laboratory, Department of Physics & Astronomy, University of North Carolina, Chapel Hill, NC, USA.|Computational Neurophysics Laboratory, Department of Physics & Astronomy, University of North Carolina, Chapel Hill, NC, USA.', 'United States|United States|United States|United States|United States', 16, 'Action Potentials|Animals|Computer Simulation|Electric Stimulation|Models, Neurological|Neurons|Pyramidal Cells|Rats|Rats, Sprague-Dawley|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1002615', '23093916', 'The response of a neuron to repeated somatic fluctuating current injections in vitro can elicit a reliable and precisely timed sequence of action potentials. The set of responses obtained across trials can also be interpreted as the response of an ensemble of similar neurons receiving the same input, with the precise spike times representing synchronous volleys that would be effective in driving postsynaptic neurons. To study the reproducibility of the output spike times for different conditions that might occur in vivo, we somatically injected aperiodic current waveforms into cortical neurons in vitro and systematically varied the amplitude and DC offset of the fluctuations. As the amplitude of the fluctuations was increased, reliability increased and the spike times remained stable over a wide range of values. However, at specific values called bifurcation points, large shifts in the spike times were obtained in response to small changes in the stimulus, resulting in multiple spike patterns that were revealed using an unsupervised classification method. Increasing the DC offset, which mimicked an overall increase in network background activity, also revealed bifurcation points and increased the reliability. Furthermore, the spike times shifted earlier with increasing offset. Although the reliability was reduced at bifurcation points, a theoretical analysis showed that the information about the stimulus time course was increased because each of the spike time patterns contained different information about the input.'),
(85694, 2012, 'plos', 'Evaluating the adequacy of gravity models as a description of human mobility for epidemic modelling', 'Truscott, James|Ferguson, Neil M', 'MRC Centre for Outbreak Analysis and Modelling, Imperial College London, London, UK. j.truscott@imperial.ac.uk|MRC Centre for Outbreak Analysis and Modelling, Imperial College London, London, UK. j.truscott@imperial.ac.uk', 'United Kingdom|United Kingdom', 42, 'Cluster Analysis|Databases, Factual|Disease Transmission, Infectious|Epidemics|Epidemiologic Methods|Human Migration|Humans|Influenza, Human|Models, Biological|Population Dynamics|United Kingdom|United States', 'Journal Article', '10.1371/journal.pcbi.1002699', '23093917', 'Gravity models have a long history of use in describing and forecasting the movements of people as well as goods and services, making them a natural basis for disease transmission rates over distance. In agent-based micro-simulations, gravity models can be directly used to represent movement of individuals and hence disease. In this paper, we consider a range of gravity models as fits to movement data from the UK and the US. We examine the ability of synthetic networks generated from fitted models to match those from the data in terms of epidemic behaviour, in particular, times to first infection. For both datasets, best fits are obtained with a two-piece matched power law distance distribution. Epidemics on synthetic UK networks match well those on data networks across all but the smallest nodes for a range of aggregation levels. We derive an expression for time to infection between nodes in terms of epidemiological and network parameters which illuminates the influence of network clustering in spread across networks and suggests an approximate relationship between the log-likelihood deviance of model fit and the match times to infection between synthetic and data networks. On synthetic US networks, the match in epidemic behaviour is initially poor and sensitive to the initially infected node. Analysis of times to infection indicates a failure of models to capture infrequent long-range contact between large nodes. An assortative model based on node population size captures this heterogeneity, considerably improving the epidemiological match between synthetic and data networks.'),
(85695, 2012, 'plos', 'Osteoprotegerin in bone metastases: mathematical solution to the puzzle', 'Ryser, Marc D|Qu, Yiding|Komarova, Svetlana V', 'Department of Mathematics and Statistics, McGill University, Montréal, Québec, Canada.|Department of Mathematics and Statistics, McGill University, Montréal, Québec, Canada.|Department of Mathematics and Statistics, McGill University, Montréal, Québec, Canada.', 'Canada|Canada|Canada', 26, 'Bone Neoplasms|Bone Resorption|Chemotaxis|Computational Biology|Gene Expression Profiling|Homeostasis|Meta-Analysis as Topic|Models, Biological|Osteoblasts|Osteoprotegerin|Parathyroid Hormone-Related Protein|RANK Ligand', 'Journal Article', '10.1371/journal.pcbi.1002703', '23093918', 'Bone is a common site for cancer metastasis. To create space for their growth, cancer cells stimulate bone resorbing osteoclasts. Cytokine RANKL is a key osteoclast activator, while osteoprotegerin (OPG) is a RANKL decoy receptor and an inhibitor of osteoclastogenesis. Consistently, systemic application of OPG decreases metastatic tumor burden in bone. However, OPG produced locally by cancer cells was shown to enhance osteolysis and tumor growth. We propose that OPG produced by cancer cells causes a local reduction in RANKL levels, inducing a steeper RANKL gradient away from the tumor and towards the bone tissue, resulting in faster resorption and tumor expansion. We tested this hypothesis using a mathematical model of nonlinear partial differential equations describing the spatial dynamics of OPG, RANKL, PTHrP, osteoclasts, tumor and bone mass. We demonstrate that at lower expression rates, tumor-derived OPG enhances the chemotactic RANKL gradient and osteolysis, whereas at higher expression rates OPG broadly inhibits RANKL and decreases osteolysis and tumor burden. Moreover, tumor expression of a soluble mediator inducing RANKL in the host tissue, such as PTHrP, is important for correct orientation of the RANKL gradient. A meta-analysis of OPG, RANKL and PTHrP expression in normal prostate, carcinoma and metastatic tissues demonstrated an increase in expression of OPG, but not RANKL, in metastatic prostate cancer, and positive correlation between OPG and PTHrP in metastatic prostate cancer. The proposed mechanism highlights the importance of the spatial distribution of receptors, decoys and ligands, and can be applied to other systems involving regulation of spatially anisotropic processes.'),
(85696, 2012, 'plos', 'CAVER 30: a tool for the analysis of transport pathways in dynamic protein structures', 'Chovancova, Eva|Pavelka, Antonin|Benes, Petr|Strnad, Ondrej|Brezovsky, Jan|Kozlikova, Barbora|Gora, Artur|Sustr, Vilem|Klvana, Martin|Medek, Petr|Biedermannova, Lada|Sochor, Jiri|Damborsky, Jiri', 'Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.|Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.|Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.|Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.|Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.|Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.|Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.|Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.|Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.|Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.|Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.|Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.|Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.', '-|-|-|-|-|-|-|-|-|-|-|-|-', 515, 'Algorithms|Cluster Analysis|Computational Biology|Crystallography|Hydrolases|Molecular Dynamics Simulation|Protein Conformation|Proteins|Software', 'Journal Article', '10.1371/journal.pcbi.1002708', '23093919', 'Tunnels and channels facilitate the transport of small molecules, ions and water solvent in a large variety of proteins. Characteristics of individual transport pathways, including their geometry, physico-chemical properties and dynamics are instrumental for understanding of structure-function relationships of these proteins, for the design of new inhibitors and construction of improved biocatalysts. CAVER is a software tool widely used for the identification and characterization of transport pathways in static macromolecular structures. Herein we present a new version of CAVER enabling automatic analysis of tunnels and channels in large ensembles of protein conformations. CAVER 3.0 implements new algorithms for the calculation and clustering of pathways. A trajectory from a molecular dynamics simulation serves as the typical input, while detailed characteristics and summary statistics of the time evolution of individual pathways are provided in the outputs. To illustrate the capabilities of CAVER 3.0, the tool was applied for the analysis of molecular dynamics simulation of the microbial enzyme haloalkane dehalogenase DhaA. CAVER 3.0 safely identified and reliably estimated the importance of all previously published DhaA tunnels, including the tunnels closed in DhaA crystal structures. Obtained results clearly demonstrate that analysis of molecular dynamics simulation is essential for the estimation of pathway characteristics and elucidation of the structural basis of the tunnel gating. CAVER 3.0 paves the way for the study of important biochemical phenomena in the area of molecular transport, molecular recognition and enzymatic catalysis. The software is freely available as a multiplatform command-line application at http://www.caver.cz.'),
(85697, 2012, 'plos', 'Probability fluxes and transition paths in a Markovian model describing complex subunit cooperativity in HCN2 channels', 'Benndorf, Klaus|Kusch, Jana|Schulz, Eckhard', 'Friedrich-Schiller-Universität Jena, Universitätsklinikum Jena, Institut für Physiologie II, Jena, Germany. Klaus.Benndorf@mti.uni-jena.de|Friedrich-Schiller-Universität Jena, Universitätsklinikum Jena, Institut für Physiologie II, Jena, Germany. Klaus.Benndorf@mti.uni-jena.de|Friedrich-Schiller-Universität Jena, Universitätsklinikum Jena, Institut für Physiologie II, Jena, Germany. Klaus.Benndorf@mti.uni-jena.de', 'Germany|Germany|Germany', 8, 'Computational Biology|Cyclic AMP|Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels|Ion Channels|Isomerism|Markov Chains|Models, Chemical|Models, Molecular|Protein Binding|Protein Conformation|Protein Subunits', 'Journal Article', '10.1371/journal.pcbi.1002721', '23093920', 'Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are voltage-gated tetrameric cation channels that generate electrical rhythmicity in neurons and cardiomyocytes. Activation can be enhanced by the binding of adenosine-3,5-cyclic monophosphate (cAMP) to an intracellular cyclic nucleotide binding domain. Based on previously determined rate constants for a complex Markovian model describing the gating of homotetrameric HCN2 channels, we analyzed probability fluxes within this model, including unidirectional probability fluxes and the probability flux along transition paths. The time-dependent probability fluxes quantify the contributions of all 13 transitions of the model to channel activation. The binding of the first, third and fourth ligand evoked robust channel opening whereas the binding of the second ligand obstructed channel opening similar to the empty channel. Analysis of the net probability fluxes in terms of the transition path theory revealed pronounced hysteresis for channel activation and deactivation. These results provide quantitative insight into the complex interaction of the four structurally equal subunits, leading to non-equality in their function.'),
(85698, 2012, 'plos', 'Spatially pooled contrast responses predict neural and perceptual similarity of naturalistic image categories', 'Groen, Iris I A|Ghebreab, Sennay|Lamme, Victor A F|Scholte, H Steven', 'Cognitive Neuroscience Group, Department of Psychology, University of Amsterdam, Amsterdam, The Netherlands.|Cognitive Neuroscience Group, Department of Psychology, University of Amsterdam, Amsterdam, The Netherlands.|Cognitive Neuroscience Group, Department of Psychology, University of Amsterdam, Amsterdam, The Netherlands.|Cognitive Neuroscience Group, Department of Psychology, University of Amsterdam, Amsterdam, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands', 37, 'Contrast Sensitivity|Electroencephalography|Evoked Potentials, Visual|Fourier Analysis|Humans|Models, Neurological|Models, Statistical|Photic Stimulation|Psychomotor Performance|Regression Analysis|Signal Processing, Computer-Assisted|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1002726', '23093921', 'The visual world is complex and continuously changing. Yet, our brain transforms patterns of light falling on our retina into a coherent percept within a few hundred milliseconds. Possibly, low-level neural responses already carry substantial information to facilitate rapid characterization of the visual input. Here, we computationally estimated low-level contrast responses to computer-generated naturalistic images, and tested whether spatial pooling of these responses could predict image similarity at the neural and behavioral level. Using EEG, we show that statistics derived from pooled responses explain a large amount of variance between single-image evoked potentials (ERPs) in individual subjects. Dissimilarity analysis on multi-electrode ERPs demonstrated that large differences between images in pooled response statistics are predictive of more dissimilar patterns of evoked activity, whereas images with little difference in statistics give rise to highly similar evoked activity patterns. In a separate behavioral experiment, images with large differences in statistics were judged as different categories, whereas images with little differences were confused. These findings suggest that statistics derived from low-level contrast responses can be extracted in early visual processing and can be relevant for rapid judgment of visual similarity. We compared our results with two other, well- known contrast statistics: Fourier power spectra and higher-order properties of contrast distributions (skewness and kurtosis). Interestingly, whereas these statistics allow for accurate image categorization, they do not predict ERP response patterns or behavioral categorization confusions. These converging computational, neural and behavioral results suggest that statistics of pooled contrast responses contain information that corresponds with perceived visual similarity in a rapid, low-level categorization task.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85699, 2012, 'plos', 'The dynamics of naturally acquired immunity to Plasmodium falciparum infection', 'Pinkevych, Mykola|Petravic, Janka|Chelimo, Kiprotich|Kazura, James W|Moormann, Ann M|Davenport, Miles P', 'Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.|Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.|Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.|Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.|Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.|Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.', 'Australia|Australia|Australia|Australia|Australia|Australia', 23, 'Adaptive Immunity|Adolescent|Child|Child, Preschool|Computer Simulation|Host-Parasite Interactions|Humans|Infant|Liver|Malaria, Falciparum|Models, Immunological|Parasitemia|Plasmodium falciparum|Recurrence', 'Journal Article', '10.1371/journal.pcbi.1002729', '23093922', 'Severe malaria occurs predominantly in young children and immunity to clinical disease is associated with cumulative exposure in holoendemic settings. The relative contribution of immunity against various stages of the parasite life cycle that results in controlling infection and limiting disease is not well understood. Here we analyse the dynamics of Plasmodium falciparum malaria infection after treatment in a cohort of 197 healthy study participants of different ages in order to model naturally acquired immunity. We find that both delayed time-to-infection and reductions in asymptomatic parasitaemias in older age groups can be explained by immunity that reduces the growth of blood stage as opposed to liver stage parasites. We found that this mechanism would require at least two components - a rapidly acting strain-specific component, as well as a slowly acquired cross-reactive or general immunity to all strains. Analysis and modelling of malaria infection dynamics and naturally acquired immunity with age provides important insights into what mechanisms of immune control may be harnessed by malaria vaccine strategists.'),
(85700, 2012, 'plos', 'Estimating the hidden burden of bovine tuberculosis in Great Britain', 'Conlan, Andrew J K|McKinley, Trevelyan J|Karolemeas, Katerina|Pollock, Ellen Brooks|Goodchild, Anthony V|Mitchell, Andrew P|Birch, Colin P D|Clifton-Hadley, Richard S|Wood, James L N', 'Disease Dynamics Unit (DDU), Department of Veterinary Medicine, University of Cambridge, Cambridge, UK. ajkc2@cam.ac.uk|Disease Dynamics Unit (DDU), Department of Veterinary Medicine, University of Cambridge, Cambridge, UK. ajkc2@cam.ac.uk|Disease Dynamics Unit (DDU), Department of Veterinary Medicine, University of Cambridge, Cambridge, UK. ajkc2@cam.ac.uk|Disease Dynamics Unit (DDU), Department of Veterinary Medicine, University of Cambridge, Cambridge, UK. ajkc2@cam.ac.uk|Disease Dynamics Unit (DDU), Department of Veterinary Medicine, University of Cambridge, Cambridge, UK. ajkc2@cam.ac.uk|Disease Dynamics Unit (DDU), Department of Veterinary Medicine, University of Cambridge, Cambridge, UK. ajkc2@cam.ac.uk|Disease Dynamics Unit (DDU), Department of Veterinary Medicine, University of Cambridge, Cambridge, UK. ajkc2@cam.ac.uk|Disease Dynamics Unit (DDU), Department of Veterinary Medicine, University of Cambridge, Cambridge, UK. ajkc2@cam.ac.uk|Disease Dynamics Unit (DDU), Department of Veterinary Medicine, University of Cambridge, Cambridge, UK. ajkc2@cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 78, 'Animal Husbandry|Animals|Cattle|Disease Outbreaks|Models, Biological|Tuberculosis, Bovine|United Kingdom', 'Journal Article', '10.1371/journal.pcbi.1002730', '23093923', 'The number of cattle herds placed under movement restrictions in Great Britain (GB) due to the suspected presence of bovine tuberculosis (bTB) has progressively increased over the past 25 years despite an intensive and costly test-and-slaughter control program. Around 38% of herds that clear movement restrictions experience a recurrent incident (breakdown) within 24 months, suggesting that infection may be persisting within herds. Reactivity to tuberculin, the basis of diagnostic testing, is dependent on the time from infection. Thus, testing efficiency varies between outbreaks, depending on weight of transmission and cannot be directly estimated. In this paper, we use Approximate Bayesian Computation (ABC) to parameterize two within-herd transmission models within a rigorous inferential framework. Previous within-herd models of bTB have relied on ad-hoc methods of parameterization and used a single model structure (SORI) where animals are assumed to become detectable by testing before they become infectious. We study such a conventional within-herd model of bTB and an alternative model, motivated by recent animal challenge studies, where there is no period of epidemiological latency before animals become infectious (SOR). Under both models we estimate that cattle-to-cattle transmission rates are non-linearly density dependent. The basic reproductive ratio for our conventional within-herd model, estimated for scenarios with no statutory controls, increases from 1.5 (0.26-4.9, 95% CI) in a herd of 30 cattle up to 4.9 (0.99-14.0) in a herd of 400. Under this model we estimate that 50% (33-67) of recurrent breakdowns in Britain can be attributed to infection missed by tuberculin testing. However this figure falls to 24% (11-42) of recurrent breakdowns under our alternative model. Under both models the estimated extrinsic force of infection increases with the burden of missed infection. Hence, improved herd-level testing is unlikely to reduce recurrence unless this extrinsic infectious pressure is simultaneously addressed.'),
(85701, 2012, 'plos', 'Linkers of cell polarity and cell cycle regulation in the fission yeast protein interaction network', 'Vaggi, Federico|Dodgson, James|Bajpai, Archana|Chessel, Anatole|Jordán, Ferenc|Sato, Masamitsu|Carazo-Salas, Rafael Edgardo|Csikász-Nagy, Attila', 'The Microsoft Research-University of Trento Centre for Computational Systems Biology, Rovereto, Italy.|The Microsoft Research-University of Trento Centre for Computational Systems Biology, Rovereto, Italy.|The Microsoft Research-University of Trento Centre for Computational Systems Biology, Rovereto, Italy.|The Microsoft Research-University of Trento Centre for Computational Systems Biology, Rovereto, Italy.|The Microsoft Research-University of Trento Centre for Computational Systems Biology, Rovereto, Italy.|The Microsoft Research-University of Trento Centre for Computational Systems Biology, Rovereto, Italy.|The Microsoft Research-University of Trento Centre for Computational Systems Biology, Rovereto, Italy.|The Microsoft Research-University of Trento Centre for Computational Systems Biology, Rovereto, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy|Italy|Italy', 9, 'Cell Cycle|Cell Polarity|Computational Biology|Protein Interaction Maps|Reproducibility of Results|Schizosaccharomyces|Schizosaccharomyces pombe Proteins|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002732', '23093924', 'The study of gene and protein interaction networks has improved our understanding of the multiple, systemic levels of regulation found in eukaryotic and prokaryotic organisms. Here we carry out a large-scale analysis of the protein-protein interaction (PPI) network of fission yeast (Schizosaccharomyces pombe) and establish a method to identify linker proteins that bridge diverse cellular processes - integrating Gene Ontology and PPI data with network theory measures. We test the method on a highly characterized subset of the genome consisting of proteins controlling the cell cycle, cell polarity and cytokinesis and identify proteins likely to play a key role in controlling the temporal changes in the localization of the polarity machinery. Experimental inspection of one such factor, the polarity-regulating RNB protein Sts5, confirms the prediction that it has a cell cycle dependent regulation. Detailed bibliographic inspection of other predicted linkers also confirms the predictive power of the method. As the method is robust to network perturbations and can successfully predict linker proteins, it provides a powerful tool to study the interplay between different cellular processes.'),
(85702, 2012, 'plos', 'The laminar cortex model: a new continuum cortex model incorporating laminar architecture', 'Du, Jiaxin|Vegh, Viktor|Reutens, David C', 'The University of Queensland, Centre for Advanced Imaging, Brisbane, Queensland, Australia.|The University of Queensland, Centre for Advanced Imaging, Brisbane, Queensland, Australia.|The University of Queensland, Centre for Advanced Imaging, Brisbane, Queensland, Australia.', 'Australia|Australia|Australia', 0, 'Action Potentials|Computational Biology|Computer Simulation|Evoked Potentials, Visual|Humans|Models, Neurological|Photic Stimulation|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1002733', '23093925', 'Local field potentials (LFPs) are widely used to study the function of local networks in the brain. They are also closely correlated with the blood-oxygen-level-dependent signal, the predominant contrast mechanism in functional magnetic resonance imaging. We developed a new laminar cortex model (LCM) to simulate the amplitude and frequency of LFPs. Our model combines the laminar architecture of the cerebral cortex and multiple continuum models to simulate the collective activity of cortical neurons. The five cortical layers (layer I, II/III, IV, V, and VI) are simulated as separate continuum models between which there are synaptic connections. The LCM was used to simulate the dynamics of the visual cortex under different conditions of visual stimulation. LFPs are reported for two kinds of visual stimulation: general visual stimulation and intermittent light stimulation. The power spectra of LFPs were calculated and compared with existing empirical data. The LCM was able to produce spontaneous LFPs exhibiting frequency-inverse (1/ƒ) power spectrum behaviour. Laminar profiles of current source density showed similarities to experimental data. General stimulation enhanced the oscillation of LFPs corresponding to gamma frequencies. During simulated intermittent light stimulation, the LCM captured the fundamental as well as high order harmonics as previously reported. The power spectrum expected with a reduction in layer IV neurons, often observed with focal cortical dysplasias associated with epilepsy was also simulated.'),
(85703, 2012, 'plos', 'Regulatory network structure as a dominant determinant of transcription factor evolutionary rate', 'Coulombe-Huntington, Jasmin|Xia, Yu', 'Bioinformatics Program, Boston University, Boston, MA, USA. jasmin@bu.edu|Bioinformatics Program, Boston University, Boston, MA, USA. jasmin@bu.edu', 'United States|United States', 0, 'Codon|Evolution, Molecular|Fungal Proteins|Gene Regulatory Networks|Genomics|Mutation|Protein Interaction Maps|Saccharomyces|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002734', '23093926', 'The evolution of transcriptional regulatory networks has thus far mostly been studied at the level of cis-regulatory elements. To gain a complete understanding of regulatory network evolution we must also study the evolutionary role of trans-factors, such as transcription factors (TFs). Here, we systematically assess genomic and network-level determinants of TF evolutionary rate in yeast, and how they compare to those of generic proteins, while carefully controlling for differences of the TF protein set, such as expression level. We found significantly distinct trends relating TF evolutionary rate to mRNA expression level, codon adaptation index, the evolutionary rate of physical interaction partners, and, confirming previous reports, to protein-protein interaction degree and regulatory in-degree. We discovered that for TFs, the dominant determinants of evolutionary rate lie in the structure of the regulatory network, such as the median evolutionary rate of target genes and the fraction of species-specific target genes. Decomposing the regulatory network by edge sign, we found that this modular evolution of TFs and their targets is limited to activating regulatory relationships. We show that fast evolving TFs tend to regulate other TFs and niche-specific processes and that their targets show larger evolutionary expression changes than targets of other TFs. We also show that the positive trend relating TF regulatory in-degree and evolutionary rate is likely related to the species-specificity of the transcriptional regulation modules. Finally, we discuss likely causes for TFs different evolutionary relationship to the physical interaction network, such as the prevalence of transient interactions in the TF subnetwork. This work suggests that positive and negative regulatory networks follow very different evolutionary rules, and that transcription factor evolution is best understood at a network- or systems-level.'),
(85704, 2012, 'plos', 'Membrane-elasticity model of Coatless vesicle budding induced by ESCRT complexes', 'Rxc3xb3xc5xbcycki, Bartosz|Boura, Evzen|Hurley, James H|Hummer, Gerhard', 'Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.|Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.|Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.|Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.', 'United States|United States|United States|United States', 29, 'Cell Membrane|Cytosol|Elasticity|Endosomal Sorting Complexes Required for Transport|Endosomes|Models, Biological|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1002736', '23093927', 'The formation of vesicles is essential for many biological processes, in particular for the trafficking of membrane proteins within cells. The Endosomal Sorting Complex Required for Transport (ESCRT) directs membrane budding away from the cytosol. Unlike other vesicle formation pathways, the ESCRT-mediated budding occurs without a protein coat. Here, we propose a minimal model of ESCRT-induced vesicle budding. Our model is based on recent experimental observations from direct fluorescence microscopy imaging that show ESCRT proteins colocalized only in the neck region of membrane buds. The model, cast in the framework of membrane elasticity theory, reproduces the experimentally observed vesicle morphologies with physically meaningful parameters. In this parameter range, the minimum energy configurations of the membrane are coatless buds with ESCRTs localized in the bud neck, consistent with experiment. The minimum energy configurations agree with those seen in the fluorescence images, with respect to both bud shapes and ESCRT protein localization. On the basis of our model, we identify distinct mechanistic pathways for the ESCRT-mediated budding process. The bud size is determined by membrane material parameters, explaining the narrow yet different bud size distributions in vitro and in vivo. Our membrane elasticity model thus sheds light on the energetics and possible mechanisms of ESCRT-induced membrane budding.'),
(85705, 2012, 'plos', 'A structural systems biology approach for quantifying the systemic consequences of missense mutations in proteins', 'Cheng, Tammy M K|Goehring, Lucas|Jeffery, Linda|Lu, Yu-En|Hayles, Jacqueline|Novák, Béla|Bates, Paul A', 'Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.|Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.|Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.|Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.|Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.|Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.|Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Computer Simulation|G2 Phase Cell Cycle Checkpoints|Humans|MAP Kinase Signaling System|Models, Molecular|Mutation, Missense|Protein Stability|Proteins|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002738', '23093928', 'Gauging the systemic effects of non-synonymous single nucleotide polymorphisms (nsSNPs) is an important topic in the pursuit of personalized medicine. However, it is a non-trivial task to understand how a change at the protein structure level eventually affects a cells behavior. This is because complex information at both the protein and pathway level has to be integrated. Given that the idea of integrating both protein and pathway dynamics to estimate the systemic impact of missense mutations in proteins remains predominantly unexplored, we investigate the practicality of such an approach by formulating mathematical models and comparing them with experimental data to study missense mutations. We present two case studies: (1) interpreting systemic perturbation for mutations within the cell cycle control mechanisms (G2 to mitosis transition) for yeast, (2) phenotypic classification of neuron-related human diseases associated with mutations within the mitogen-activated protein kinase (MAPK) pathway. We show that the application of simplified mathematical models is feasible for understanding the effects of small sequence changes on cellular behavior. Furthermore, we show that the systemic impact of missense mutations can be effectively quantified as a combination of protein stability change and pathway perturbation.'),
(85706, 2012, 'plos', 'Phasic firing in vasopressin cells: understanding its functional significance through computational models', 'MacGregor, Duncan J|Leng, Gareth', 'Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.', 'United Kingdom|United Kingdom', 0, 'Action Potentials|Animals|Computer Simulation|Models, Neurological|Neurons|Osmotic Pressure|Rats|Supraoptic Nucleus|Synapses|Vasopressins', 'Journal Article', '10.1371/journal.pcbi.1002740', '23093929', 'Vasopressin neurons, responding to input generated by osmotic pressure, use an intrinsic mechanism to shift from slow irregular firing to a distinct phasic pattern, consisting of long bursts and silences lasting tens of seconds. With increased input, bursts lengthen, eventually shifting to continuous firing. The phasic activity remains asynchronous across the cells and is not reflected in the population output signal. Here we have used a computational vasopressin neuron model to investigate the functional significance of the phasic firing pattern. We generated a concise model of the synaptic input driven spike firing mechanism that gives a close quantitative match to vasopressin neuron spike activity recorded in vivo, tested against endogenous activity and experimental interventions. The integrate-and-fire based model provides a simple physiological explanation of the phasic firing mechanism involving an activity-dependent slow depolarising afterpotential (DAP) generated by a calcium-inactivated potassium leak current. This is modulated by the slower, opposing, action of activity-dependent dendritic dynorphin release, which inactivates the DAP, the opposing effects generating successive periods of bursting and silence. Model cells are not spontaneously active, but fire when perturbed by random perturbations mimicking synaptic input. We constructed one population of such phasic neurons, and another population of similar cells but which lacked the ability to fire phasically. We then studied how these two populations differed in the way that they encoded changes in afferent inputs. By comparison with the non-phasic population, the phasic population responds linearly to increases in tonic synaptic input. Non-phasic cells respond to transient elevations in synaptic input in a way that strongly depends on background activity levels, phasic cells in a way that is independent of background levels, and show a similar strong linearization of the response. These findings show large differences in information coding between the populations, and apparent functional advantages of asynchronous phasic firing.'),
(85707, 2012, 'plos', 'Determining host metabolic limitations on viral replication via integrated modeling and experimental perturbation', 'Birch, Elsa W|Ruggero, Nicholas A|Covert, Markus W', 'Chemical Engineering, Stanford University, Stanford, CA, USA.|Chemical Engineering, Stanford University, Stanford, CA, USA.|Chemical Engineering, Stanford University, Stanford, CA, USA.', 'United States|United States|United States', 0, 'Algorithms|Bacteriophage T7|Computer Simulation|Culture Media|Escherichia coli|Host-Pathogen Interactions|Metabolic Networks and Pathways|Models, Biological|Reproducibility of Results|Systems Biology|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.1002746', '23093930', 'Viral replication relies on host metabolic machinery and precursors to produce large numbers of progeny - often very rapidly. A fundamental example is the infection of Escherichia coli by bacteriophage T7. The resource draw imposed by viral replication represents a significant and complex perturbation to the extensive and interconnected network of host metabolic pathways. To better understand this system, we have integrated a set of structured ordinary differential equations quantifying T7 replication and an E. coli flux balance analysis metabolic model. Further, we present here an integrated simulation algorithm enforcing mutual constraint by the models across the entire duration of phage replication. This method enables quantitative dynamic prediction of virion production given only specification of host nutritional environment, and predictions compare favorably to experimental measurements of phage replication in multiple environments. The level of detail of our computational predictions facilitates exploration of the dynamic changes in host metabolic fluxes that result from viral resource consumption, as well as analysis of the limiting processes dictating maximum viral progeny production. For example, although it is commonly assumed that viral infection dynamics are predominantly limited by the amount of protein synthesis machinery in the host, our results suggest that in many cases metabolic limitation is at least as strict. Taken together, these results emphasize the importance of considering viral infections in the context of host metabolism.'),
(85708, 2012, 'plos', 'Predictive dynamics of human pain perception', 'Cecchi, Guillermo A|Huang, Lejian|Hashmi, Javeria Ali|Baliki, Marwan|Centeno, María V|Rish, Irina|Apkarian, A Vania', 'Computational Biology Center, T.J. Watson IBM Research Laboratory, Yorktown Heights, New York, USA. gcecchi@us.ibm.com|Computational Biology Center, T.J. Watson IBM Research Laboratory, Yorktown Heights, New York, USA. gcecchi@us.ibm.com|Computational Biology Center, T.J. Watson IBM Research Laboratory, Yorktown Heights, New York, USA. gcecchi@us.ibm.com|Computational Biology Center, T.J. Watson IBM Research Laboratory, Yorktown Heights, New York, USA. gcecchi@us.ibm.com|Computational Biology Center, T.J. Watson IBM Research Laboratory, Yorktown Heights, New York, USA. gcecchi@us.ibm.com|Computational Biology Center, T.J. Watson IBM Research Laboratory, Yorktown Heights, New York, USA. gcecchi@us.ibm.com|Computational Biology Center, T.J. Watson IBM Research Laboratory, Yorktown Heights, New York, USA. gcecchi@us.ibm.com', 'United States|United States|United States|United States|United States|United States|United States', 0, 'Adult|Artificial Intelligence|Brain|Female|Hot Temperature|Humans|Magnetic Resonance Imaging|Male|Models, Neurological|Pain|Pain Perception|Psychophysics|Random Allocation|Regression Analysis', 'Journal Article', '10.1371/journal.pcbi.1002719', '23133342', 'While the static magnitude of thermal pain perception has been shown to follow a power-law function of the temperature, its dynamical features have been largely overlooked. Due to the slow temporal experience of pain, multiple studies now show that the time evolution of its magnitude can be captured with continuous online ratings. Here we use such ratings to model quantitatively the temporal dynamics of thermal pain perception. We show that a differential equation captures the details of the temporal evolution in pain ratings in individual subjects for different stimulus pattern complexities, and also demonstrates strong predictive power to infer pain ratings, including readouts based only on brain functional images.'),
(85709, 2012, 'plos', 'How recent history affects perception: the normative approach and its heuristic approximation', 'Raviv, Ofri|Ahissar, Merav|Loewenstein, Yonatan', 'The Edmond & Lily Safra Center for Brain Sciences, Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel. ofri.raviv@mail.huji.ac.il|The Edmond & Lily Safra Center for Brain Sciences, Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel. ofri.raviv@mail.huji.ac.il|The Edmond & Lily Safra Center for Brain Sciences, Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel. ofri.raviv@mail.huji.ac.il', 'Israel|Israel|Israel', 46, 'Acoustic Stimulation|Adult|Bayes Theorem|Computer Simulation|Decision Making|Discrimination (Psychology)|Humans|Memory|Models, Biological|Monte Carlo Method', 'Journal Article', '10.1371/journal.pcbi.1002731', '23133343', 'There is accumulating evidence that prior knowledge about expectations plays an important role in perception. The Bayesian framework is the standard computational approach to explain how prior knowledge about the distribution of expected stimuli is incorporated with noisy observations in order to improve performance. However, it is unclear what information about the prior distribution is acquired by the perceptual system over short periods of time and how this information is utilized in the process of perceptual decision making. Here we address this question using a simple two-tone discrimination task. We find that the contraction bias, in which small magnitudes are overestimated and large magnitudes are underestimated, dominates the pattern of responses of human participants. This contraction bias is consistent with the Bayesian hypothesis in which the true prior information is available to the decision-maker. However, a trial-by-trial analysis of the pattern of responses reveals that the contribution of most recent trials to performance is overweighted compared with the predictions of a standard Bayesian model. Moreover, we study participants performance in a-typical distributions of stimuli and demonstrate substantial deviations from the ideal Bayesian detector, suggesting that the brain utilizes a heuristic approximation of the Bayesian inference. We propose a biologically plausible model, in which decision in the two-tone discrimination task is based on a comparison between the second tone and an exponentially-decaying average of the first tone and past tones. We show that this model accounts for both the contraction bias and the deviations from the ideal Bayesian detector hypothesis. These findings demonstrate the power of Bayesian-like heuristics in the brain, as well as their limitations in their failure to fully adapt to novel environments.'),
(85710, 2012, 'plos', 'The effect of bacterial recombination on adaptation on fitness landscapes with limited peak accessibility', 'Moradigaravand, Danesh|Engelstädter, Jan', 'Institute of Biogeochemistry and Pollutant Dynamics, ETH Zurich, Zurich, Switzerland. danesh.moradigaravand@env.ethz.ch|Institute of Biogeochemistry and Pollutant Dynamics, ETH Zurich, Zurich, Switzerland. danesh.moradigaravand@env.ethz.ch', 'Switzerland|Switzerland', 0, 'Adaptation, Biological|Biological Evolution|Computational Biology|Computer Simulation|Genetic Fitness|Genetics, Population|Genotype|Models, Genetic|Mutation|Recombination, Genetic|Selection, Genetic|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002735', '23133344', 'There is ample empirical evidence revealing that fitness landscapes are often complex: the fitness effect of a newly arisen mutation can depend strongly on the allelic state at other loci. However, little is known about the effects of recombination on adaptation on such fitness landscapes. Here, we investigate how recombination influences the rate of adaptation on a special type of complex fitness landscapes. On these landscapes, the mutational trajectories from the least to the most fit genotype are interrupted by genotypes with low relative fitness. We study the dynamics of adapting populations on landscapes with different compositions and numbers of low fitness genotypes, with and without recombination. Our results of the deterministic model (assuming an infinite population size) show that recombination generally decelerates adaptation on these landscapes. However, in finite populations, this deceleration is outweighed by the accelerating Fisher-Muller effect under certain conditions. We conclude that recombination has complex effects on adaptation that are highly dependent on the particular fitness landscape, population size and recombination rate.'),
(85711, 2012, 'plos', 'Next-generation sequencing of human mitochondrial reference genomes uncovers high heteroplasmy frequency', 'Sosa, Maria Ximena|Sivakumar, I K Ashok|Maragh, Samantha|Veeramachaneni, Vamsi|Hariharan, Ramesh|Parulekar, Minothi|Fredrikson, Karin M|Harkins, Timothy T|Lin, Jeffrey|Feldman, Andrew B|Tata, Pramila|Ehret, Georg B|Chakravarti, Aravinda', 'McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.', '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', 45, 'African Continental Ancestry Group|DNA, Mitochondrial|Databases, Genetic|European Continental Ancestry Group|Genetic Variation|Genome, Mitochondrial|Genomics|HapMap Project|Humans|Polymerase Chain Reaction|Sequence Alignment|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1002737', '23133345', 'We describe methods for rapid sequencing of the entire human mitochondrial genome (mtgenome), which involve long-range PCR for specific amplification of the mtgenome, pyrosequencing, quantitative mapping of sequence reads to identify sequence variants and heteroplasmy, as well as de novo sequence assembly. These methods have been used to study 40 publicly available HapMap samples of European (CEU) and African (YRI) ancestry to demonstrate a sequencing error rate <5.63×10(-4), nucleotide diversity of 1.6×10(-3) for CEU and 3.7×10(-3) for YRI, patterns of sequence variation consistent with earlier studies, but a higher rate of heteroplasmy varying between 10% and 50%. These results demonstrate that next-generation sequencing technologies allow interrogation of the mitochondrial genome in greater depth than previously possible which may be of value in biology and medicine.'),
(85712, 2012, 'plos', 'The role of social contacts and original antigenic sin in shaping the age pattern of immunity to seasonal influenza', 'Kucharski, Adam J|Gog, Julia R', 'Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, United Kingdom. ak640@cam.ac.uk|Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, United Kingdom. ak640@cam.ac.uk', 'United Kingdom|United Kingdom', 0, 'Age Factors|Algorithms|Antibodies, Viral|Antigens, Viral|Australia|Cluster Analysis|Finland|Humans|Influenza A Virus, H1N1 Subtype|Influenza A Virus, H3N2 Subtype|Influenza Vaccines|Influenza, Human|Markov Chains|Models, Immunological|Monte Carlo Method|Pandemics', 'Journal Article', '10.1371/journal.pcbi.1002741', '23133346', 'Recent serological studies of seasonal influenza A in humans suggest a striking characteristic profile of immunity against age, which holds across different countries and against different subtypes of influenza. For both H1N1 and H3N2, the proportion of the population seropositive to recently circulated strains peaks in school-age children, reaches a minimum between ages 35-65, then rises again in the older ages. This pattern is little understood. Variable mixing between different age classes can have a profound effect on disease dynamics, and is hence the obvious candidate explanation for the profile, but using a mathematical model of multiple influenza strains, we see that age dependent transmission based on mixing data from social contact surveys cannot on its own explain the observed pattern. Instead, the number of seropositive individuals in a population may be a consequence of original antigenic sin, if the first infection of a lifetime dominates subsequent immune responses, we demonstrate that it is possible to reproduce the observed relationship between age and seroprevalence. We propose a candidate mechanism for this relationship, by which original antigenic sin, along with antigenic drift and vaccination, results in the age profile of immunity seen in empirical studies.'),
(85713, 2012, 'plos', 'Modeling protective anti-tumor immunity via preventative cancer vaccines using a hybrid agent-based and delay differential equation approach', 'Kim, Peter S|Lee, Peter P', 'School of Mathematics and Statistics, University of Sydney, Sydney, New South Wales, Australia.|School of Mathematics and Statistics, University of Sydney, Sydney, New South Wales, Australia.', 'Australia|Australia', 29, 'Antigens, Neoplasm|Cancer Vaccines|Computational Biology|Humans|Lymph Nodes|Models, Immunological|Neoplasms|T-Lymphocytes, Cytotoxic', 'Journal Article', '10.1371/journal.pcbi.1002742', '23133347', 'A next generation approach to cancer envisions developing preventative vaccinations to stimulate a persons immune cells, particularly cytotoxic T lymphocytes (CTLs), to eliminate incipient tumors before clinical detection. The purpose of our study is to quantitatively assess whether such an approach would be feasible, and if so, how many anti-cancer CTLs would have to be primed against tumor antigen to provide significant protection. To understand the relevant dynamics, we develop a two-compartment model of tumor-immune interactions at the tumor site and the draining lymph node. We model interactions at the tumor site using an agent-based model (ABM) and dynamics in the lymph node using a system of delay differential equations (DDEs). We combine the models into a hybrid ABM-DDE system and investigate dynamics over a wide range of parameters, including cell proliferation rates, tumor antigenicity, CTL recruitment times, and initial memory CTL populations. Our results indicate that an anti-cancer memory CTL pool of 3% or less can successfully eradicate a tumor population over a wide range of model parameters, implying that a vaccination approach is feasible. In addition, sensitivity analysis of our model reveals conditions that will result in rapid tumor destruction, oscillation, and polynomial rather than exponential decline in the tumor population due to tumor geometry.'),
(85714, 2012, 'plos', 'Incorporating 16S gene copy number information improves estimates of microbial diversity and abundance', 'Kembel, Steven W|Wu, Martin|Eisen, Jonathan A|Green, Jessica L', 'Institute of Ecology & Evolution, University of Oregon, Eugene, Oregon, USA. kembel.steven_w@uqam.ca|Institute of Ecology & Evolution, University of Oregon, Eugene, Oregon, USA. kembel.steven_w@uqam.ca|Institute of Ecology & Evolution, University of Oregon, Eugene, Oregon, USA. kembel.steven_w@uqam.ca|Institute of Ecology & Evolution, University of Oregon, Eugene, Oregon, USA. kembel.steven_w@uqam.ca', 'United States|United States|United States|United States', 237, 'Bacteria|Biodiversity|Cluster Analysis|Computer Simulation|Databases, Genetic|Gene Dosage|Humans|Microbial Consortia|Models, Biological|Oceans and Seas|Phylogeny|RNA, Ribosomal, 16S|Skin|Water Microbiology', 'Journal Article', '10.1371/journal.pcbi.1002743', '23133348', 'The abundance of different SSU rRNA (16S) gene sequences in environmental samples is widely used in studies of microbial ecology as a measure of microbial community structure and diversity. However, the genomic copy number of the 16S gene varies greatly - from one in many species to up to 15 in some bacteria and to hundreds in some microbial eukaryotes. As a result of this variation the relative abundance of 16S genes in environmental samples can be attributed both to variation in the relative abundance of different organisms, and to variation in genomic 16S copy number among those organisms. Despite this fact, many studies assume that the abundance of 16S gene sequences is a surrogate measure of the relative abundance of the organisms containing those sequences. Here we present a method that uses data on sequences and genomic copy number of 16S genes along with phylogenetic placement and ancestral state estimation to estimate organismal abundances from environmental DNA sequence data. We use theory and simulations to demonstrate that 16S genomic copy number can be accurately estimated from the short reads typically obtained from high-throughput environmental sequencing of the 16S gene, and that organismal abundances in microbial communities are more strongly correlated with estimated abundances obtained from our method than with gene abundances. We re-analyze several published empirical data sets and demonstrate that the use of gene abundance versus estimated organismal abundance can lead to different inferences about community diversity and structure and the identity of the dominant taxa in microbial communities. Our approach will allow microbial ecologists to make more accurate inferences about microbial diversity and abundance based on 16S sequence data.'),
(85715, 2012, 'plos', 'Evolutionary analysis of human immunodeficiency virus type 1 therapies based on conditionally replicating vectors', 'Ke, Ruian|Lloyd-Smith, James O', 'Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, USA. ruian@ucla.edu|Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, USA. ruian@ucla.edu', 'United States|United States', 10, 'Antiviral Agents|CD4-Positive T-Lymphocytes|Cell Death|Drug Resistance, Viral|Evolution, Molecular|Genetic Fitness|Genome, Viral|Genotype|HIV Infections|HIV-1|Host-Pathogen Interactions|Humans|Models, Genetic|Phenotype|Virion|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.1002744', '23133349', 'Efforts to reduce the viral load of human immunodeficiency virus type 1 (HIV-1) during long-term treatment are challenged by the evolution of anti-viral resistance mutants. Recent studies have shown that gene therapy approaches based on conditionally replicating vectors (CRVs) could have many advantages over anti-viral drugs and other approaches to therapy, potentially including the ability to circumvent the problem of evolved resistance. However, research to date has not explored the evolutionary consequences of long-term treatment of HIV-1 infections with conditionally replicating vectors. In this study, we analyze a computational model of the within-host co-evolutionary dynamics of HIV-1 and conditionally replicating vectors, using the recently proposed therapeutic interfering particle as an example. The model keeps track of the stochastic process of viral mutation, and the deterministic population dynamics of T cells as well as different strains of CRV and HIV-1 particles. We show that early in the co-infection, mutant HIV-1 genotypes that escape suppression by CRV therapy appear, this is similar to the dynamics observed in drug treatments and other gene therapies. In contrast to other treatments, however, the CRV population is able to evolve and catch up with the dominant HIV-1 escape mutant and persist long-term in most cases. On evolutionary grounds, gene therapies based on CRVs appear to be a promising tool for long-term treatment of HIV-1. Our model allows us to propose design principles to optimize the efficacy of this class of gene therapies. In addition, because of the analogy between CRVs and naturally-occurring defective interfering particles, our results also shed light on the co-evolutionary dynamics of wild-type viruses and their defective interfering particles during natural infections.'),
(85716, 2012, 'plos', 'Emergence of the mitochondrial reticulum from fission and fusion dynamics', 'Sukhorukov, Valerii M|Dikov, Daniel|Reichert, Andreas S|Meyer-Hermann, Michael', 'Helmholtz Centre for Infection Research, Braunschweig, Germany. vsukhorukov@yahoo.com|Helmholtz Centre for Infection Research, Braunschweig, Germany. vsukhorukov@yahoo.com|Helmholtz Centre for Infection Research, Braunschweig, Germany. vsukhorukov@yahoo.com|Helmholtz Centre for Infection Research, Braunschweig, Germany. vsukhorukov@yahoo.com', 'Germany|Germany|Germany|Germany', 0, 'Animals|Cluster Analysis|Computational Biology|HeLa Cells|Humans|Mitochondria|Mitochondrial Dynamics|Models, Biological|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002745', '23133350', 'Mitochondria form a dynamic tubular reticulum within eukaryotic cells. Currently, quantitative understanding of its morphological characteristics is largely absent, despite major progress in deciphering the molecular fission and fusion machineries shaping its structure. Here we address the principles of formation and the large-scale organization of the cell-wide network of mitochondria. On the basis of experimentally determined structural features we establish the tip-to-tip and tip-to-side fission and fusion events as dominant reactions in the motility of this organelle. Subsequently, we introduce a graph-based model of the chondriome able to encompass its inherent variability in a single framework. Using both mean-field deterministic and explicit stochastic mathematical methods we establish a relationship between the chondriome structural network characteristics and underlying kinetic rate parameters. The computational analysis indicates that mitochondrial networks exhibit a percolation threshold. Intrinsic morphological instability of the mitochondrial reticulum resulting from its vicinity to the percolation transition is proposed as a novel mechanism that can be utilized by cells for optimizing their functional competence via dynamic remodeling of the chondriome. The detailed size distribution of the network components predicted by the dynamic graph representation introduces a relationship between chondriome characteristics and cell function. It forms a basis for understanding the architecture of mitochondria as a cell-wide but inhomogeneous organelle. Analysis of the reticulum adaptive configuration offers a direct clarification for its impact on numerous physiological processes strongly dependent on mitochondrial dynamics and organization, such as efficiency of cellular metabolism, tissue differentiation and aging.'),
(85717, 2012, 'plos', 'Integrating cellular metabolism into a multiscale whole-body model', 'Krauss, Markus|Schaller, Stephan|Borchers, Steffen|Findeisen, Rolf|Lippert, Jörg|Kuepfer, Lars', 'Bayer Technology Services GmbH, Computational Systems Biology, Leverkusen, Germany.|Bayer Technology Services GmbH, Computational Systems Biology, Leverkusen, Germany.|Bayer Technology Services GmbH, Computational Systems Biology, Leverkusen, Germany.|Bayer Technology Services GmbH, Computational Systems Biology, Leverkusen, Germany.|Bayer Technology Services GmbH, Computational Systems Biology, Leverkusen, Germany.|Bayer Technology Services GmbH, Computational Systems Biology, Leverkusen, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany', 75, 'Acetaminophen|Allopurinol|Ammonia|Chemical and Drug Induced Liver Injury|Computational Biology|Computer Simulation|Hepatocytes|Humans|Hyperuricemia|Inactivation, Metabolic|Liver|Metabolism|Models, Biological|Urea|Urea Cycle Disorders, Inborn|Uric Acid', 'Journal Article', '10.1371/journal.pcbi.1002750', '23133351', 'Cellular metabolism continuously processes an enormous range of external compounds into endogenous metabolites and is as such a key element in human physiology. The multifaceted physiological role of the metabolic network fulfilling the catalytic conversions can only be fully understood from a whole-body perspective where the causal interplay of the metabolic states of individual cells, the surrounding tissue and the whole organism are simultaneously considered. We here present an approach relying on dynamic flux balance analysis that allows the integration of metabolic networks at the cellular scale into standardized physiologically-based pharmacokinetic models at the whole-body level. To evaluate our approach we integrated a genome-scale network reconstruction of a human hepatocyte into the liver tissue of a physiologically-based pharmacokinetic model of a human adult. The resulting multiscale model was used to investigate hyperuricemia therapy, ammonia detoxification and paracetamol-induced toxication at a systems level. The specific models simultaneously integrate multiple layers of biological organization and offer mechanistic insights into pathology and medication. The approach presented may in future support a mechanistic understanding in diagnostics and drug development.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85718, 2012, 'plos', 'Disease prevention versus data privacy: using landcover maps to inform spatial epidemic models', 'Tildesley, Michael J|Ryan, Sadie J', 'Centre for Complexity Science, Zeeman Building, University of Warwick, Coventry, United Kingdom. M.J.Tildesley@warwick.ac.uk|Centre for Complexity Science, Zeeman Building, University of Warwick, Coventry, United Kingdom. M.J.Tildesley@warwick.ac.uk', 'United Kingdom|United Kingdom', 15, 'Agriculture|Animal Diseases|Animals|Cattle|Computational Biology|Confidentiality|Disease Outbreaks|Foot-and-Mouth Disease|Livestock|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002723', '23133352', 'The availability of epidemiological data in the early stages of an outbreak of an infectious disease is vital for modelers to make accurate predictions regarding the likely spread of disease and preferred intervention strategies. However, in some countries, the necessary demographic data are only available at an aggregate scale. We investigated the ability of models of livestock infectious diseases to predict epidemic spread and obtain optimal control policies in the event of imperfect, aggregated data. Taking a geographic information approach, we used land cover data to predict UK farm locations and investigated the influence of using these synthetic location data sets upon epidemiological predictions in the event of an outbreak of foot-and-mouth disease. When broadly classified land cover data were used to create synthetic farm locations, model predictions deviated significantly from those simulated on true data. However, when more resolved subclass land use data were used, moderate to highly accurate predictions of epidemic size, duration and optimal vaccination and ring culling strategies were obtained. This suggests that a geographic information approach may be useful where individual farm-level data are not available, to allow predictive analyses to be carried out regarding the likely spread of disease. This method can also be used for contingency planning in collaboration with policy makers to determine preferred control strategies in the event of a future outbreak of infectious disease in livestock.'),
(85719, 2012, 'plos', 'Evolution of associative learning in chemical networks', 'McGregor, Simon|Vasas, Vera|Husbands, Phil|Fernando, Chrisantha', 'Department of Informatics, University of Sussex, Falmer, Brighton, United Kingdom.|Department of Informatics, University of Sussex, Falmer, Brighton, United Kingdom.|Department of Informatics, University of Sussex, Falmer, Brighton, United Kingdom.|Department of Informatics, University of Sussex, Falmer, Brighton, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Bayes Theorem|Biochemical Phenomena|Computational Biology|Computer Simulation|Evolution, Molecular|Logistic Models|Metabolism|Models, Chemical', 'Journal Article', '10.1371/journal.pcbi.1002739', '23133353', 'Organisms that can learn about their environment and modify their behaviour appropriately during their lifetime are more likely to survive and reproduce than organisms that do not. While associative learning - the ability to detect correlated features of the environment - has been studied extensively in nervous systems, where the underlying mechanisms are reasonably well understood, mechanisms within single cells that could allow associative learning have received little attention. Here, using in silico evolution of chemical networks, we show that there exists a diversity of remarkably simple and plausible chemical solutions to the associative learning problem, the simplest of which uses only one core chemical reaction. We then asked to what extent a linear combination of chemical concentrations in the network could approximate the ideal Bayesian posterior of an environment given the stimulus history so far? This Bayesian analysis revealed the memory traces of the chemical network. The implication of this paper is that there is little reason to believe that a lack of suitable phenotypic variation would prevent associative learning from evolving in cell signalling, metabolic, gene regulatory, or a mixture of these networks in cells.'),
(85720, 2012, 'plos', 'Theory on the coupled stochastic dynamics of transcription and splice-site recognition', 'Murugan, Rajamanickam|Kreiman, Gabriel', 'Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India.|Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India.', 'India|India', 5, 'Animals|Computational Biology|Computer Simulation|Gene Expression Profiling|Humans|Introns|Mice|Models, Genetic|Oligonucleotide Array Sequence Analysis|RNA Precursors|RNA Splice Sites|RNA Splicing|Reproducibility of Results|Ribonucleoproteins, Small Nuclear|Stochastic Processes|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002747', '23133354', 'Eukaryotic genes are typically split into exons that need to be spliced together to form the mature mRNA. The splicing process depends on the dynamics and interactions among transcription by the RNA polymerase II complex (RNAPII) and the spliceosomal complex consisting of multiple small nuclear ribonucleo proteins (snRNPs). Here we propose a biophysically plausible initial theory of splicing that aims to explain the effects of the stochastic dynamics of snRNPs on the splicing patterns of eukaryotic genes. We consider two different ways to model the dynamics of snRNPs: pure three-dimensional diffusion and a combination of three- and one-dimensional diffusion along the emerging pre-mRNA. Our theoretical analysis shows that there exists an optimum position of the splice sites on the growing pre-mRNA at which the time required for snRNPs to find the 5 donor site is minimized. The minimization of the overall search time is achieved mainly via the increase in non-specific interactions between the snRNPs and the growing pre-mRNA. The theory further predicts that there exists an optimum transcript length that maximizes the probabilities for exons to interact with the snRNPs. We evaluate these theoretical predictions by considering human and mouse exon microarray data as well as RNAseq data from multiple different tissues. We observe that there is a broad optimum position of splice sites on the growing pre-mRNA and an optimum transcript length, which are roughly consistent with the theoretical predictions. The theoretical and experimental analyses suggest that there is a strong interaction between the dynamics of RNAPII and the stochastic nature of snRNP search for 5 donor splicing sites.'),
(85721, 2012, 'plos', 'A characterization of scale invariant responses in enzymatic networks', 'Skataric, Maja|Sontag, Eduardo D', 'Department of Electrical Engineering, Rutgers University, Piscataway, New Jersey, USA.|Department of Electrical Engineering, Rutgers University, Piscataway, New Jersey, USA.', 'Jersey|Jersey', 19, 'Enzymes|Escherichia coli|Metabolic Networks and Pathways|Models, Biological|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002748', '23133355', 'An ubiquitous property of biological sensory systems is adaptation: a step increase in stimulus triggers an initial change in a biochemical or physiological response, followed by a more gradual relaxation toward a basal, pre-stimulus level. Adaptation helps maintain essential variables within acceptable bounds and allows organisms to readjust themselves to an optimum and non-saturating sensitivity range when faced with a prolonged change in their environment. Recently, it was shown theoretically and experimentally that many adapting systems, both at the organism and single-cell level, enjoy a remarkable additional feature: scale invariance, meaning that the initial, transient behavior remains (approximately) the same even when the background signal level is scaled. In this work, we set out to investigate under what conditions a broadly used model of biochemical enzymatic networks will exhibit scale-invariant behavior. An exhaustive computational study led us to discover a new property of surprising simplicity and generality, uniform linearizations with fast output (ULFO), whose validity we show is both necessary and sufficient for scale invariance of three-node enzymatic networks (and sufficient for any number of nodes). Based on this study, we go on to develop a mathematical explanation of how ULFO results in scale invariance. Our work provides a surprisingly consistent, simple, and general framework for understanding this phenomenon, and results in concrete experimental predictions.'),
(85722, 2012, 'plos', 'The role of flexibility and conformational selection in the binding promiscuity of PDZ domains', 'Münz, Márton|Hein, Jotun|Biggin, Philip C', 'Structural Bioinformatics and Computational Biochemistry, University of Oxford, Oxford, United Kingdom.|Structural Bioinformatics and Computational Biochemistry, University of Oxford, Oxford, United Kingdom.|Structural Bioinformatics and Computational Biochemistry, University of Oxford, Oxford, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 45, 'Amino Acid Sequence|Animals|Binding Sites|Cluster Analysis|Computational Biology|Drosophila Proteins|Humans|Mice|Molecular Dynamics Simulation|Molecular Sequence Data|PDZ Domains|Protein Binding|Proteins|Rats|Sequence Alignment|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002749', '23133356', 'In molecular recognition, it is often the case that ligand binding is coupled to conformational change in one or both of the binding partners. Two hypotheses describe the limiting cases involved, the first is the induced fit and the second is the conformational selection model. The conformational selection model requires that the protein adopts conformations that are similar to the ligand-bound conformation in the absence of ligand, whilst the induced-fit model predicts that the ligand-bound conformation of the protein is only accessible when the ligand is actually bound. The flexibility of the apo protein clearly plays a major role in these interpretations. For many proteins involved in signaling pathways there is the added complication that they are often promiscuous in that they are capable of binding to different ligand partners. The relationship between protein flexibility and promiscuity is an area of active research and is perhaps best exemplified by the PDZ domain family of proteins. In this study we use molecular dynamics simulations to examine the relationship between flexibility and promiscuity in five PDZ domains: the human Dvl2 (Dishevelled-2) PDZ domain, the human Erbin PDZ domain, the PDZ1 domain of InaD (inactivation no after-potential D protein) from fruit fly, the PDZ7 domain of GRIP1 (glutamate receptor interacting protein 1) from rat and the PDZ2 domain of PTP-BL (protein tyrosine phosphatase) from mouse. We show that despite their high structural similarity, the PDZ binding sites have significantly different dynamics. Importantly, the degree of binding pocket flexibility was found to be closely related to the various characteristics of peptide binding specificity and promiscuity of the five PDZ domains. Our findings suggest that the intrinsic motions of the apo structures play a key role in distinguishing functional properties of different PDZ domains and allow us to make predictions that can be experimentally tested.'),
(85723, 2012, 'plos', 'Comparative analysis of RNA families reveals distinct repertoires for each domain of life', 'Hoeppner, Marc P|Gardner, Paul P|Poole, Anthony M', 'Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. mphoeppner@gmail.com|Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. mphoeppner@gmail.com|Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. mphoeppner@gmail.com', 'Sweden|Sweden|Sweden', 0, 'Archaea|Bacteria|Databases, Nucleic Acid|Eukaryota|Evolution, Molecular|Genome|Genomics|Phylogeny|RNA', 'Journal Article', '10.1371/journal.pcbi.1002752', '23133357', 'The RNA world hypothesis, that RNA genomes and catalysts preceded DNA genomes and genetically-encoded protein catalysts, has been central to models for the early evolution of life on Earth. A key part of such models is continuity between the earliest stages in the evolution of life and the RNA repertoires of extant lineages. Some assessments seem consistent with a diverse RNA world, yet direct continuity between modern RNAs and an RNA world has not been demonstrated for the majority of RNA families, and, anecdotally, many RNA functions appear restricted in their distribution. Despite much discussion of the possible antiquity of RNA families, no systematic analyses of RNA family distribution have been performed. To chart the broad evolutionary history of known RNA families, we performed comparative genomic analysis of over 3 million RNA annotations spanning 1446 families from the Rfam 10 database. We report that 99% of known RNA families are restricted to a single domain of life, revealing discrete repertoires for each domain. For the 1% of RNA families/clans present in more than one domain, over half show evidence of horizontal gene transfer (HGT), and the rest show a vertical trace, indicating the presence of a complex protein synthesis machinery in the Last Universal Common Ancestor (LUCA) and consistent with the evolutionary history of the most ancient protein-coding genes. However, with limited interdomain transfer and few RNA families exhibiting demonstrable antiquity as predicted under RNA world continuity, our results indicate that the majority of modern cellular RNA repertoires have primarily evolved in a domain-specific manner.'),
(85724, 2012, 'plos', 'Reconstructing the dynamics of HIV evolution within hosts from serial deep sequence data', 'Poon, Art F Y|Swenson, Luke C|Bunnik, Evelien M|Edo-Matas, Diana|Schuitemaker, Hanneke|van t Wout, Angélique B|Harrigan, P Richard', 'BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada. apoon@cfenet.ubc.ca|BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada. apoon@cfenet.ubc.ca|BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada. apoon@cfenet.ubc.ca|BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada. apoon@cfenet.ubc.ca|BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada. apoon@cfenet.ubc.ca|BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada. apoon@cfenet.ubc.ca|BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada. apoon@cfenet.ubc.ca', 'Canada|Canada|Canada|Canada|Canada|Canada|Canada', 0, 'Algorithms|Amino Acid Sequence|Computational Biology|Evolution, Molecular|Genetic Fitness|Genotype|HIV Infections|HIV-1|High-Throughput Nucleotide Sequencing|Host-Pathogen Interactions|Humans|Molecular Sequence Data|Mutation|Phenotype|Phylogeny|RNA, Viral|Receptors, CCR5|Receptors, CXCR4', 'Journal Article', '10.1371/journal.pcbi.1002753', '23133358', 'At the early stage of infection, human immunodeficiency virus (HIV)-1 predominantly uses the CCR5 coreceptor for host cell entry. The subsequent emergence of HIV variants that use the CXCR4 coreceptor in roughly half of all infections is associated with an accelerated decline of CD4+ T-cells and rate of progression to AIDS. The presence of a fitness valley separating CCR5- and CXCR4-using genotypes is postulated to be a biological determinant of whether the HIV coreceptor switch occurs. Using phylogenetic methods to reconstruct the evolutionary dynamics of HIV within hosts enables us to discriminate between competing models of this process. We have developed a phylogenetic pipeline for the molecular clock analysis, ancestral reconstruction, and visualization of deep sequence data. These data were generated by next-generation sequencing of HIV RNA extracted from longitudinal serum samples (median 7 time points) from 8 untreated subjects with chronic HIV infections (Amsterdam Cohort Studies on HIV-1 infection and AIDS). We used the known dates of sampling to directly estimate rates of evolution and to map ancestral mutations to a reconstructed timeline in units of days. HIV coreceptor usage was predicted from reconstructed ancestral sequences using the geno2pheno algorithm. We determined that the first mutations contributing to CXCR4 use emerged about 16 (per subject range 4 to 30) months before the earliest predicted CXCR4-using ancestor, which preceded the first positive cell-based assay of CXCR4 usage by 10 (range 5 to 25) months. CXCR4 usage arose in multiple lineages within 5 of 8 subjects, and ancestral lineages following alternate mutational pathways before going extinct were common. We observed highly patient-specific distributions and time-scales of mutation accumulation, implying that the role of a fitness valley is contingent on the genotype of the transmitted variant.'),
(85725, 2012, 'plos', 'Dynamic control of selectivity in the ubiquitination pathway revealed by an ASP to GLU substitution in an intra-molecular salt-bridge network', 'van Wijk, Sjoerd J L|Melquiond, Adrien S J|de Vries, Sjoerd J|Timmers, H Th Marc|Bonvin, Alexandre M J J', 'Department of Molecular Cancer Research, Division of Biomedical Genetics and Netherlands Proteomics Center, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Molecular Cancer Research, Division of Biomedical Genetics and Netherlands Proteomics Center, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Molecular Cancer Research, Division of Biomedical Genetics and Netherlands Proteomics Center, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Molecular Cancer Research, Division of Biomedical Genetics and Netherlands Proteomics Center, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Molecular Cancer Research, Division of Biomedical Genetics and Netherlands Proteomics Center, University Medical Center Utrecht, Utrecht, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 0, 'Amino Acid Sequence|Amino Acid Substitution|Aspartic Acid|Computational Biology|Glutamic Acid|Humans|Hydrogen Bonding|Models, Molecular|Molecular Sequence Data|Protein Binding|Protein Conformation|Protein Structure, Tertiary|Reproducibility of Results|Sequence Alignment|Static Electricity|Two-Hybrid System Techniques|Ubiquitin-Conjugating Enzymes|Ubiquitin-Protein Ligases|Ubiquitination', 'Journal Article', '10.1371/journal.pcbi.1002754', '23133359', 'Ubiquitination relies on a subtle balance between selectivity and promiscuity achieved through specific interactions between ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s). Here, we report how a single aspartic to glutamic acid substitution acts as a dynamic switch to tip the selectivity balance of human E2s for interaction toward E3 RING-finger domains. By combining molecular dynamic simulations, experimental yeast-two-hybrid screen of E2-E3 (RING) interactions and mutagenesis, we reveal how the dynamics of an internal salt-bridge network at the rim of the E2-E3 interaction surface controls the balance between an open, binding competent, and a closed, binding incompetent state. The molecular dynamic simulations shed light on the fine mechanism of this molecular switch and allowed us to identify its components, namely an aspartate/glutamate pair, a lysine acting as the central switch and a remote aspartate. Perturbations of single residues in this network, both inside and outside the interaction surface, are sufficient to switch the global E2 interaction selectivity as demonstrated experimentally. Taken together, our results indicate a new mechanism to control E2-E3 interaction selectivity at an atomic level, highlighting how minimal changes in amino acid side-chain affecting the dynamics of intramolecular salt-bridges can be crucial for protein-protein interactions. These findings indicate that the widely accepted sequence-structure-function paradigm should be extended to sequence-structure-dynamics-function relationship and open new possibilities for control and fine-tuning of protein interaction selectivity.'),
(85726, 2012, 'plos', 'Determinants of translation elongation speed and ribosomal profiling biases in mouse embryonic stem cells', 'Dana, Alexandra|Tuller, Tamir', 'The Department of Biomedical Engineering, Tel-Aviv University, Tel-Aviv, Israel.|The Department of Biomedical Engineering, Tel-Aviv University, Tel-Aviv, Israel.', 'Israel|Israel', 0, 'Amino Acids|Animals|Codon|Computer Simulation|Embryonic Stem Cells|Mice|Nucleotides|Peptide Chain Elongation, Translational|RNA, Messenger|RNA, Transfer|Ribosomes|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002755', '23133360', 'Ribosomal profiling is a promising approach with increasing popularity for studying translation. This approach enables monitoring the ribosomal density along genes at a resolution of single nucleotides.In this study, we focused on ribosomal density profiles of mouse embryonic stem cells. Our analysis suggests, for the first time, that even in mammals such as M. musculus the elongation speed is significantly and directly affected by determinants of the coding sequence such as: 1) the adaptation of codons to the tRNA pool, 2) the local mRNA folding of the coding sequence, 3) the local charge of amino acids encoded in the codon sequence. In addition, our analyses suggest that in general, the translation velocity of ribosomes is slower at the beginning of the coding sequence and tends to increase downstream.Finally, a comparison of these data to the expected biophysical behavior of translation suggests that it suffers from some unknown biases. Specifically, the ribosomal flux measured on the experimental data increases along the coding sequence, however, according to any biophysical model of ribosomal movement lacking internal initiation sites, the flux is expected to remain constant or decrease. Thus, developing experimental and/or statistical methods for understanding, detecting and dealing with such biases is of high importance.'),
(85727, 2012, 'plos', 'A mathematical model of CR3/TLR2 crosstalk in the context of Francisella tularensis infection', 'Leander, Rachel|Dai, Shipan|Schlesinger, Larry S|Friedman, Avner', 'Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio, USA.|Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio, USA.|Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio, USA.|Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio, USA.', 'United States|United States|United States|United States', 0, 'Computer Simulation|Francisella tularensis|Host-Pathogen Interactions|Humans|Macrophage-1 Antigen|Macrophages|Models, Biological|Phagocytosis|Signal Transduction|Toll-Like Receptor 2|Tularemia', 'Journal Article', '10.1371/journal.pcbi.1002757', '23133361', 'Complement Receptor 3 (CR3) and Toll-like Receptor 2 (TLR2) are pattern recognition receptors expressed on the surface of human macrophages. Although these receptors are essential components for recognition by the innate immune system, pathogen coordinated crosstalk between them can suppress the production of protective cytokines and promote infection. Recognition of the virulent Schu S4 strain of the intracellular pathogen Francisella tularensis by host macrophages involves CR3/TLR2 crosstalk. Although experimental data provide evidence that Lyn kinase and PI3K are essential components of the CR3 pathway that influences TLR2 activity, additional responsible upstream signaling components remain unknown. In this paper we construct a mathematical model of CR3 and TLR2 signaling in response to F. tularensis. After demonstrating that the model is consistent with experimental results we perform numerical simulations to evaluate the contributions that Akt and Ras-GAP make to ERK inhibition. The model confirms that phagocytosis-associated changes in the composition of the cell membrane can inhibit ERK activity and predicts that Akt and Ras-GAP synergize to inhibit ERK.'),
(85728, 2012, 'plos', 'Impact of stoichiometry representation on simulation of genotype-phenotype relationships in metabolic networks', 'Brochado, Ana Rita|Andrejev, Sergej|Maranas, Costas D|Patil, Kiran R', 'Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.|Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.|Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.|Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.', 'Germany|Germany|Germany|Germany', 27, 'Algorithms|Computational Biology|Computer Simulation|Gene Regulatory Networks|Genotype|Metabolic Networks and Pathways|Models, Biological|Phenotype|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1002758', '23133362', 'Genome-scale metabolic networks provide a comprehensive structural framework for modeling genotype-phenotype relationships through flux simulations. The solution space for the metabolic flux state of the cell is typically very large and optimization-based approaches are often necessary for predicting the active metabolic state under specific environmental conditions. The objective function to be used in such optimization algorithms is directly linked with the biological hypothesis underlying the model and therefore it is one of the most relevant parameters for successful modeling. Although linear combination of selected fluxes is widely used for formulating metabolic objective functions, we show that the resulting optimization problem is sensitive towards stoichiometry representation of the metabolic network. This undesirable sensitivity leads to different simulation results when using numerically different but biochemically equivalent stoichiometry representations and thereby makes biological interpretation intrinsically subjective and ambiguous. We hereby propose a new method, Minimization of Metabolites Balance (MiMBl), which decouples the artifacts of stoichiometry representation from the formulation of the desired objective functions, by casting objective functions using metabolite turnovers rather than fluxes. By simulating perturbed metabolic networks, we demonstrate that the use of stoichiometry representation independent algorithms is fundamental for unambiguously linking modeling results with biological interpretation. For example, MiMBl allowed us to expand the scope of metabolic modeling in elucidating the mechanistic basis of several genetic interactions in Saccharomyces cerevisiae.'),
(85729, 2012, 'plos', 'Music in our ears: the biological bases of musical timbre perception', 'Patil, Kailash|Pressnitzer, Daniel|Shamma, Shihab|Elhilali, Mounya', 'Department of Electrical and Computer Engineering, Center for Language and Speech Processing, Johns Hopkins University, Baltimore, Maryland, USA.|Department of Electrical and Computer Engineering, Center for Language and Speech Processing, Johns Hopkins University, Baltimore, Maryland, USA.|Department of Electrical and Computer Engineering, Center for Language and Speech Processing, Johns Hopkins University, Baltimore, Maryland, USA.|Department of Electrical and Computer Engineering, Center for Language and Speech Processing, Johns Hopkins University, Baltimore, Maryland, USA.', 'United States|United States|United States|United States', 0, 'Acoustic Stimulation|Adult|Algorithms|Auditory Cortex|Auditory Perception|Computational Biology|Female|Humans|Judgment|Male|Models, Neurological|Music|Psychophysics|Recognition (Psychology)|Sound', 'Journal Article', '10.1371/journal.pcbi.1002759', '23133363', 'Timbre is the attribute of sound that allows humans and other animals to distinguish among different sound sources. Studies based on psychophysical judgments of musical timbre, ecological analyses of sounds physical characteristics as well as machine learning approaches have all suggested that timbre is a multifaceted attribute that invokes both spectral and temporal sound features. Here, we explored the neural underpinnings of musical timbre. We used a neuro-computational framework based on spectro-temporal receptive fields, recorded from over a thousand neurons in the mammalian primary auditory cortex as well as from simulated cortical neurons, augmented with a nonlinear classifier. The model was able to perform robust instrument classification irrespective of pitch and playing style, with an accuracy of 98.7%. Using the same front end, the model was also able to reproduce perceptual distance judgments between timbres as perceived by human listeners. The study demonstrates that joint spectro-temporal features, such as those observed in the mammalian primary auditory cortex, are critical to provide the rich-enough representation necessary to account for perceptual judgments of timbre by human listeners, as well as recognition of musical instruments.'),
(85730, 2012, 'plos', 'pH-Dependent conformational changes in proteins and their effect on experimental pK(a)s: the case of Nitrophorin 4', 'Di Russo, Natali V|Estrin, Dario A|Martí, Marcelo A|Roitberg, Adrian E', 'Quantum Theory Project and Department of Chemistry, University of Florida, Gainesville, Florida, USA.|Quantum Theory Project and Department of Chemistry, University of Florida, Gainesville, Florida, USA.|Quantum Theory Project and Department of Chemistry, University of Florida, Gainesville, Florida, USA.|Quantum Theory Project and Department of Chemistry, University of Florida, Gainesville, Florida, USA.', 'United States|United States|United States|United States', 0, 'Animals|Aspartic Acid|Computational Biology|Computer Simulation|Hemeproteins|Hydrogen-Ion Concentration|Insect Proteins|Models, Chemical|Models, Molecular|Protein Conformation|Protein Folding|Rhodnius|Salivary Proteins and Peptides', 'Journal Article', '10.1371/journal.pcbi.1002761', '23133364', 'The acid-base behavior of amino acids is an important subject of study due to their prominent role in enzyme catalysis, substrate binding and protein structure. Due to interactions with the protein environment, their pK(a)s can be shifted from their solution values and, if a protein has two stable conformations, it is possible for a residue to have different microscopic, conformation-dependent pK(a) values. In those cases, interpretation of experimental measurements of the pK(a) is complicated by the coupling between pH, protonation state and protein conformation. We explored these issues using Nitrophorin 4 (NP4), a protein that releases NO in a pH sensitive manner. At pH 5.5 NP4 is in a closed conformation where NO is tightly bound, while at pH 7.5 Asp30 becomes deprotonated, causing the conformation to change to an open state from which NO can easily escape. Using constant pH molecular dynamics we found two distinct microscopic Asp30 pK(a)s: 8.5 in the closed structure and 4.3 in the open structure. Using a four-state model, we then related the obtained microscopic values to the experimentally observed apparent pK(a), obtaining a value of 6.5, in excellent agreement with experimental data. This value must be interpreted as the pH at which the closed to open population transition takes place. More generally, our results show that it is possible to relate microscopic structure dependent pKa values to experimentally observed ensemble dependent apparent pK(a)s and that the insight gained in the relatively simple case of NP4 can be useful in several more complex cases involving a pH dependent transition, of great biochemical interest.'),
(85731, 2012, 'plos', 'Phenomenological model for predicting the catabolic potential of an arbitrary nutrient', 'Seaver, Samuel M D|Sales-Pardo, Marta|Guimerà, Roger|Amaral, Luís A Nunes', 'Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, USA.|Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, USA.|Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, USA.|Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, USA.', 'United States|United States|United States|United States', 1, 'Bacteria|Biomass|Carbon|Carbon Cycle|Computer Simulation|Metabolism|Models, Biological|Reproducibility of Results|Saccharomyces cerevisiae|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002762', '23133365', 'The ability of microbial species to consume compounds found in the environment to generate commercially-valuable products has long been exploited by humanity. The untapped, staggering diversity of microbial organisms offers a wealth of potential resources for tackling medical, environmental, and energy challenges. Understanding microbial metabolism will be crucial to many of these potential applications. Thermodynamically-feasible metabolic reconstructions can be used, under some conditions, to predict the growth rate of certain microbes using constraint-based methods. While these reconstructions are powerful, they are still cumbersome to build and, because of the complexity of metabolic networks, it is hard for researchers to gain from these reconstructions an understanding of why a certain nutrient yields a given growth rate for a given microbe. Here, we present a simple model of biomass production that accurately reproduces the predictions of thermodynamically-feasible metabolic reconstructions. Our model makes use of only: i) a nutrients structure and function, ii) the presence of a small number of enzymes in the organism, and iii) the carbon flow in pathways that catabolize nutrients. When applied to test organisms, our model allows us to predict whether a nutrient can be a carbon source with an accuracy of about 90% with respect to in silico experiments. In addition, our model provides excellent predictions of whether a medium will produce more or less growth than another (p<10(-6)) and good predictions of the actual value of the in silico biomass production.'),
(85732, 2012, 'plos', 'Mesoscopic model of actin-based propulsion', 'Zhu, Jie|Mogilner, Alex', 'Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, California, USA.|Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, California, USA.', 'United States|United States', 0, 'Actins|Computational Biology|Computer Simulation|Elastic Modulus|Microspheres|Models, Biological|Models, Molecular|Movement|Polymerization', 'Journal Article', '10.1371/journal.pcbi.1002764', '23133366', 'Two theoretical models dominate current understanding of actin-based propulsion: microscopic polymerization ratchet model predicts that growing and writhing actin filaments generate forces and movements, while macroscopic elastic propulsion model suggests that deformation and stress of growing actin gel are responsible for the propulsion. We examine both experimentally and computationally the 2D movement of ellipsoidal beads propelled by actin tails and show that neither of the two models can explain the observed bistability of the orientation of the beads. To explain the data, we develop a 2D hybrid mesoscopic model by reconciling these two models such that individual actin filaments undergoing nucleation, elongation, attachment, detachment and capping are embedded into the boundary of a node-spring viscoelastic network representing the macroscopic actin gel. Stochastic simulations of this in silico actin network show that the combined effects of the macroscopic elastic deformation and microscopic ratchets can explain the observed bistable orientation of the actin-propelled ellipsoidal beads. To test the theory further, we analyze observed distribution of the curvatures of the trajectories and show that the hybrid models predictions fit the data. Finally, we demonstrate that the model can explain both concave-up and concave-down force-velocity relations for growing actin networks depending on the characteristic time scale and network recoil. To summarize, we propose that both microscopic polymerization ratchets and macroscopic stresses of the deformable actin network are responsible for the force and movement generation.'),
(85733, 2012, 'plos', 'Structural insights into the inhibition of actin-capping protein by interactions with phosphatidic acid and phosphatidylinositol (4,5)-bisphosphate', 'Pleskot, Roman|Pejchar, Pxc5x99emysl|xc5xbdxc3xa1rskxc3xbd, Viktor|Staiger, Christopher J|Potockxc3xbd, Martin', 'Institute of Experimental Botany, Academy of Sciences of the Czech Republic, Prague, Czech Republic.|Institute of Experimental Botany, Academy of Sciences of the Czech Republic, Prague, Czech Republic.|Institute of Experimental Botany, Academy of Sciences of the Czech Republic, Prague, Czech Republic.|Institute of Experimental Botany, Academy of Sciences of the Czech Republic, Prague, Czech Republic.|Institute of Experimental Botany, Academy of Sciences of the Czech Republic, Prague, Czech Republic.', '-|-|-|-|-', 34, 'Actin Capping Proteins|Amino Acid Sequence|Animals|Arabidopsis Proteins|Avian Proteins|Chickens|Computational Biology|Hydrophobic and Hydrophilic Interactions|Models, Molecular|Molecular Sequence Data|Mutation|Phosphatidic Acids|Phosphatidylinositol Phosphates|Phylogeny|Protein Binding|Sequence Alignment|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1002765', '23133367', 'The actin cytoskeleton is a dynamic structure that coordinates numerous fundamental processes in eukaryotic cells. Dozens of actin-binding proteins are known to be involved in the regulation of actin filament organization or turnover and many of these are stimulus-response regulators of phospholipid signaling. One of these proteins is the heterodimeric actin-capping protein (CP) which binds the barbed end of actin filaments with high affinity and inhibits both addition and loss of actin monomers at this end. The ability of CP to bind filaments is regulated by signaling phospholipids, which inhibit the activity of CP, however, the exact mechanism of this regulation and the residues on CP responsible for lipid interactions is not fully resolved. Here, we focus on the interaction of CP with two signaling phospholipids, phosphatidic acid (PA) and phosphatidylinositol (4,5)-bisphosphate (PIP(2)). Using different methods of computational biology such as homology modeling, molecular docking and coarse-grained molecular dynamics, we uncovered specific modes of high affinity interaction between membranes containing PA/phosphatidylcholine (PC) and plant CP, as well as between PIP(2)/PC and animal CP. In particular, we identified differences in the binding of membrane lipids by animal and plant CP, explaining previously published experimental results. Furthermore, we pinpoint the critical importance of the C-terminal part of plant CPxcexb1 subunit for CP-membrane interactions. We prepared a GST-fusion protein for the C-terminal domain of plant xcexb1 subunit and verified this hypothesis with lipid-binding assays in vitro.'),
(85734, 2012, 'plos', 'Decorrelation of neural-network activity by inhibitory feedback', 'Tetzlaff, Tom|Helias, Moritz|Einevoll, Gaute T|Diesmann, Markus', 'Institute of Neuroscience and Medicine (INM-6), Computational and Systems Neuroscience, Research Center Jülich, Jülich, Germany. t.tetzlaff@fz-juelich.de|Institute of Neuroscience and Medicine (INM-6), Computational and Systems Neuroscience, Research Center Jülich, Jülich, Germany. t.tetzlaff@fz-juelich.de|Institute of Neuroscience and Medicine (INM-6), Computational and Systems Neuroscience, Research Center Jülich, Jülich, Germany. t.tetzlaff@fz-juelich.de|Institute of Neuroscience and Medicine (INM-6), Computational and Systems Neuroscience, Research Center Jülich, Jülich, Germany. t.tetzlaff@fz-juelich.de', 'Germany|Germany|Germany|Germany', 88, 'Action Potentials|Animals|Computer Simulation|Feedback, Physiological|Models, Neurological|Nerve Net|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002596', '23133368', 'Correlations in spike-train ensembles can seriously impair the encoding of information by their spatio-temporal structure. An inevitable source of correlation in finite neural networks is common presynaptic input to pairs of neurons. Recent studies demonstrate that spike correlations in recurrent neural networks are considerably smaller than expected based on the amount of shared presynaptic input. Here, we explain this observation by means of a linear network model and simulations of networks of leaky integrate-and-fire neurons. We show that inhibitory feedback efficiently suppresses pairwise correlations and, hence, population-rate fluctuations, thereby assigning inhibitory neurons the new role of active decorrelation. We quantify this decorrelation by comparing the responses of the intact recurrent network (feedback system) and systems where the statistics of the feedback channel is perturbed (feedforward system). Manipulations of the feedback statistics can lead to a significant increase in the power and coherence of the population response. In particular, neglecting correlations within the ensemble of feedback channels or between the external stimulus and the feedback amplifies population-rate fluctuations by orders of magnitude. The fluctuation suppression in homogeneous inhibitory networks is explained by a negative feedback loop in the one-dimensional dynamics of the compound activity. Similarly, a change of coordinates exposes an effective negative feedback loop in the compound dynamics of stable excitatory-inhibitory networks. The suppression of input correlations in finite networks is explained by the population averaged correlations in the linear network model: In purely inhibitory networks, shared-input correlations are canceled by negative spike-train correlations. In excitatory-inhibitory networks, spike-train correlations are typically positive. Here, the suppression of input correlations is not a result of the mere existence of correlations between excitatory (E) and inhibitory (I) neurons, but a consequence of a particular structure of correlations among the three possible pairings (EE, EI, II).'),
(85735, 2012, 'plos', 'Coordinated optimization of visual cortical maps (I) symmetry-based analysis', 'Reichl, Lars|Heide, Dominik|Löwel, Siegrid|Crowley, Justin C|Kaschube, Matthias|Wolf, Fred', 'Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany. reichl@nld.ds.mpg.de|Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany. reichl@nld.ds.mpg.de|Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany. reichl@nld.ds.mpg.de|Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany. reichl@nld.ds.mpg.de|Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany. reichl@nld.ds.mpg.de|Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany. reichl@nld.ds.mpg.de', 'Germany|Germany|Germany|Germany|Germany|Germany', 0, 'Animals|Biological Evolution|Brain Mapping|Computational Biology|Dominance, Ocular|Mammals|Models, Neurological|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1002466', '23144599', 'In the primary visual cortex of primates and carnivores, functional architecture can be characterized by maps of various stimulus features such as orientation preference (OP), ocular dominance (OD), and spatial frequency. It is a long-standing question in theoretical neuroscience whether the observed maps should be interpreted as optima of a specific energy functional that summarizes the design principles of cortical functional architecture. A rigorous evaluation of this optimization hypothesis is particularly demanded by recent evidence that the functional architecture of orientation columns precisely follows species invariant quantitative laws. Because it would be desirable to infer the form of such an optimization principle from the biological data, the optimization approach to explain cortical functional architecture raises the following questions: i) What are the genuine ground states of candidate energy functionals and how can they be calculated with precision and rigor? ii) How do differences in candidate optimization principles impact on the predicted map structure and conversely what can be learned about a hypothetical underlying optimization principle from observations on map structure? iii) Is there a way to analyze the coordinated organization of cortical maps predicted by optimization principles in general? To answer these questions we developed a general dynamical systems approach to the combined optimization of visual cortical maps of OP and another scalar feature such as OD or spatial frequency preference. From basic symmetry assumptions we obtain a comprehensive phenomenological classification of possible inter-map coupling energies and examine representative examples. We show that each individual coupling energy leads to a different class of OP solutions with different correlations among the maps such that inferences about the optimization principle from map layout appear viable. We systematically assess whether quantitative laws resembling experimental observations can result from the coordinated optimization of orientation columns with other feature maps.'),
(85736, 2012, 'plos', 'A graphical modelling approach to the dissection of highly correlated transcription factor binding site profiles', 'Stojnic, Robert|Fu, Audrey Qiuyan|Adryan, Boris', 'Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.|Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.|Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 3, 'Algorithms|Animals|Bayes Theorem|Binding Sites|Computational Biology|Drosophila Proteins|Drosophila melanogaster|Embryo, Nonmammalian|Mesoderm|Models, Genetic|Models, Molecular|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002725', '23144600', 'Inferring the combinatorial regulatory code of transcription factors (TFs) from genome-wide TF binding profiles is challenging. A major reason is that TF binding profiles significantly overlap and are therefore highly correlated. Clustered occurrence of multiple TFs at genomic sites may arise from chromatin accessibility and local cooperation between TFs, or binding sites may simply appear clustered if the profiles are generated from diverse cell populations. Overlaps in TF binding profiles may also result from measurements taken at closely related time intervals. It is thus of great interest to distinguish TFs that directly regulate gene expression from those that are indirectly associated with gene expression. Graphical models, in particular Bayesian networks, provide a powerful mathematical framework to infer different types of dependencies. However, existing methods do not perform well when the features (here: TF binding profiles) are highly correlated, when their association with the biological outcome is weak, and when the sample size is small. Here, we develop a novel computational method, the Neighbourhood Consistent PC (NCPC) algorithms, which deal with these scenarios much more effectively than existing methods do. We further present a novel graphical representation, the Direct Dependence Graph (DDGraph), to better display the complex interactions among variables. NCPC and DDGraph can also be applied to other problems involving highly correlated biological features. Both methods are implemented in the R package ddgraph, available as part of Bioconductor (http://bioconductor.org/packages/2.11/bioc/html/ddgraph.html). Applied to real data, our method identified TFs that specify different classes of cis-regulatory modules (CRMs) in Drosophila mesoderm differentiation. Our analysis also found depletion of the early transcription factor Twist binding at the CRMs regulating expression in visceral and somatic muscle cells at later stages, which suggests a CRM-specific repression mechanism that so far has not been characterised for this class of mesodermal CRMs.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85737, 2012, 'plos', 'Functional inference of complex anatomical tendinous networks at a macroscopic scale via sparse experimentation', 'Saxena, Anupam|Lipson, Hod|Valero-Cuevas, Francisco J', 'Faculty Building #369, Mechanical Engineering, Indian Institute of Technology, Kanpur, India.|Faculty Building #369, Mechanical Engineering, Indian Institute of Technology, Kanpur, India.|Faculty Building #369, Mechanical Engineering, Indian Institute of Technology, Kanpur, India.', 'India|India|India', 0, 'Algorithms|Biomechanical Phenomena|Computational Biology|Computer Simulation|Fingers|Humans|Models, Biological|Reproducibility of Results|Tendons', 'Journal Article', '10.1371/journal.pcbi.1002751', '23144601', 'In systems and computational biology, much effort is devoted to functional identification of systems and networks at the molecular-or cellular scale. However, similarly important networks exist at anatomical scales such as the tendon network of human fingers: the complex array of collagen fibers that transmits and distributes muscle forces to finger joints. This network is critical to the versatility of the human hand, and its function has been debated since at least the 16(th) century. Here, we experimentally infer the structure (both topology and parameter values) of this network through sparse interrogation with force inputs. A population of models representing this structure co-evolves in simulation with a population of informative future force inputs via the predator-prey estimation-exploration algorithm. Model fitness depends on their ability to explain experimental data, while the fitness of future force inputs depends on causing maximal functional discrepancy among current models. We validate our approach by inferring two known synthetic Latex networks, and one anatomical tendon network harvested from a cadavers middle finger. We find that functionally similar but structurally diverse models can exist within a narrow range of the training set and cross-validation errors. For the Latex networks, models with low training set error [<4%] and resembling the known network have the smallest cross-validation errors [xe2x88xbc5%]. The low training set [<4%] and cross validation [<7.2%] errors for models for the cadaveric specimen demonstrate what, to our knowledge, is the first experimental inference of the functional structure of complex anatomical networks. This work expands current bioinformatics inference approaches by demonstrating that sparse, yet informative interrogation of biological specimens holds significant computational advantages in accurate and efficient inference over random testing, or assuming model topology and only inferring parameters values. These findings also hold clues to both our evolutionary history and the development of versatile machines.'),
(85738, 2012, 'plos', 'Coordinated optimization of visual cortical maps (II) numerical studies', 'Reichl, Lars|Heide, Dominik|Löwel, Siegrid|Crowley, Justin C|Kaschube, Matthias|Wolf, Fred', 'Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany. reichl@nld.ds.mpg.de|Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany. reichl@nld.ds.mpg.de|Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany. reichl@nld.ds.mpg.de|Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany. reichl@nld.ds.mpg.de|Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany. reichl@nld.ds.mpg.de|Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany. reichl@nld.ds.mpg.de', 'Germany|Germany|Germany|Germany|Germany|Germany', 1, 'Animals|Brain Mapping|Computational Biology|Computer Simulation|Dominance, Ocular|Ferrets|Galago|Models, Neurological|Tupaiidae|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1002756', '23144602', 'In the juvenile brain, the synaptic architecture of the visual cortex remains in a state of flux for months after the natural onset of vision and the initial emergence of feature selectivity in visual cortical neurons. It is an attractive hypothesis that visual cortical architecture is shaped during this extended period of juvenile plasticity by the coordinated optimization of multiple visual cortical maps such as orientation preference (OP), ocular dominance (OD), spatial frequency, or direction preference. In part (I) of this study we introduced a class of analytically tractable coordinated optimization models and solved representative examples, in which a spatially complex organization of the OP map is induced by interactions between the maps. We found that these solutions near symmetry breaking threshold predict a highly ordered map layout. Here we examine the time course of the convergence towards attractor states and optima of these models. In particular, we determine the timescales on which map optimization takes place and how these timescales can be compared to those of visual cortical development and plasticity. We also assess whether our models exhibit biologically more realistic, spatially irregular solutions at a finite distance from threshold, when the spatial periodicities of the two maps are detuned and when considering more than 2 feature dimensions. We show that, although maps typically undergo substantial rearrangement, no other solutions than pinwheel crystals and stripes dominate in the emerging layouts. Pinwheel crystallization takes place on a rather short timescale and can also occur for detuned wavelengths of different maps. Our numerical results thus support the view that neither minimal energy states nor intermediate transient states of our coordinated optimization models successfully explain the architecture of the visual cortex. We discuss several alternative scenarios that may improve the agreement between model solutions and biological observations.'),
(85739, 2012, 'plos', 'Efficient communication through coherence requires oscillations structured to minimize interference between signals', 'Akam, Thomas E|Kullmann, Dimitri M', 'University of College London Institute of Neurology, London, United Kingdom. thomas.akam@neuro.fchampalimaud.org|University of College London Institute of Neurology, London, United Kingdom. thomas.akam@neuro.fchampalimaud.org', 'United Kingdom|United Kingdom', 0, 'Animals|Brain|Cell Communication|Computational Biology|Computer Simulation|Mammals|Models, Neurological|Nerve Net|Neurons', 'Journal Article', '10.1371/journal.pcbi.1002760', '23144603', 'The communication through coherence (CTC) hypothesis proposes that selective communication among neural networks is achieved by coherence between firing rate oscillation in a sending region and gain modulation in a receiving region. Although this hypothesis has stimulated extensive work, it remains unclear whether the mechanism can in principle allow reliable and selective information transfer. Here we use a simple mathematical model to investigate how accurately coherent gain modulation can filter a population-coded target signal from task-irrelevant distracting inputs. We show that selective communication can indeed be achieved, although the structure of oscillatory activity in the target and distracting networks must satisfy certain previously unrecognized constraints. Firstly, the target input must be differentiated from distractors by the amplitude, phase or frequency of its oscillatory modulation. When distracting inputs oscillate incoherently in the same frequency band as the target, communication accuracy is severely degraded because of varying overlap between the firing rate oscillations of distracting inputs and the gain modulation in the receiving region. Secondly, the oscillatory modulation of the target input must be strong in order to achieve a high signal-to-noise ratio relative to stochastic spiking of individual neurons. Thus, whilst providing a quantitative demonstration of the power of coherent oscillatory gain modulation to flexibly control information flow, our results identify constraints imposed by the need to avoid interference between signals, and reveal a likely organizing principle for the structure of neural oscillations in the brain.'),
(85740, 2012, 'plos', 'Ten simple rules to protect your intellectual property', 'Jolly, Mark|Fletcher, Anthony C|Bourne, Philip E', 'University of College London Institute of Neurology, London, United Kingdom. thomas.akam@neuro.fchampalimaud.org|University of College London Institute of Neurology, London, United Kingdom. thomas.akam@neuro.fchampalimaud.org|University of College London Institute of Neurology, London, United Kingdom. thomas.akam@neuro.fchampalimaud.org', 'United Kingdom|United Kingdom|United Kingdom', 0, 'European Union|Intellectual Property|Patents as Topic|Science|United States', 'Editorial', '10.1371/journal.pcbi.1002766', '23144604', '-'),
(85741, 2012, 'plos', 'Functional analysis of metabolic channeling and regulation in lignin biosynthesis: a computational approach', 'Lee, Yun|Escamilla-Treviño, Luis|Dixon, Richard A|Voit, Eberhard O', 'The Interdisciplinary Bioengineering Program, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.|The Interdisciplinary Bioengineering Program, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.|The Interdisciplinary Bioengineering Program, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.|The Interdisciplinary Bioengineering Program, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.', 'Georgia|Georgia|Georgia|Georgia', 21, 'Aldehydes|Caffeic Acids|Computational Biology|Computer Simulation|Enzymes|Lignin|Medicago|Metabolic Networks and Pathways|Methyltransferases|Plant Proteins|Receptors, CCR', 'Journal Article', '10.1371/journal.pcbi.1002769', '23144605', 'Lignin is a polymer in secondary cell walls of plants that is known to have negative impacts on forage digestibility, pulping efficiency, and sugar release from cellulosic biomass. While targeted modifications of different lignin biosynthetic enzymes have permitted the generation of transgenic plants with desirable traits, such as improved digestibility or reduced recalcitrance to saccharification, some of the engineered plants exhibit monomer compositions that are clearly at odds with the expected outcomes when the biosynthetic pathway is perturbed. In Medicago, such discrepancies were partly reconciled by the recent finding that certain biosynthetic enzymes may be spatially organized into two independent channels for the synthesis of guaiacyl (G) and syringyl (S) lignin monomers. Nevertheless, the mechanistic details, as well as the biological function of these interactions, remain unclear. To decipher the working principles of this and similar control mechanisms, we propose and employ here a novel computational approach that permits an expedient and exhaustive assessment of hundreds of minimal designs that could arise in vivo. Interestingly, this comparative analysis not only helps distinguish two most parsimonious mechanisms of crosstalk between the two channels by formulating a targeted and readily testable hypothesis, but also suggests that the G lignin-specific channel is more important for proper functioning than the S lignin-specific channel. While the proposed strategy of analysis in this article is tightly focused on lignin synthesis, it is likely to be of similar utility in extracting unbiased information in a variety of situations, where the spatial organization of molecular components is critical for coordinating the flow of cellular information, and where initially various control designs seem equally valid.'),
(85742, 2012, 'plos', 'Stochastic modeling of expression kinetics identifies messenger half-lives and reveals sequential waves of co-ordinated transcription and decay', 'Cacace, Filippo|Paci, Paola|Cusimano, Valerio|Germani, Alfredo|Farina, Lorenzo', 'Università Campus Biomedico, Rome, Italy.|Università Campus Biomedico, Rome, Italy.|Università Campus Biomedico, Rome, Italy.|Università Campus Biomedico, Rome, Italy.|Università Campus Biomedico, Rome, Italy.', 'Italy|Italy|Italy|Italy|Italy', 0, 'Algorithms|Computational Biology|Kinetics|Models, Genetic|Plasmodium falciparum|RNA Stability|Saccharomycetales|Stochastic Processes|Transcriptional Activation', 'Journal Article', '10.1371/journal.pcbi.1002772', '23144606', 'The transcriptome in a cell is finely regulated by a large number of molecular mechanisms able to control the balance between mRNA production and degradation. Recent experimental findings have evidenced that fine and specific regulation of degradation is needed for proper orchestration of a global cell response to environmental conditions. We developed a computational technique based on stochastic modeling, to infer condition-specific individual mRNA half-lives directly from gene expression time-courses. Predictions from our method were validated by experimentally measured mRNA decay rates during the intraerythrocytic developmental cycle of Plasmodium falciparum. We then applied our methodology to publicly available data on the reproductive and metabolic cycle of budding yeast. Strikingly, our analysis revealed, in all cases, the presence of periodic changes in decay rates of sequentially induced genes and co-ordination strategies between transcription and degradation, thus suggesting a general principle for the proper coordination of transcription and degradation machinery in response to internal and/or external stimuli.'),
(85743, 2012, 'plos', 'Distinct neurogenomic states in basal ganglia subregions relate differently to singing behavior in songbirds', 'Hilliard, Austin T|Miller, Julie E|Horvath, Steve|White, Stephanie A', 'Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA.|Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA.|Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA.|Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA.', 'United States|United States|United States|United States', 22, 'Animals|Basal Ganglia|Cluster Analysis|Computational Biology|Finches|Gene Expression|Gene Expression Profiling|Gene Regulatory Networks|Globus Pallidus|Models, Biological|Oligonucleotide Array Sequence Analysis|Singing|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002773', '23144607', 'Both avian and mammalian basal ganglia are involved in voluntary motor control. In birds, such movements include hopping, perching and flying. Two organizational features that distinguish the songbird basal ganglia are that striatal and pallidal neurons are intermingled, and that neurons dedicated to vocal-motor function are clustered together in a dense cell group known as area X that sits within the surrounding striato-pallidum. This specification allowed us to perform molecular profiling of two striato-pallidal subregions, comparing transcriptional patterns in tissue dedicated to vocal-motor function (area X) to those in tissue that contains similar cell types but supports non-vocal behaviors: the striato-pallidum ventral to area X (VSP), our focus here. Since any behavior is likely underpinned by the coordinated actions of many molecules, we constructed gene co-expression networks from microarray data to study large-scale transcriptional patterns in both subregions. Our goal was to investigate any relationship between VSP network structure and singing and identify gene co-expression groups, or modules, found in the VSP but not area X. We observed mild, but surprising, relationships between VSP modules and song spectral features, and found a group of four VSP modules that were highly specific to the region. These modules were unrelated to singing, but were composed of genes involved in many of the same biological processes as those we previously observed in area X-specific singing-related modules. The VSP-specific modules were also enriched for processes disrupted in Parkinsons and Huntingtons Diseases. Our results suggest that the activation/inhibition of a single pathway is not sufficient to functionally specify area X versus the VSP and support the notion that molecular processes are not in and of themselves specialized for behavior. Instead, unique interactions between molecular pathways create functional specificity in particular brain regions during distinct behavioral states.'),
(85744, 2012, 'plos', 'Strategy diversity stabilizes mutualism through investment cycles, phase polymorphism, and spatial bubbles', 'Boza, Gergely|Kun, Adám|Scheuring, István|Dieckmann, Ulf', 'Evolution and Ecology Program, International Institute for Applied Systems Analysis (IIASA), Laxenburg, Austria. boza@iiasa.ac.at|Evolution and Ecology Program, International Institute for Applied Systems Analysis (IIASA), Laxenburg, Austria. boza@iiasa.ac.at|Evolution and Ecology Program, International Institute for Applied Systems Analysis (IIASA), Laxenburg, Austria. boza@iiasa.ac.at|Evolution and Ecology Program, International Institute for Applied Systems Analysis (IIASA), Laxenburg, Austria. boza@iiasa.ac.at', 'Austria|Austria|Austria|Austria', 1, 'Biological Evolution|Models, Biological|Mutation|Symbiosis|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002660', '23166478', 'There is continuing interest in understanding factors that facilitate the evolution and stability of cooperation within and between species. Such interactions will often involve plasticity in investment behavior, in response to the interacting partners investments. Our aim here is to investigate the evolution and stability of reciprocal investment behavior in interspecific interactions, a key phenomenon strongly supported by experimental observations. In particular, we present a comprehensive analysis of a continuous reciprocal investment game between mutualists, both in well-mixed and spatially structured populations, and we demonstrate a series of novel mechanisms for maintaining interspecific mutualism. We demonstrate that mutualistic partners invariably follow investment cycles, during which mutualism first increases, before both partners eventually reduce their investments to zero, so that these cycles always conclude with full defection. We show that the key mechanism for stabilizing mutualism is phase polymorphism along the investment cycle. Although mutualistic partners perpetually change their strategies, the community-level distribution of investment levels becomes stationary. In spatially structured populations, the maintenance of polymorphism is further facilitated by dynamic mosaic structures, in which mutualistic partners form expanding and collapsing spatial bubbles or clusters. Additionally, we reveal strategy-diversity thresholds, both for well-mixed and spatially structured mutualistic communities, and discuss factors for meeting these thresholds, and thus maintaining mutualism. Our results demonstrate that interspecific mutualism, when considered as plastic investment behavior, can be unstable, and, in agreement with empirical observations, may involve a polymorphism of investment levels, varying both in space and in time. Identifying the mechanisms maintaining such polymorphism, and hence mutualism in natural communities, provides a significant step towards understanding the coevolution and population dynamics of mutualistic interactions.'),
(85745, 2012, 'plos', 'This Déjà vu feeling--analysis of multidomain protein evolution in eukaryotic genomes', 'Zmasek, Christian M|Godzik, Adam', 'Program in Bioinformatics and Systems Biology, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA. czmasek@sanfordburnham.org|Program in Bioinformatics and Systems Biology, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA. czmasek@sanfordburnham.org', 'United States|United States', 0, 'Animals|Eukaryota|Evolution, Molecular|Genome|Models, Biological|Phylogeny|Protein Structure, Tertiary|Proteins', 'Journal Article', '10.1371/journal.pcbi.1002701', '23166479', 'Evolutionary innovation in eukaryotes and especially animals is at least partially driven by genome rearrangements and the resulting emergence of proteins with new domain combinations, and thus potentially novel functionality. Given the random nature of such rearrangements, one could expect that proteins with particularly useful multidomain combinations may have been rediscovered multiple times by parallel evolution. However, existing reports suggest a minimal role of this phenomenon in the overall evolution of eukaryotic proteomes. We assembled a collection of 172 complete eukaryotic genomes that is not only the largest, but also the most phylogenetically complete set of genomes analyzed so far. By employing a maximum parsimony approach to compare repertoires of Pfam domains and their combinations, we show that independent evolution of domain combinations is significantly more prevalent than previously thought. Our results indicate that about 25% of all currently observed domain combinations have evolved multiple times. Interestingly, this percentage is even higher for sets of domain combinations in individual species, with, for instance, 70% of the domain combinations found in the human genome having evolved independently at least once in other species. We also show that previous, much lower estimates of this rate are most likely due to the small number and biased phylogenetic distribution of the genomes analyzed. The process of independent emergence of identical domain combination is widespread, not limited to domains with specific functional categories. Besides data from large-scale analyses, we also present individual examples of independent domain combination evolution. The surprisingly large contribution of parallel evolution to the development of the domain combination repertoire in extant genomes has profound consequences for our understanding of the evolution of pathways and cellular processes in eukaryotes and for comparative functional genomics.'),
(85746, 2012, 'plos', 'Chemotactic migration of T cells towards dendritic cells promotes the detection of rare antigens', 'Vroomans, Renske M A|Marée, Athanasius F M|de Boer, Rob J|Beltman, Joost B', 'Theoretical Biology, Utrecht University, Utrecht, The Netherlands.|Theoretical Biology, Utrecht University, Utrecht, The Netherlands.|Theoretical Biology, Utrecht University, Utrecht, The Netherlands.|Theoretical Biology, Utrecht University, Utrecht, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands', 0, 'Antigens|Cell Movement|Chemotaxis|Computer Simulation|Cytokines|Dendritic Cells|Models, Immunological|T-Lymphocytes', 'Journal Article', '10.1371/journal.pcbi.1002763', '23166480', 'In many immunological processes chemoattraction is thought to play a role in guiding cells to their sites of action. However, based on in vivo two-photon microscopy experiments in the absence of cognate antigen, T cell migration in lymph nodes (LNs) has been roughly described as a random walk. Although it has been shown that dendritic cells (DCs) carrying cognate antigen in some circumstances attract T cells chemotactically, it is currently still unclear whether chemoattraction of T cells towards DCs helps or hampers scanning. Chemoattraction towards DCs could on the one hand help T cells to rapidly find DCs. On the other hand, it could be deleterious if DCs become shielded by a multitude of attracted yet non-specific T cells. Results from a recent simulation study suggested that the deleterious effect dominates. We re-addressed the question whether T cell chemoattraction towards DCs is expected to promote or hamper the detection of rare antigens using the Cellular Potts Model, a formalism that allows for dynamic, flexible cellular shapes and cell migration. Our simulations show that chemoattraction of T cells enhances the DC scanning efficiency, leading to an increased probability that rare antigen-specific T cells find DCs carrying cognate antigen. Desensitization of T cells after contact with a DC further improves the scanning efficiency, yielding an almost threefold enhancement compared to random migration. Moreover, the chemotaxis-driven migration still roughly appears as a random walk, hence fine-tuned analysis of cell tracks will be required to detect chemotaxis within microscopy data.'),
(85747, 2012, 'plos', 'A Bayesian inference framework to reconstruct transmission trees using epidemiological and genetic data', 'Morelli, Marco J|Thébaud, Gaël|Chadœuf, Joël|King, Donald P|Haydon, Daniel T|Soubeyrand, Samuel', 'Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.|Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.|Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.|Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.|Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.|Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 71, 'Algorithms|Animals|Bayes Theorem|Cattle|Computational Biology|Computer Simulation|Disease Transmission, Infectious|Epidemics|Epidemiologic Methods|Foot-and-Mouth Disease|Models, Biological|Sheep|United Kingdom', 'Journal Article', '10.1371/journal.pcbi.1002768', '23166481', 'The accurate identification of the route of transmission taken by an infectious agent through a host population is critical to understanding its epidemiology and informing measures for its control. However, reconstruction of transmission routes during an epidemic is often an underdetermined problem: data about the location and timings of infections can be incomplete, inaccurate, and compatible with a large number of different transmission scenarios. For fast-evolving pathogens like RNA viruses, inference can be strengthened by using genetic data, nowadays easily and affordably generated. However, significant statistical challenges remain to be overcome in the full integration of these different data types if transmission trees are to be reliably estimated. We present here a framework leading to a bayesian inference scheme that combines genetic and epidemiological data, able to reconstruct most likely transmission patterns and infection dates. After testing our approach with simulated data, we apply the method to two UK epidemics of Foot-and-Mouth Disease Virus (FMDV): the 2007 outbreak, and a subset of the large 2001 epidemic. In the first case, we are able to confirm the role of a specific premise as the link between the two phases of the epidemics, while transmissions more densely clustered in space and time remain harder to resolve. When we consider data collected from the 2001 epidemic during a time of national emergency, our inference scheme robustly infers transmission chains, and uncovers the presence of undetected premises, thus providing a useful tool for epidemiological studies in real time. The generation of genetic data is becoming routine in epidemiological investigations, but the development of analytical tools maximizing the value of these data remains a priority. Our method, while applied here in the context of FMDV, is general and with slight modification can be used in any situation where both spatiotemporal and genetic data are available.'),
(85748, 2012, 'plos', 'Elastic energy storage and radial forces in the myofilament lattice depend on sarcomere length', 'Williams, C David|Regnier, Michael|Daniel, Thomas L', 'Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA. cdave@uw.edu|Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA. cdave@uw.edu|Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA. cdave@uw.edu', 'United States|United States|United States', 0, 'Biomechanical Phenomena|Computational Biology|Elasticity|Models, Biological|Myofibrils|Myosins|Sarcomeres|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002770', '23166482', 'We most often consider muscle as a motor generating force in the direction of shortening, but less often consider its roles as a spring or a brake. Here we develop a fully three-dimensional spatially explicit model of muscle to isolate the locations of forces and energies that are difficult to separate experimentally. We show the strain energy in the thick and thin filaments is less than one third the strain energy in attached cross-bridges. This result suggests the cross-bridges act as springs, storing energy within muscle in addition to generating the force which powers muscle. Comparing model estimates of energy consumed to elastic energy stored, we show that the ratio of these two properties changes with sarcomere length. The model predicts storage of a greater fraction of energy at short sarcomere lengths, suggesting a mechanism by which muscle function shifts as force production declines, from motor to spring. Additionally, we investigate the force that muscle produces in the radial or transverse direction, orthogonal to the direction of shortening. We confirm prior experimental estimates that place radial forces on the same order of magnitude as axial forces, although we find that radial forces and axial forces vary differently with changes in sarcomere length.'),
(85749, 2012, 'plos', 'Sensorimotor learning biases choice behavior: a learning neural field model for decision making', 'Klaes, Christian|Schneegans, Sebastian|Schöner, Gregor|Gail, Alexander', 'Bernstein Center for Computational Neuroscience, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany.|Bernstein Center for Computational Neuroscience, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany.|Bernstein Center for Computational Neuroscience, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany.|Bernstein Center for Computational Neuroscience, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany.', 'Germany|Germany|Germany|Germany', 0, 'Animals|Association Learning|Brain Mapping|Choice Behavior|Computational Biology|Computer Simulation|Decision Making|Electroencephalography|Haplorhini|Models, Neurological|Reward', 'Journal Article', '10.1371/journal.pcbi.1002774', '23166483', 'According to a prominent view of sensorimotor processing in primates, selection and specification of possible actions are not sequential operations. Rather, a decision for an action emerges from competition between different movement plans, which are specified and selected in parallel. For action choices which are based on ambiguous sensory input, the frontoparietal sensorimotor areas are considered part of the common underlying neural substrate for selection and specification of action. These areas have been shown capable of encoding alternative spatial motor goals in parallel during movement planning, and show signatures of competitive value-based selection among these goals. Since the same network is also involved in learning sensorimotor associations, competitive action selection (decision making) should not only be driven by the sensory evidence and expected reward in favor of either action, but also by the subjects learning history of different sensorimotor associations. Previous computational models of competitive neural decision making used predefined associations between sensory input and corresponding motor output. Such hard-wiring does not allow modeling of how decisions are influenced by sensorimotor learning or by changing reward contingencies. We present a dynamic neural field model which learns arbitrary sensorimotor associations with a reward-driven Hebbian learning algorithm. We show that the model accurately simulates the dynamics of action selection with different reward contingencies, as observed in monkey cortical recordings, and that it correctly predicted the pattern of choice errors in a control experiment. With our adaptive model we demonstrate how network plasticity, which is required for association learning and adaptation to new reward contingencies, can influence choice behavior. The field model provides an integrated and dynamic account for the operations of sensorimotor integration, working memory and action selection required for decision making in ambiguous choice situations.'),
(85750, 2012, 'plos', 'Functional connectivity and tuning curves in populations of simultaneously recorded neurons', 'Stevenson, Ian H|London, Brian M|Oby, Emily R|Sachs, Nicholas A|Reimer, Jacob|Englitz, Bernhard|David, Stephen V|Shamma, Shihab A|Blanche, Timothy J|Mizuseki, Kenji|Zandvakili, Amin|Hatsopoulos, Nicholas G|Miller, Lee E|Kording, Konrad P', 'Redwood Center for Theoretical Neuroscience, University of California, Berkeley, Berkeley, CA, USA. i-stevenson@berkeley.edu|Redwood Center for Theoretical Neuroscience, University of California, Berkeley, Berkeley, CA, USA. i-stevenson@berkeley.edu|Redwood Center for Theoretical Neuroscience, University of California, Berkeley, Berkeley, CA, USA. i-stevenson@berkeley.edu|Redwood Center for Theoretical Neuroscience, University of California, Berkeley, Berkeley, CA, USA. i-stevenson@berkeley.edu|Redwood Center for Theoretical Neuroscience, University of California, Berkeley, Berkeley, CA, USA. i-stevenson@berkeley.edu|Redwood Center for Theoretical Neuroscience, University of California, Berkeley, Berkeley, CA, USA. i-stevenson@berkeley.edu|Redwood Center for Theoretical Neuroscience, University of California, Berkeley, Berkeley, CA, USA. i-stevenson@berkeley.edu|Redwood Center for Theoretical Neuroscience, University of California, Berkeley, Berkeley, CA, USA. i-stevenson@berkeley.edu|Redwood Center for Theoretical Neuroscience, University of California, Berkeley, Berkeley, CA, USA. i-stevenson@berkeley.edu|Redwood Center for Theoretical Neuroscience, University of California, Berkeley, Berkeley, CA, USA. i-stevenson@berkeley.edu|Redwood Center for Theoretical Neuroscience, University of California, Berkeley, Berkeley, CA, USA. i-stevenson@berkeley.edu|Redwood Center for Theoretical Neuroscience, University of California, Berkeley, Berkeley, CA, USA. i-stevenson@berkeley.edu|Redwood Center for Theoretical Neuroscience, University of California, Berkeley, Berkeley, CA, USA. i-stevenson@berkeley.edu|Redwood Center for Theoretical Neuroscience, University of California, Berkeley, Berkeley, CA, USA. i-stevenson@berkeley.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|United States', 0, 'Action Potentials|Animals|Brain|Computational Biology|Computer Simulation|Databases, Factual|Electrodes|Electrophysiology|Macaca|Models, Neurological|Models, Statistical|Nerve Net|Neurons', 'Journal Article', '10.1371/journal.pcbi.1002775', '23166484', 'How interactions between neurons relate to tuned neural responses is a longstanding question in systems neuroscience. Here we use statistical modeling and simultaneous multi-electrode recordings to explore the relationship between these interactions and tuning curves in six different brain areas. We find that, in most cases, functional interactions between neurons provide an explanation of spiking that complements and, in some cases, surpasses the influence of canonical tuning curves. Modeling functional interactions improves both encoding and decoding accuracy by accounting for noise correlations and features of the external world that tuning curves fail to capture. In cortex, modeling coupling alone allows spikes to be predicted more accurately than tuning curve models based on external variables. These results suggest that statistical models of functional interactions between even relatively small numbers of neurons may provide a useful framework for examining neural coding.'),
(85751, 2012, 'plos', 'The dominant folding route minimizes backbone distortion in SH3', 'Lammert, Heiko|Noel, Jeffrey K|Onuchic, José N', 'Center for Theoretical Biological Physics and Department of Physics, Rice University, Houston, TX, USA.|Center for Theoretical Biological Physics and Department of Physics, Rice University, Houston, TX, USA.|Center for Theoretical Biological Physics and Department of Physics, Rice University, Houston, TX, USA.', 'United States|United States|United States', 16, 'Computational Biology|Entropy|Models, Chemical|Models, Molecular|Protein Folding|Proteins|src Homology Domains', 'Journal Article', '10.1371/journal.pcbi.1002776', '23166485', 'Energetic frustration in protein folding is minimized by evolution to create a smooth and robust energy landscape. As a result the geometry of the native structure provides key constraints that shape protein folding mechanisms. Chain connectivity in particular has been identified as an essential component for realistic behavior of protein folding models. We study the quantitative balance of energetic and geometrical influences on the folding of SH3 in a structure-based model with minimal energetic frustration. A decomposition of the two-dimensional free energy landscape for the folding reaction into relevant energy and entropy contributions reveals that the entropy of the chain is not responsible for the folding mechanism. Instead the preferred folding route through the transition state arises from a cooperative energetic effect. Off-pathway structures are penalized by excess distortion in local backbone configurations and contact pair distances. This energy cost is a new ingredient in the malleable balance of interactions that controls the choice of routes during protein folding.'),
(85752, 2012, 'plos', 'The origin of minus-end directionality and mechanochemistry of Ncd motors', 'Jana, Biman|Hyeon, Changbong|Onuchic, Josxc3xa9 N', 'Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.|Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.|Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.', 'United States|United States|United States', 0, 'Adenosine Diphosphate|Adenosine Triphosphate|Binding Sites|Biomechanical Phenomena|Computational Biology|Computer Simulation|Kinesin|Models, Chemical|Models, Molecular|Principal Component Analysis|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1002783', '23166486', 'Adaptation of molecular structure to the ligand chemistry and interaction with the cytoskeletal filament are key to understanding the mechanochemistry of molecular motors. Despite the striking structural similarity with kinesin-1, which moves towards plus-end, Ncd motors exhibit minus-end directionality on microtubules (MTs). Here, by employing a structure-based model of protein folding, we show that a simple repositioning of the neck-helix makes the dynamics of Ncd non-processive and minus-end directed as opposed to kinesin-1. Our computational model shows that Ncd in solution can have both symmetric and asymmetric conformations with disparate ADP binding affinity, also revealing that there is a strong correlation between distortion of motor head and decrease in ADP binding affinity in the asymmetric state. The nucleotide (NT) free-ADP (xcfx86-ADP) state bound to MTs favors the symmetric conformation whose coiled-coil stalk points to the plus-end. Upon ATP binding, an enhanced flexibility near the head-neck junction region, which we have identified as the important structural element for directional motility, leads to reorienting the coiled-coil stalk towards the minus-end by stabilizing the asymmetric conformation. The minus-end directionality of the Ncd motor is a remarkable example that demonstrates how motor proteins in the kinesin superfamily diversify their functions by simply rearranging the structural elements peripheral to the catalytic motor head domain.'),
(85753, 2012, 'plos', 'The role of exposure history on HIV acquisition: insights from repeated low-dose challenge studies', 'Regoes, Roland R', 'Integrative Biology, ETH Zurich, Zurich, Switzerland. roland.regoes@env.ethz.ch', 'Switzerland', 0, 'AIDS Vaccines|Animals|Computational Biology|Databases, Factual|Disease Models, Animal|Disease Susceptibility|HIV Infections|Immunization|Macaca|Models, Biological|Simian Acquired Immunodeficiency Syndrome|Simian Immunodeficiency Virus|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002767', '23180981', 'To assess the efficacy of HIV vaccine candidates or preventive treatment, many research groups have started to challenge monkeys repeatedly with low doses of the virus. Such challenge data provide a unique opportunity to assess the importance of exposure history for the acquisition of the infection. I developed stochastic models to analyze previously published challenge data. In the mathematical models, I allowed for variation of the animals susceptibility to infection across challenge repeats, or across animals. In none of the studies I analyzed, I found evidence for an immunizing effect of non-infecting challenges, and in most studies, there is no evidence for variation in the susceptibilities to the challenges across animals. A notable exception was a challenge experiment by Letvin et al. Sci Translat Med (2011) conducted with the strain SIVsmE660. The challenge data of this experiment showed significant susceptibility variation from animal-to-animal, which is consistent with previously established genetic differences between the involved animals. For the studies which did not show significant immunizing effects and susceptibility differences, I conducted a power analysis and could thus exclude a very strong immunization effect for some of the studies. These findings validate the assumption that non-infecting challenges do not immunize an animal - an assumption that is central in the argument that repeated low-dose challenge experiments increase the statistical power of preclinical HIV vaccine trials. They are also relevant for our understanding of the role of exposure history for HIV acquisition and forecasting the epidemiological spread of HIV.'),
(85754, 2012, 'plos', 'Internal representations of temporal statistics and feedback calibrate motor-sensory interval timing', 'Acerbi, Luigi|Wolpert, Daniel M|Vijayakumar, Sethu', 'Institute of Perception, Action and Behaviour, School of Informatics, University of Edinburgh, Edinburgh, United Kingdom. L.Acerbi@sms.ed.ac.uk|Institute of Perception, Action and Behaviour, School of Informatics, University of Edinburgh, Edinburgh, United Kingdom. L.Acerbi@sms.ed.ac.uk|Institute of Perception, Action and Behaviour, School of Informatics, University of Edinburgh, Edinburgh, United Kingdom. L.Acerbi@sms.ed.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 66, 'Bayes Theorem|Feedback, Sensory|Humans|Models, Biological|Psychomotor Performance|Statistics, Nonparametric|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1002771', '23209386', 'Humans have been shown to adapt to the temporal statistics of timing tasks so as to optimize the accuracy of their responses, in agreement with the predictions of Bayesian integration. This suggests that they build an internal representation of both the experimentally imposed distribution of time intervals (the prior) and of the error (the loss function). The responses of a Bayesian ideal observer depend crucially on these internal representations, which have only been previously studied for simple distributions. To study the nature of these representations we asked subjects to reproduce time intervals drawn from underlying temporal distributions of varying complexity, from uniform to highly skewed or bimodal while also varying the error mapping that determined the performance feedback. Interval reproduction times were affected by both the distribution and feedback, in good agreement with a performance-optimizing Bayesian observer and actor model. Bayesian model comparison highlighted that subjects were integrating the provided feedback and represented the experimental distribution with a smoothed approximation. A nonparametric reconstruction of the subjective priors from the data shows that they are generally in agreement with the true distributions up to third-order moments, but with systematically heavier tails. In particular, higher-order statistical features (kurtosis, multimodality) seem much harder to acquire. Our findings suggest that humans have only minor constraints on learning lower-order statistical properties of unimodal (including peaked and skewed) distributions of time intervals under the guidance of corrective feedback, and that their behavior is well explained by Bayesian decision theory.'),
(85755, 2012, 'plos', 'Molecular basis of calcium-sensitizing and desensitizing mutations of the human cardiac troponin C regulatory domain: a multi-scale simulation study', 'Kekenes-Huskey, Peter Michael|Lindert, Steffen|McCammon, James Andrew', 'Department of Pharmacology, Center for Theoretical Biological Physics, National Computational Biomedical Resource and Howard Hughes Medical Institute, University of California San Diego, La Jolla, California, United States of America. pkekeneshuskey@ucsd.edu|Department of Pharmacology, Center for Theoretical Biological Physics, National Computational Biomedical Resource and Howard Hughes Medical Institute, University of California San Diego, La Jolla, California, United States of America. pkekeneshuskey@ucsd.edu|Department of Pharmacology, Center for Theoretical Biological Physics, National Computational Biomedical Resource and Howard Hughes Medical Institute, University of California San Diego, La Jolla, California, United States of America. pkekeneshuskey@ucsd.edu', 'United States|United States|United States', 0, 'Binding Sites|Calcium|Computational Biology|Humans|Molecular Dynamics Simulation|Mutation|Protein Structure, Tertiary|Troponin C', 'Journal Article', '10.1371/journal.pcbi.1002777', '23209387', 'Troponin C (TnC) is implicated in the initiation of myocyte contraction via binding of cytosolic Caxc2xb2xe2x81xba and subsequent recognition of the Troponin I switch peptide. Mutations of the cardiac TnC N-terminal regulatory domain have been shown to alter both calcium binding and myofilament force generation. We have performed molecular dynamics simulations of engineered TnC variants that increase or decrease Caxc2xb2xe2x81xba sensitivity, in order to understand the structural basis of their impact on TnC function. We will use the distinction for mutants that are associated with increased Caxc2xb2xe2x81xba affinity and for those mutants with reduced affinity. Our studies demonstrate that for GOF mutants V44Q and L48Q, the structure of the physiologically-active site II Caxc2xb2xe2x81xba binding site in the Caxc2xb2xe2x81xba-free (apo) state closely resembled the Caxc2xb2xe2x81xba-bound (holo) state. In contrast, site II is very labile for LOF mutants E40A and V79Q in the apo form and bears little resemblance with the holo conformation. We hypothesize that these phenomena contribute to the increased association rate, k(on), for the GOF mutants relative to LOF. Furthermore, we observe significant positive and negative positional correlations between helices in the GOF holo mutants that are not found in the LOF mutants. We anticipate these correlations may contribute either directly to Caxc2xb2xe2x81xba affinity or indirectly through TnI association. Our observations based on the structure and dynamics of mutant TnC provide rationale for binding trends observed in GOF and LOF mutants and will guide the development of inotropic drugs that target TnC.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85756, 2012, 'plos', 'Phase resetting reveals network dynamics underlying a bacterial cell cycle', 'Lin, Yihan|Li, Ying|Crosson, Sean|Dinner, Aaron R|Scherer, Norbert F', 'Department of Chemistry, University of Chicago, Chicago, Illinois, United States of America.|Department of Chemistry, University of Chicago, Chicago, Illinois, United States of America.|Department of Chemistry, University of Chicago, Chicago, Illinois, United States of America.|Department of Chemistry, University of Chicago, Chicago, Illinois, United States of America.|Department of Chemistry, University of Chicago, Chicago, Illinois, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Bacterial Proteins|Caulobacter crescentus|Cell Cycle|DNA-Binding Proteins|Models, Biological|Mutation|Systems Biology|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002778', '23209388', 'Genomic and proteomic methods yield networks of biological regulatory interactions but do not provide direct insight into how those interactions are organized into functional modules, or how information flows from one module to another. In this work we introduce an approach that provides this complementary information and apply it to the bacterium Caulobacter crescentus, a paradigm for cell-cycle control. Operationally, we use an inducible promoter to express the essential transcriptional regulatory gene ctrA in a periodic, pulsed fashion. This chemical perturbation causes the population of cells to divide synchronously, and we use the resulting advance or delay of the division times of single cells to construct a phase resetting curve. We find that delay is strongly favored over advance. This finding is surprising since it does not follow from the temporal expression profile of CtrA and, in turn, simulations of existing network models. We propose a phenomenological model that suggests that the cell-cycle network comprises two distinct functional modules that oscillate autonomously and couple in a highly asymmetric fashion. These features collectively provide a new mechanism for tight temporal control of the cell cycle in C. crescentus. We discuss how the procedure can serve as the basis for a general approach for probing network dynamics, which we term chemical perturbation spectroscopy (CPS).'),
(85757, 2012, 'plos', 'Bioinformatics for the Human Microbiome Project', 'Gevers, Dirk|Pop, Mihai|Schloss, Patrick D|Huttenhower, Curtis', 'The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. dgevers@broadinstitute.org|The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. dgevers@broadinstitute.org|The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. dgevers@broadinstitute.org|The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. dgevers@broadinstitute.org', 'United States|United States|United States|United States', 0, 'Computational Biology|Database Management Systems|Databases, Factual|Humans|Metagenome|Metagenomics', 'Journal Article', '10.1371/journal.pcbi.1002779', '23209389', '-'),
(85758, 2012, 'plos', 'Temporal expression-based analysis of metabolism', 'Collins, Sara B|Reznik, Ed|Segrxc3xa8, Daniel', 'Program in Bioinformatics, Boston University, Boston, Massachusetts, United States of America.|Program in Bioinformatics, Boston University, Boston, Massachusetts, United States of America.|Program in Bioinformatics, Boston University, Boston, Massachusetts, United States of America.', 'United States|United States|United States', 28, 'Acetates|Algorithms|Kinetics|Metabolism|Models, Biological|Pyruvic Acid|Reproducibility of Results|Sensitivity and Specificity|Shewanella|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002781', '23209390', 'Metabolic flux is frequently rerouted through cellular metabolism in response to dynamic changes in the intra- and extra-cellular environment. Capturing the mechanisms underlying these metabolic transitions in quantitative and predictive models is a prominent challenge in systems biology. Progress in this regard has been made by integrating high-throughput gene expression data into genome-scale stoichiometric models of metabolism. Here, we extend previous approaches to perform a Temporal Expression-based Analysis of Metabolism (TEAM). We apply TEAM to understanding the complex metabolic dynamics of the respiratorily versatile bacterium Shewanella oneidensis grown under aerobic, lactate-limited conditions. TEAM predicts temporal metabolic flux distributions using time-series gene expression data. Increased predictive power is achieved by supplementing these data with a large reference compendium of gene expression, which allows us to take into account the unique character of the distribution of expression of each individual gene. We further propose a straightforward method for studying the sensitivity of TEAM to changes in its fundamental free threshold parameter xcexb8, and reveal that discrete zones of distinct metabolic behavior arise as this parameter is changed. By comparing the qualitative characteristics of these zones to additional experimental data, we are able to constrain the range of xcexb8 to a small, well-defined interval. In parallel, the sensitivity analysis reveals the inherently difficult nature of dynamic metabolic flux modeling: small errors early in the simulation propagate to relatively large changes later in the simulation. We expect that handling such history-dependent sensitivities will be a major challenge in the future development of dynamic metabolic-modeling techniques.'),
(85759, 2012, 'plos', 'Kinetics of amyloid aggregation: a study of the GNNQQNY prion sequence', 'Nasica-Labouze, Jessica|Mousseau, Normand', 'Dxc3xa9partement de Physique and Gxc3x89PROM, Universitxc3xa9 de Montrxc3xa9al, Montrxc3xa9al, Quxc3xa9bec, Canada. jessica.nasica-labouze@umontreal.ca|Dxc3xa9partement de Physique and Gxc3x89PROM, Universitxc3xa9 de Montrxc3xa9al, Montrxc3xa9al, Quxc3xa9bec, Canada. jessica.nasica-labouze@umontreal.ca', 'Canada|Canada', 0, 'Amino Acid Sequence|Amyloid|Biochemical Phenomena|Computational Biology|Kinetics|Molecular Dynamics Simulation|Oligopeptides', 'Journal Article', '10.1371/journal.pcbi.1002782', '23209391', 'The small amyloid-forming GNNQQNY fragment of the prion sequence has been the subject of extensive experimental and numerical studies over the last few years. Using unbiased molecular dynamics with the OPEP coarse-grained potential, we focus here on the onset of aggregation in a 20-mer system. With a total of 16.9 xcexbcs of simulations at 280 K and 300 K, we show that the GNNQQNY aggregation follows the classical nucleation theory (CNT) in that the number of monomers in the aggregate is a very reliable descriptor of aggregation. We find that the critical nucleus size in this finite-size system is between 4 and 5 monomers at 280 K and 5 and 6 at 300 K, in overall agreement with experiment. The kinetics of growth cannot be fully accounted for by the CNT, however. For example, we observe considerable rearrangements after the nucleus is formed, as the system attempts to optimize its organization. We also clearly identify two large families of structures that are selected at the onset of aggregation demonstrating the presence of well-defined polymorphism, a signature of amyloid growth, already in the 20-mer aggregate.'),
(85760, 2012, 'plos', 'The ortholog conjecture is untestable by the current gene ontology but is supported by RNA sequencing data', 'Chen, Xiaoshu|Zhang, Jianzhi', 'Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America.', 'United States|United States', 40, 'Animals|Female|Gene Expression Profiling|Genes|Genomics|Humans|Liver|Male|Mice|Molecular Sequence Annotation|Oligonucleotide Array Sequence Analysis|Proteins|Sequence Analysis, RNA', 'Journal Article', '10.1371/journal.pcbi.1002784', '23209392', 'The ortholog conjecture posits that orthologous genes are functionally more similar than paralogous genes. This conjecture is a cornerstone of phylogenomics and is used daily by both computational and experimental biologists in predicting, interpreting, and understanding gene functions. A recent study, however, challenged the ortholog conjecture on the basis of experimentally derived Gene Ontology (GO) annotations and microarray gene expression data in human and mouse. It instead proposed that the functional similarity of homologous genes is primarily determined by the cellular context in which the genes act, explaining why a greater functional similarity of (within-species) paralogs than (between-species) orthologs was observed. Here we show that GO-based functional similarity between human and mouse orthologs, relative to that between paralogs, has been increasing in the last five years. Further, compared with paralogs, orthologs are less likely to be included in the same study, causing an underestimation in their functional similarity. A close examination of functional studies of homologs with identical protein sequences reveals experimental biases, annotation errors, and homology-based functional inferences that are labeled in GO as experimental. These problems and the temporary nature of the GO-based finding make the current GO inappropriate for testing the ortholog conjecture. RNA sequencing (RNA-Seq) is known to be superior to microarray for comparing the expressions of different genes or in different species. Our analysis of a large RNA-Seq dataset of multiple tissues from eight mammals and the chicken shows that the expression similarity between orthologs is significantly higher than that between within-species paralogs, supporting the ortholog conjecture and refuting the cellular context hypothesis for gene expression. We conclude that the ortholog conjecture remains largely valid to the extent that it has been tested, but further scrutiny using more and better functional data is needed.'),
(85761, 2012, 'plos', 'Universal pacemaker of genome evolution', 'Snir, Sagi|Wolf, Yuri I|Koonin, Eugene V', 'Department of Evolutionary and Environmental Biology and The Institute of Evolution, University of Haifa Mount Carmel, Haifa, Israel.|Department of Evolutionary and Environmental Biology and The Institute of Evolution, University of Haifa Mount Carmel, Haifa, Israel.|Department of Evolutionary and Environmental Biology and The Institute of Evolution, University of Haifa Mount Carmel, Haifa, Israel.', 'Israel|Israel|Israel', 0, 'Computational Biology|Evolution, Molecular|Genome, Archaeal|Genome, Bacterial|Least-Squares Analysis|Models, Genetic|Phylogeny', 'Journal Article', '10.1371/journal.pcbi.1002785', '23209393', 'A fundamental observation of comparative genomics is that the distribution of evolution rates across the complete sets of orthologous genes in pairs of related genomes remains virtually unchanged throughout the evolution of life, from bacteria to mammals. The most straightforward explanation for the conservation of this distribution appears to be that the relative evolution rates of all genes remain nearly constant, or in other words, that evolutionary rates of different genes are strongly correlated within each evolving genome. This correlation could be explained by a model that we denoted Universal PaceMaker (UPM) of genome evolution. The UPM model posits that the rate of evolution changes synchronously across genome-wide sets of genes in all evolving lineages. Alternatively, however, the correlation between the evolutionary rates of genes could be a simple consequence of molecular clock (MC). We sought to differentiate between the MC and UPM models by fitting thousands of phylogenetic trees for bacterial and archaeal genes to supertrees that reflect the dominant trend of vertical descent in the evolution of archaea and bacteria and that were constrained according to the two models. The goodness of fit for the UPM model was better than the fit for the MC model, with overwhelming statistical significance, although similarly to the MC, the UPM is strongly overdispersed. Thus, the results of this analysis reveal a universal, genome-wide pacemaker of evolution that could have been in operation throughout the history of life.'),
(85762, 2012, 'plos', 'How random is social behaviour? Disentangling social complexity through the study of a wild house mouse population', 'Perony, Nicolas|Tessone, Claudio J|König, Barbara|Schweitzer, Frank', 'Chair of Systems Design, ETH Zurich, Zurich, Switzerland. nperony@ethz.ch|Chair of Systems Design, ETH Zurich, Zurich, Switzerland. nperony@ethz.ch|Chair of Systems Design, ETH Zurich, Zurich, Switzerland. nperony@ethz.ch|Chair of Systems Design, ETH Zurich, Zurich, Switzerland. nperony@ethz.ch', 'Switzerland|Switzerland|Switzerland|Switzerland', 17, 'Animals|Behavior, Animal|Computational Biology|Female|Male|Mice|Models, Biological|Social Behavior|Spatial Behavior|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002786', '23209394', 'Out of all the complex phenomena displayed in the behaviour of animal groups, many are thought to be emergent properties of rather simple decisions at the individual level. Some of these phenomena may also be explained by random processes only. Here we investigate to what extent the interaction dynamics of a population of wild house mice (Mus domesticus) in their natural environment can be explained by a simple stochastic model. We first introduce the notion of perceptual landscape, a novel tool used here to describe the utilisation of space by the mouse colony based on the sampling of individuals in discrete locations. We then implement the behavioural assumptions of the perceptual landscape in a multi-agent simulation to verify their accuracy in the reproduction of observed social patterns. We find that many high-level features--with the exception of territoriality--of our behavioural dataset can be accounted for at the population level through the use of this simplified representation. Our findings underline the potential importance of random factors in the apparent complexity of the mices social structure. These results resonate in the general context of adaptive behaviour versus elementary environmental interactions.'),
(85763, 2012, 'plos', 'Weakly circadian cells improve resynchrony', 'Webb, Alexis B|Taylor, Stephanie R|Thoroughman, Kurt A|Doyle, Francis J|Herzog, Erik D', 'Department of Biology, Washington University, St. Louis, Missouri, United States of America.|Department of Biology, Washington University, St. Louis, Missouri, United States of America.|Department of Biology, Washington University, St. Louis, Missouri, United States of America.|Department of Biology, Washington University, St. Louis, Missouri, United States of America.|Department of Biology, Washington University, St. Louis, Missouri, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Animals|Cells, Cultured|Circadian Clocks|Computational Biology|Mice|Models, Neurological|Neurons|Suprachiasmatic Nucleus', 'Journal Article', '10.1371/journal.pcbi.1002787', '23209395', 'The mammalian suprachiasmatic nuclei (SCN) contain thousands of neurons capable of generating near 24-h rhythms. When isolated from their network, SCN neurons exhibit a range of oscillatory phenotypes: sustained or damping oscillations, or arrhythmic patterns. The implications of this variability are unknown. Experimentally, we found that cells within SCN explants recover from pharmacologically-induced desynchrony by re-establishing rhythmicity and synchrony in waves, independent of their intrinsic circadian period We therefore hypothesized that a cells location within the network may also critically determine its resynchronization. To test this, we employed a deterministic, mechanistic model of circadian oscillators where we could independently control cell-intrinsic and network-connectivity parameters. We found that small changes in key parameters produced the full range of oscillatory phenotypes seen in biological cells, including similar distributions of period, amplitude and ability to cycle. The model also predicted that weaker oscillators could adjust their phase more readily than stronger oscillators. Using these model cells we explored potential biological consequences of their number and placement within the network. We found that the population synchronized to a higher degree when weak oscillators were at highly connected nodes within the network. A mathematically independent phase-amplitude model reproduced these findings. Thus, small differences in cell-intrinsic parameters contribute to large changes in the oscillatory ability of a cell, but the location of weak oscillators within the network also critically shapes the degree of synchronization for the population.'),
(85764, 2012, 'plos', 'Reconstructing mammalian sleep dynamics with data assimilation', 'Sedigh-Sarvestani, Madineh|Schiff, Steven J|Gluckman, Bruce J', 'Center for Neural Engineering, Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, Pennsylvania, United States of America. m.sedigh.sarvestani@gmail.com|Center for Neural Engineering, Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, Pennsylvania, United States of America. m.sedigh.sarvestani@gmail.com|Center for Neural Engineering, Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, Pennsylvania, United States of America. m.sedigh.sarvestani@gmail.com', 'United States|United States|United States', 21, 'Algorithms|Animals|Computational Biology|Computer Simulation|Models, Biological|Rats|Sleep|Wakefulness', 'Journal Article', '10.1371/journal.pcbi.1002788', '23209396', 'Data assimilation is a valuable tool in the study of any complex system, where measurements are incomplete, uncertain, or both. It enables the user to take advantage of all available information including experimental measurements and short-term model forecasts of a system. Although data assimilation has been used to study other biological systems, the study of the sleep-wake regulatory network has yet to benefit from this toolset. We present a data assimilation framework based on the unscented Kalman filter (UKF) for combining sparse measurements together with a relatively high-dimensional nonlinear computational model to estimate the state of a model of the sleep-wake regulatory system. We demonstrate with simulation studies that a few noisy variables can be used to accurately reconstruct the remaining hidden variables. We introduce a metric for ranking relative partial observability of computational models, within the UKF framework, that allows us to choose the optimal variables for measurement and also provides a methodology for optimizing framework parameters such as UKF covariance inflation. In addition, we demonstrate a parameter estimation method that allows us to track non-stationary model parameters and accommodate slow dynamics not included in the UKF filter model. Finally, we show that we can even use observed discretized sleep-state, which is not one of the model variables, to reconstruct model state and estimate unknown parameters. Sleep is implicated in many neurological disorders from epilepsy to schizophrenia, but simultaneous observation of the many brain components that regulate this behavior is difficult. We anticipate that this data assimilation framework will enable better understanding of the detailed interactions governing sleep and wake behavior and provide for better, more targeted, therapies.'),
(85765, 2012, 'plos', 'Simulations of long-term community dynamics in coral reefs--how perturbations shape trajectories', 'Kubicek, Andreas|Muhando, Christopher|Reuter, Hauke', 'Leibniz Center for Tropical Marine Ecology, Bremen, Germany. andreas.kubicek@zmt-bremen.de|Leibniz Center for Tropical Marine Ecology, Bremen, Germany. andreas.kubicek@zmt-bremen.de|Leibniz Center for Tropical Marine Ecology, Bremen, Germany. andreas.kubicek@zmt-bremen.de', 'Germany|Germany|Germany', 0, 'Animals|Anthozoa|Chlorophyta|Computational Biology|Coral Reefs|Ecosystem|Microalgae|Models, Biological|Population Dynamics|Tanzania|Temperature', 'Journal Article', '10.1371/journal.pcbi.1002791', '23209397', 'Tropical coral reefs feature extraordinary biodiversity and high productivity rates in oligotrophic waters. Due to increasing frequencies of perturbations--anthropogenic and natural--many reefs are under threat. Such perturbations often have devastating effects on these unique ecosystems and especially if they occur simultaneously and amplify each others impact, they might trigger a phase shift and create irreversible conditions.We developed a generic, spatially explicit, individual-based model in which competition drives the dynamics of a virtual benthic reef community--comprised of scleractinian corals and algae--under different environmental settings. Higher system properties, like population dynamics or community composition arise through self-organization as emergent properties. The model was parameterized for a typical coral reef site at Zanzibar, Tanzania and features coral bleaching and physical disturbance regimes as major sources of perturbations. Our results show that various types and modes (intensities and frequencies) of perturbations create diverse outcomes and that the switch from high diversity to single species dominance can be evoked by small changes in a key parameter. Here we extend the understanding of coral reef resilience and the identification of key processes, drivers and respective thresholds, responsible for changes in local situations. One future goal is to provide a tool which may aid decision making processes in management of coral reefs.'),
(85766, 2012, 'plos', 'Experimental studies and dynamics modeling analysis of the swimming and diving of whirligig beetles (Coleoptera: Gyrinidae)', 'Xu, Zhonghua|Lenaghan, Scott C|Reese, Benjamin E|Jia, Xinghua|Zhang, Mingjun', 'Department of Mechanical, Aerospace, and Biomedical Engineering, University of Tennessee, Knoxville, Tennessee, United States of America.|Department of Mechanical, Aerospace, and Biomedical Engineering, University of Tennessee, Knoxville, Tennessee, United States of America.|Department of Mechanical, Aerospace, and Biomedical Engineering, University of Tennessee, Knoxville, Tennessee, United States of America.|Department of Mechanical, Aerospace, and Biomedical Engineering, University of Tennessee, Knoxville, Tennessee, United States of America.|Department of Mechanical, Aerospace, and Biomedical Engineering, University of Tennessee, Knoxville, Tennessee, United States of America.', 'United States|United States|United States|United States|United States', 13, 'Animals|Coleoptera|Computational Biology|Computer Simulation|Diving|Models, Biological|Swimming|Video Recording', 'Journal Article', '10.1371/journal.pcbi.1002792', '23209398', 'Whirligig beetles (Coleoptera, Gyrinidae) can fly through the air, swiftly swim on the surface of water, and quickly dive across the air-water interface. The propulsive efficiency of the species is believed to be one of the highest measured for a thrust generating apparatus within the animal kingdom. The goals of this research were to understand the distinctive biological mechanisms that allow the beetles to swim and dive, while searching for potential bio-inspired robotics applications. Through static and dynamic measurements obtained using a combination of microscopy and high-speed imaging, parameters associated with the morphology and beating kinematics of the whirligig beetles legs in swimming and diving were obtained. Using data obtained from these experiments, dynamics models of both swimming and diving were developed. Through analysis of simulations conducted using these models it was possible to determine several key principles associated with the swimming and diving processes. First, we determined that curved swimming trajectories were more energy efficient than linear trajectories, which explains why they are more often observed in nature. Second, we concluded that the hind legs were able to propel the beetle farther than the middle legs, and also that the hind legs were able to generate a larger angular velocity than the middle legs. However, analysis of circular swimming trajectories showed that the middle legs were important in maintaining stable trajectories, and thus were necessary for steering. Finally, we discovered that in order for the beetle to transition from swimming to diving, the legs must change the plane in which they beat, which provides the force required to alter the tilt angle of the body necessary to break the surface tension of water. We have further examined how the principles learned from this study may be applied to the design of bio-inspired swimming/diving robots.'),
(85767, 2012, 'plos', 'Accurate prediction of the dynamical changes within the second PDZ domain of PTP1e', 'Cilia, Elisa|Vuister, Geerten W|Lenaerts, Tom', 'MLG, Département dInformatique, Université Libre de Bruxelles, Brussels, Belgium.|MLG, Département dInformatique, Université Libre de Bruxelles, Brussels, Belgium.|MLG, Département dInformatique, Université Libre de Bruxelles, Brussels, Belgium.', 'Belgium|Belgium|Belgium', 0, 'Amino Acid Sequence|Animals|Computational Biology|Humans|Mice|Models, Molecular|Molecular Sequence Data|Monte Carlo Method|PDZ Domains|Protein Conformation|Protein Interaction Maps|Protein Tyrosine Phosphatase, Non-Receptor Type 13|Sequence Alignment', 'Journal Article', '10.1371/journal.pcbi.1002794', '23209399', 'Experimental NMR relaxation studies have shown that peptide binding induces dynamical changes at the side-chain level throughout the second PDZ domain of PTP1e, identifying as such the collection of residues involved in long-range communication. Even though different computational approaches have identified subsets of residues that were qualitatively comparable, no quantitative analysis of the accuracy of these predictions was thus far determined. Here, we show that our information theoretical method produces quantitatively better results with respect to the experimental data than some of these earlier methods. Moreover, it provides a global network perspective on the effect experienced by the different residues involved in the process. We also show that these predictions are consistent within both the human and mouse variants of this domain. Together, these results improve the understanding of intra-protein communication and allostery in PDZ domains, underlining at the same time the necessity of producing similar data sets for further validation of thses kinds of methods.'),
(85768, 2012, 'plos', 'ACME: automated cell morphology extractor for comprehensive reconstruction of cell membranes', 'Mosaliganti, Kishore R|Noche, Ramil R|Xiong, Fengzhu|Swinburne, Ian A|Megason, Sean G', 'Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States', 69, 'Algorithms|Animals|Automation|Cell Membrane|Cell Shape|Fluorescence|Zebrafish', 'Journal Article', '10.1371/journal.pcbi.1002780', '23236265', 'The quantification of cell shape, cell migration, and cell rearrangements is important for addressing classical questions in developmental biology such as patterning and tissue morphogenesis. Time-lapse microscopic imaging of transgenic embryos expressing fluorescent reporters is the method of choice for tracking morphogenetic changes and establishing cell lineages and fate maps in vivo. However, the manual steps involved in curating thousands of putative cell segmentations have been a major bottleneck in the application of these technologies especially for cell membranes. Segmentation of cell membranes while more difficult than nuclear segmentation is necessary for quantifying the relations between changes in cell morphology and morphogenesis. We present a novel and fully automated method to first reconstruct membrane signals and then segment out cells from 3D membrane images even in dense tissues. The approach has three stages: 1) detection of local membrane planes, 2) voting to fill structural gaps, and 3) region segmentation. We demonstrate the superior performance of the algorithms quantitatively on time-lapse confocal and two-photon images of zebrafish neuroectoderm and paraxial mesoderm by comparing its results with those derived from human inspection. We also compared with synthetic microscopic images generated by simulating the process of imaging with fluorescent reporters under varying conditions of noise. Both the over-segmentation and under-segmentation percentages of our method are around 5%. The volume overlap of individual cells, compared to expert manual segmentation, is consistently over 84%. By using our software (ACME) to study somite formation, we were able to segment touching cells with high accuracy and reliably quantify changes in morphogenetic parameters such as cell shape and size, and the arrangement of epithelial and mesenchymal cells. Our software has been developed and tested on Windows, Mac, and Linux platforms and is available publicly under an open source BSD license (https://github.com/krm15/ACME).'),
(85769, 2012, 'plos', 'Sensitivity analysis of flux determination in heart by Hxe2x82x82 xc2xb9xe2x81xb8O -provided labeling using a dynamic Isotopologue model of energy transfer pathways', 'Schryer, David W|Peterson, Pearu|Illaste, Ardo|Vendelin, Marko', 'Laboratory of Systems Biology, Institute of Cybernetics, Tallinn University of Technology, Estonia.|Laboratory of Systems Biology, Institute of Cybernetics, Tallinn University of Technology, Estonia.|Laboratory of Systems Biology, Institute of Cybernetics, Tallinn University of Technology, Estonia.|Laboratory of Systems Biology, Institute of Cybernetics, Tallinn University of Technology, Estonia.', 'Estonia|Estonia|Estonia|Estonia', 0, 'Energy Transfer|Heart|Models, Theoretical|Oxygen Isotopes', 'Journal Article', '10.1371/journal.pcbi.1002795', '23236266', 'To characterize intracellular energy transfer in the heart, two organ-level methods have frequently been employed: xc2xb3xc2xb9P xe2x88x92 NMR inversion and saturation transfer, and dynamic xc2xb9xe2x81xb8O labeling. Creatine kinase (CK) fluxes obtained by following oxygen labeling have been considerably smaller than the fluxes determined by xc2xb3xc2xb9P xe2x88x92 NMR saturation transfer. It has been proposed that dynamic xc2xb9xe2x81xb8O labeling determines net flux through CK shuttle, whereas xc2xb3xc2xb9P xe2x88x92 NMR saturation transfer measures total unidirectional flux. However, to our knowledge, no sensitivity analysis of flux determination by oxygen labeling has been performed, limiting our ability to compare flux distributions predicted by different methods. Here we analyze oxygen labeling in a physiological heart phosphotransfer network with active CK and adenylate kinase (AdK) shuttles and establish which fluxes determine the labeling state. A mathematical model consisting of a system of ordinary differential equations was composed describing xc2xb9xe2x81xb8O enrichment in each phosphoryl group and inorganic phosphate. By varying flux distributions in the model and calculating the labeling, we analyzed labeling sensitivity to different fluxes in the heart. We observed that the labeling state is predominantly sensitive to total unidirectional CK and AdK fluxes and not to net fluxes. We conclude that measuring dynamic incorporation of xc2xb9xe2x81xb8O into the high-energy phosphotransfer network in heart does not permit unambiguous determination of energetic fluxes with a higher magnitude than the ATP synthase rate when the bidirectionality of fluxes is taken into account. Our analysis suggests that the flux distributions obtained using dynamic xc2xb9xe2x81xb8O labeling, after removing the net flux assumption, are comparable with those from xc2xb3xc2xb9P xe2x88x92 NMR inversion and saturation transfer.'),
(85770, 2012, 'plos', 'Genomic hallmarks of genes involved in chromosomal translocations in hematological cancer', 'Shugay, Mikhail|Ortiz de Mendíbil, Iñigo|Vizmanos, José L|Novo, Francisco J', 'Department of Genetics, University of Navarra, Pamplona, Spain.|Department of Genetics, University of Navarra, Pamplona, Spain.|Department of Genetics, University of Navarra, Pamplona, Spain.|Department of Genetics, University of Navarra, Pamplona, Spain.', 'Spain|Spain|Spain|Spain', 0, '3 Untranslated Regions|Gene Expression Profiling|Genes, Neoplasm|Genomics|Hematologic Neoplasms|Humans|Translocation, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002797', '23236267', 'Reciprocal chromosomal translocations (RCTs) leading to the formation of fusion genes are important drivers of hematological cancers. Although the general requirements for breakage and fusion are fairly well understood, quantitative support for a general mechanism of RCT formation is still lacking. The aim of this paper is to analyze available high-throughput datasets with computational and robust statistical methods, in order to identify genomic hallmarks of translocation partner genes (TPGs). Our results show that fusion genes are generally overexpressed due to increased promoter activity of 5 TPGs and to more stable 3-UTR regions of 3 TPGs. Furthermore, expression profiling of 5 TPGs and of interaction partners of 3 TPGs indicates that these features can help to explain tissue specificity of hematological translocations. Analysis of protein domains retained in fusion proteins shows that the co-occurrence of specific domain combinations is non-random and that distinct functional classes of fusion proteins tend to be associated with different components of the gene fusion network. This indicates that the configuration of fusion proteins plays an important role in determining which 5 and 3 TPGs will combine in specific fusion genes. It is generally accepted that chromosomal proximity in the nucleus can explain the specific pairing of 5 and 3 TPGS and the recurrence of hematological translocations. Using recently available data for chromosomal contact probabilities (Hi-C) we show that TPGs are preferentially located in early replicated regions and occupy distinct clusters in the nucleus. However, our data suggest that, in general, nuclear position of TPGs in hematological cancers explains neither TPG pairing nor clinical frequency. Taken together, our results support a model in which genomic features related to regulation of expression and replication timing determine the set of candidate genes more likely to be translocated in hematological tissues, with functional constraints being responsible for specific gene combinations.'),
(85771, 2012, 'plos', 'Predicting spatial and temporal gene expression using an integrative model of transcription factor occupancy and chromatin state', 'Wilczynski, Bartek|Liu, Ya-Hsin|Yeo, Zhen Xuan|Furlong, Eileen E M', 'Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany. bartek@mimuw.edu.pl|Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany. bartek@mimuw.edu.pl|Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany. bartek@mimuw.edu.pl|Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany. bartek@mimuw.edu.pl', 'Germany|Germany|Germany|Germany', 30, 'Algorithms|Animals|Bayes Theorem|Chromatin|Drosophila|Enhancer Elements, Genetic|Gene Expression|Models, Theoretical|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002798', '23236268', 'Precise patterns of spatial and temporal gene expression are central to metazoan complexity and act as a driving force for embryonic development. While there has been substantial progress in dissecting and predicting cis-regulatory activity, our understanding of how information from multiple enhancer elements converge to regulate a genes expression remains elusive. This is in large part due to the number of different biological processes involved in mediating regulation as well as limited availability of experimental measurements for many of them. Here, we used a Bayesian approach to model diverse experimental regulatory data, leading to accurate predictions of both spatial and temporal aspects of gene expression. We integrated whole-embryo information on transcription factor recruitment to multiple cis-regulatory modules, insulator binding and histone modification status in the vicinity of individual gene loci, at a genome-wide scale during Drosophila development. The model uses Bayesian networks to represent the relation between transcription factor occupancy and enhancer activity in specific tissues and stages. All parameters are optimized in an Expectation Maximization procedure providing a model capable of predicting tissue- and stage-specific activity of new, previously unassayed genes. Performing the optimization with subsets of input data demonstrated that neither enhancer occupancy nor chromatin state alone can explain all gene expression patterns, but taken together allow for accurate predictions of spatio-temporal activity. Model predictions were validated using the expression patterns of more than 600 genes recently made available by the BDGP consortium, demonstrating an average 15-fold enrichment of genes expressed in the predicted tissue over a naïve model. We further validated the model by experimentally testing the expression of 20 predicted target genes of unknown expression, resulting in an accuracy of 95% for temporal predictions and 50% for spatial. While this is, to our knowledge, the first genome-wide approach to predict tissue-specific gene expression in metazoan development, our results suggest that integrative models of this type will become more prevalent in the future.'),
(85772, 2012, 'plos', 'Ten simple rules for the open development of scientific software', 'Prlixc4x87, Andreas|Procter, James B', 'Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany. bartek@mimuw.edu.pl|Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany. bartek@mimuw.edu.pl', 'Germany|Germany', 64, 'Guidelines as Topic|Software', 'Editorial', '10.1371/journal.pcbi.1002802', '23236269', '-'),
(85773, 2012, 'plos', 'SnIPRE: selection inference using a Poisson random effects model', 'Eilertson, Kirsten E|Booth, James G|Bustamante, Carlos D', 'Bioinformatics Core, J David Gladstone Institutes, San Francisco, California, United States of America. cdbustam@stanford.edu|Bioinformatics Core, J David Gladstone Institutes, San Francisco, California, United States of America. cdbustam@stanford.edu|Bioinformatics Core, J David Gladstone Institutes, San Francisco, California, United States of America. cdbustam@stanford.edu', 'United States|United States|United States', 0, 'Computer Simulation|Humans|Mutation|Poisson Distribution|Polymorphism, Genetic|Selection, Genetic|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002806', '23236270', 'We present an approach for identifying genes under natural selection using polymorphism and divergence data from synonymous and non-synonymous sites within genes. A generalized linear mixed model is used to model the genome-wide variability among categories of mutations and estimate its functional consequence. We demonstrate how the models estimated fixed and random effects can be used to identify genes under selection. The parameter estimates from our generalized linear model can be transformed to yield population genetic parameter estimates for quantities including the average selection coefficient for new mutations at a locus, the synonymous and non-synynomous mutation rates, and species divergence times. Furthermore, our approach incorporates stochastic variation due to the evolutionary process and can be fit using standard statistical software. The model is fit in both the empirical Bayes and Bayesian settings using the lme4 package in R, and Markov chain Monte Carlo methods in WinBUGS. Using simulated data we compare our method to existing approaches for detecting genes under selection: the McDonald-Kreitman test, and two versions of the Poisson random field based method MKprf. Overall, we find our method universally outperforms existing methods for detecting genes subject to selection using polymorphism and divergence data.'),
(85774, 2012, 'plos', 'Electron transfer interactome of cytochrome C', 'Volkov, Alexander N|van Nuland, Nico A J', 'Jean Jeener NMR Centre, Structural Biology Brussels, Vrije Universiteit Brussel, Belgium. ovolkov@vub.ac.be|Jean Jeener NMR Centre, Structural Biology Brussels, Vrije Universiteit Brussel, Belgium. ovolkov@vub.ac.be', 'Belgium|Belgium', 0, 'Cytochromes c|Electron Transport|Models, Molecular|Oxidation-Reduction|Protein Binding|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002807', '23236271', 'Lying at the heart of many vital cellular processes such as photosynthesis and respiration, biological electron transfer (ET) is mediated by transient interactions among proteins that recognize multiple binding partners. Accurate description of the ET complexes - necessary for a comprehensive understanding of the cellular signaling and metabolism - is compounded by their short lifetimes and pronounced binding promiscuity. Here, we used a computational approach relying solely on the steric properties of the individual proteins to predict the ET properties of protein complexes constituting the functional interactome of the eukaryotic cytochrome c (Cc). Cc is a small, soluble, highly-conserved electron carrier protein that coordinates the electron flow among different redox partners. In eukaryotes, Cc is a key component of the mitochondrial respiratory chain, where it shuttles electrons between its reductase and oxidase, and an essential electron donor or acceptor in a number of other redox systems. Starting from the structures of individual proteins, we performed extensive conformational sampling of the ET-competent binding geometries, which allowed mapping out functional epitopes in the Cc complexes, estimating the upper limit of the ET rate in a given system, assessing ET properties of different binding stoichiometries, and gauging the effect of domain mobility on the intermolecular ET. The resulting picture of the Cc interactome 1) reveals that most ET-competent binding geometries are located in electrostatically favorable regions, 2) indicates that the ET can take place from more than one protein-protein orientation, and 3) suggests that protein dynamics within redox complexes, and not the electron tunneling event itself, is the rate-limiting step in the intermolecular ET. Further, we show that the functional epitope size correlates with the extent of dynamics in the Cc complexes and thus can be used as a diagnostic tool for protein mobility.'),
(85775, 2012, 'plos', 'Quantitative dynamics of telomere bouquet formation', 'Richards, David M|Greer, Emma|Martin, Azahara C|Moore, Graham|Shaw, Peter J|Howard, Martin', 'Computational and Systems Biology, John Innes Centre, Norwich Research Park, Norwich, Norfolk, United Kingdom.|Computational and Systems Biology, John Innes Centre, Norwich Research Park, Norwich, Norfolk, United Kingdom.|Computational and Systems Biology, John Innes Centre, Norwich Research Park, Norwich, Norfolk, United Kingdom.|Computational and Systems Biology, John Innes Centre, Norwich Research Park, Norwich, Norfolk, United Kingdom.|Computational and Systems Biology, John Innes Centre, Norwich Research Park, Norwich, Norfolk, United Kingdom.|Computational and Systems Biology, John Innes Centre, Norwich Research Park, Norwich, Norfolk, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 13, 'Chromosomes, Plant|Genes, Plant|Hybridization, Genetic|Models, Theoretical|Secale|Telomere|Triticum', 'Journal Article', '10.1371/journal.pcbi.1002812', '23236272', 'The mechanism by which homologous chromosomes pair during meiosis, as a prelude to recombination, has long been mysterious. At meiosis, the telomeres in many organisms attach to the nuclear envelope and move together to form the telomere bouquet, perhaps to facilitate the homologous search. It is believed that diffusion alone is not sufficient to account for the formation of the bouquet, and that some directed movement is also required. Here we consider the formation of the telomere bouquet in a wheat-rye hybrid both experimentally and using mathematical modelling. The large size of the wheat nucleus and wheats commercial importance make chromosomal pairing in wheat a particularly interesting and important process, which may well shed light on pairing in other organisms. We show that, prior to bouquet formation, sister chromatid telomeres are always attached to a hemisphere of the nuclear membrane and tend to associate in pairs. We study a mutant lacking the Ph1 locus, a locus ensuring correct homologous chromosome pairing, and discover that bouquet formation is delayed in the wild type compared to the mutant. Further, we develop a mathematical model of bouquet formation involving diffusion and directed movement, where we show that directed movement alone is sufficient to explain bouquet formation dynamics.'),
(85776, 2012, 'plos', 'Molecular evolution of peptide ligands with custom-tailored characteristics for targeting of glycostructures', 'Röckendorf, Niels|Borschbach, Markus|Frey, Andreas', 'Division of Mucosal Immunology & Diagnostics, Priority Program Asthma & Allergy, Research Center Borstel, Airway Research Center North, Member of the German Center for Lung Research, Germany.|Division of Mucosal Immunology & Diagnostics, Priority Program Asthma & Allergy, Research Center Borstel, Airway Research Center North, Member of the German Center for Lung Research, Germany.|Division of Mucosal Immunology & Diagnostics, Priority Program Asthma & Allergy, Research Center Borstel, Airway Research Center North, Member of the German Center for Lung Research, Germany.', 'Germany|Germany|Germany', 0, 'Algorithms|Amino Acid Sequence|Evolution, Molecular|Fluorescent Dyes|G(M1) Ganglioside|Ligands|Molecular Sequence Data|Mutation|Peptides', 'Journal Article', '10.1371/journal.pcbi.1002800', '23271960', 'As an advanced approach to identify suitable targeting molecules required for various diagnostic and therapeutic interventions, we developed a procedure to devise peptides with customizable features by an iterative computer-assisted optimization strategy. An evolutionary algorithm was utilized to breed peptides in silico and the fitness of peptides was determined in an appropriate laboratory in vitro assay. The influence of different evolutional parameters and mechanisms such as mutation rate, crossover probability, gaussian variation and fitness value scaling on the course of this artificial evolutional process was investigated. As a proof of concept peptidic ligands for a model target molecule, the cell surface glycolipid ganglioside G(M1), were identified. Consensus sequences describing local fitness optima were reached from diverse sets of L- and proteolytically stable D lead peptides. Ten rounds of evolutional optimization encompassing a total of just 4400 peptides lead to an increase in affinity of the peptides towards fluorescently labeled ganglioside G(M1) by a factor of 100 for L- and 400 for D-peptides.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85777, 2012, 'plos', 'Tuning promoter strength through RNA polymerase binding site design in Escherichia coli', 'Brewster, Robert C|Jones, Daniel L|Phillips, Rob', 'Department of Applied Physics, California Institute of Technology, Pasadena, California, United States of America.|Department of Applied Physics, California Institute of Technology, Pasadena, California, United States of America.|Department of Applied Physics, California Institute of Technology, Pasadena, California, United States of America.', 'United States|United States|United States', 86, 'Base Sequence|Binding Sites|DNA, Bacterial|DNA-Directed RNA Polymerases|Escherichia coli|Promoter Regions, Genetic|Sequence Homology, Nucleic Acid|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002811', '23271961', 'One of the paramount goals of synthetic biology is to have the ability to tune transcriptional networks to targeted levels of expression at will. As a step in that direction, we have constructed a set of 18 unique binding sites for E. coli RNA Polymerase (RNAP) xcexb4xe2x81xb7xe2x81xb0 holoenzyme, designed using a model of sequence-dependent binding energy combined with a thermodynamic model of transcription to produce a targeted level of gene expression. This promoter set allows us to determine the correspondence between the absolute numbers of mRNA molecules or protein products and the predicted promoter binding energies measured in k(B)T energy units. These binding sites adhere on average to the predicted level of gene expression over 3 orders of magnitude in constitutive gene expression, to within a factor of 3 in both protein and mRNA copy number. With these promoters in hand, we then place them under the regulatory control of a bacterial repressor and show that again there is a strict correspondence between the measured and predicted levels of expression, demonstrating the transferability of the promoters to an alternate regulatory context. In particular, our thermodynamic model predicts the expression from our promoters under a range of repressor concentrations between several per cell up to over 100 per cell. After correcting the predicted polymerase binding strength using the data from the unregulated promoter, the thermodynamic model accurately predicts the expression for the simple repression strains to within 30%. Demonstration of modular promoter design, where parts of the circuit (such as RNAP/TF binding strength and transcription factor copy number) can be independently chosen from a stock list and combined to give a predictable result, has important implications as an engineering tool for use in synthetic biology.'),
(85778, 2012, 'plos', 'Climbing fiber burst size and olivary sub-threshold oscillations in a network setting', 'De Gruijl, Jornt R|Bazzigaluppi, Paolo|de Jeu, Marcel T G|De Zeeuw, Chris I', 'Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands. j.de.gruijl@nin.knaw.nl|Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands. j.de.gruijl@nin.knaw.nl|Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands. j.de.gruijl@nin.knaw.nl|Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands. j.de.gruijl@nin.knaw.nl', 'Netherlands|Netherlands|Netherlands|Netherlands', 0, 'Action Potentials|Animals|Mice|Olivary Nucleus', 'Journal Article', '10.1371/journal.pcbi.1002814', '23271962', 'The inferior olivary nucleus provides one of the two main inputs to the cerebellum: the so-called climbing fibers. Activation of climbing fibers is generally believed to be related to timing of motor commands and/or motor learning. Climbing fiber spikes lead to large all-or-none action potentials in cerebellar Purkinje cells, overriding any other ongoing activity and silencing these cells for a brief period of time afterwards. Empirical evidence shows that the climbing fiber can transmit a short burst of spikes as a result of an olivary cell somatic spike, potentially increasing the information being transferred to the cerebellum per climbing fiber activation. Previously reported results from in vitro studies suggested that the information encoded in the climbing fiber burst is related to the occurrence of the spike relative to the ongoing sub-threshold membrane potential oscillation of the olivary cell, i.e. that the phase of the oscillation is reflected in the size of the climbing fiber burst. We used a detailed three-compartmental model of an inferior olivary cell to further investigate the possible factors determining the size of the climbing fiber burst. Our findings suggest that the phase-dependency of the burst size is present but limited and that charge flow between soma and dendrite is a major determinant of the climbing fiber burst. From our findings it follows that phenomena such as cell ensemble synchrony can have a big effect on the climbing fiber burst size through dendrodendritic gap-junctional coupling between olivary cells.'),
(85779, 2012, 'plos', 'Localizing genes to cerebellar layers by classifying ISH images', 'Kirsch, Lior|Liscovitch, Noa|Chechik, Gal', 'The Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel.|The Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel.|The Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel.', 'Israel|Israel|Israel', 0, 'Animals|Cerebellum|Gene Expression|In Situ Hybridization|Mice', 'Journal Article', '10.1371/journal.pcbi.1002790', '23284274', 'Gene expression controls how the brain develops and functions. Understanding control processes in the brain is particularly hard since they involve numerous types of neurons and glia, and very little is known about which genes are expressed in which cells and brain layers. Here we describe an approach to detect genes whose expression is primarily localized to a specific brain layer and apply it to the mouse cerebellum. We learn typical spatial patterns of expression from a few markers that are known to be localized to specific layers, and use these patterns to predict localization for new genes. We analyze images of in-situ hybridization (ISH) experiments, which we represent using histograms of local binary patterns (LBP) and train image classifiers and gene classifiers for four layers of the cerebellum: the Purkinje, granular, molecular and white matter layer. On held-out data, the layer classifiers achieve accuracy above 94% (AUC) by representing each image at multiple scales and by combining multiple image scores into a single gene-level decision. When applied to the full mouse genome, the classifiers predict specific layer localization for hundreds of new genes in the Purkinje and granular layers. Many genes localized to the Purkinje layer are likely to be expressed in astrocytes, and many others are involved in lipid metabolism, possibly due to the unusual size of Purkinje cells.'),
(85780, 2012, 'plos', 'Modelling hair follicle growth dynamics as an excitable medium', 'Murray, Philip J|Maini, Philip K|Plikus, Maksim V|Chuong, Cheng-Ming|Baker, Ruth E', 'Centre for Mathematical Biology, Mathematical Institute, Oxford, United Kingdom. murrayp@maths.ox.ac.uk|Centre for Mathematical Biology, Mathematical Institute, Oxford, United Kingdom. murrayp@maths.ox.ac.uk|Centre for Mathematical Biology, Mathematical Institute, Oxford, United Kingdom. murrayp@maths.ox.ac.uk|Centre for Mathematical Biology, Mathematical Institute, Oxford, United Kingdom. murrayp@maths.ox.ac.uk|Centre for Mathematical Biology, Mathematical Institute, Oxford, United Kingdom. murrayp@maths.ox.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Animals|Hair|Mice|Models, Biological|Stem Cells', 'Journal Article', '10.1371/journal.pcbi.1002804', '23284275', 'The hair follicle system represents a tractable model for the study of stem cell behaviour in regenerative adult epithelial tissue. However, although there are numerous spatial scales of observation (molecular, cellular, follicle and multi follicle), it is not yet clear what mechanisms underpin the follicle growth cycle. In this study we seek to address this problem by describing how the growth dynamics of a large population of follicles can be treated as a classical excitable medium. Defining caricature interactions at the molecular scale and treating a single follicle as a functional unit, a minimal model is proposed in which the follicle growth cycle is an emergent phenomenon. Expressions are derived, in terms of parameters representing molecular regulation, for the time spent in the different functional phases of the cycle, a formalism that allows the model to be directly compared with a previous cellular automaton model and experimental measurements made at the single follicle scale. A multi follicle model is constructed and numerical simulations are used to demonstrate excellent qualitative agreement with a range of experimental observations. Notably, the excitable medium equations exhibit a wider family of solutions than the previous work and we demonstrate how parameter changes representing altered molecular regulation can explain perturbed patterns in Wnt over-expression and BMP down-regulation mouse models. Further experimental scenarios that could be used to test the fundamental premise of the model are suggested. The key conclusion from our work is that positive and negative regulatory interactions between activators and inhibitors can give rise to a range of experimentally observed phenomena at the follicle and multi follicle spatial scales and, as such, could represent a core mechanism underlying hair follicle growth.'),
(85781, 2012, 'plos', 'Task-dependent changes in cross-level coupling between single neurons and oscillatory activity in multiscale networks', 'Canolty, Ryan T|Ganguly, Karunesh|Carmena, Jose M', 'Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, California, USA.|Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, California, USA.|Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, California, USA.', 'United States|United States|United States', 0, 'Action Potentials|Animals|Brain|Macaca mulatta|Male|Microelectrodes|Multivariate Analysis|Neurons', 'Journal Article', '10.1371/journal.pcbi.1002809', '23284276', 'Understanding the principles governing the dynamic coordination of functional brain networks remains an important unmet goal within neuroscience. How do distributed ensembles of neurons transiently coordinate their activity across a variety of spatial and temporal scales? While a complete mechanistic account of this process remains elusive, evidence suggests that neuronal oscillations may play a key role in this process, with different rhythms influencing both local computation and long-range communication. To investigate this question, we recorded multiple single unit and local field potential (LFP) activity from microelectrode arrays implanted bilaterally in macaque motor areas. Monkeys performed a delayed center-out reach task either manually using their natural arm (Manual Control, MC) or under direct neural control through a brain-machine interface (Brain Control, BC). In accord with prior work, we found that the spiking activity of individual neurons is coupled to multiple aspects of the ongoing motor beta rhythm (10-45 Hz) during both MC and BC, with neurons exhibiting a diversity of coupling preferences. However, here we show that for identified single neurons, this beta-to-rate mapping can change in a reversible and task-dependent way. For example, as beta power increases, a given neuron may increase spiking during MC but decrease spiking during BC, or exhibit a reversible shift in the preferred phase of firing. The within-task stability of coupling, combined with the reversible cross-task changes in coupling, suggest that task-dependent changes in the beta-to-rate mapping play a role in the transient functional reorganization of neural ensembles. We characterize the range of task-dependent changes in the mapping from beta amplitude, phase, and inter-hemispheric phase differences to the spike rates of an ensemble of simultaneously-recorded neurons, and discuss the potential implications that dynamic remapping from oscillatory activity to spike rate and timing may hold for models of computation and communication in distributed functional brain networks.'),
(85782, 2012, 'plos', 'Parameter identifiability and sensitivity analysis predict targets for enhancement of STAT1 activity in pancreatic cancer and stellate cells', 'Rateitschak, Katja|Winter, Felix|Lange, Falko|Jaster, Robert|Wolkenhauer, Olaf', 'Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany. katja.rateitschak@uni-rostock.de|Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany. katja.rateitschak@uni-rostock.de|Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany. katja.rateitschak@uni-rostock.de|Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany. katja.rateitschak@uni-rostock.de|Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany. katja.rateitschak@uni-rostock.de', 'Germany|Germany|Germany|Germany|Germany', 17, 'Cell Line, Tumor|Fluorescent Antibody Technique|Humans|Pancreatic Neoplasms|STAT1 Transcription Factor|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002815', '23284277', 'The present work exemplifies how parameter identifiability analysis can be used to gain insights into differences in experimental systems and how uncertainty in parameter estimates can be handled. The case study, presented here, investigates interferon-gamma (IFNxcexb3) induced STAT1 signalling in two cell types that play a key role in pancreatic cancer development: pancreatic stellate and cancer cells. IFNxcexb3 inhibits the growth for both types of cells and may be prototypic of agents that simultaneously hit cancer and stroma cells. We combined time-course experiments with mathematical modelling to focus on the common situation in which variations between profiles of experimental time series, from different cell types, are observed. To understand how biochemical reactions are causing the observed variations, we performed a parameter identifiability analysis. We successfully identified reactions that differ in pancreatic stellate cells and cancer cells, by comparing confidence intervals of parameter value estimates and the variability of model trajectories. Our analysis shows that useful information can also be obtained from nonidentifiable parameters. For the prediction of potential therapeutic targets we studied the consequences of uncertainty in the values of identifiable and nonidentifiable parameters. Interestingly, the sensitivity of model variables is robust against parameter variations and against differences between IFNxcexb3 induced STAT1 signalling in pancreatic stellate and cancer cells. This provides the basis for a prediction of therapeutic targets that are valid for both cell types.'),
(85783, 2012, 'plos', 'The evolution of cell-to-cell communication in a sporulating bacterium', 'van Gestel, Jordi|Nowak, Martin A|Tarnita, Corina E', 'Theoretical Biology Group, Centre for Ecological and Evolutionary Studies, University of Groningen, Groningen, The Netherlands. jordivangestel@gmail.com|Theoretical Biology Group, Centre for Ecological and Evolutionary Studies, University of Groningen, Groningen, The Netherlands. jordivangestel@gmail.com|Theoretical Biology Group, Centre for Ecological and Evolutionary Studies, University of Groningen, Groningen, The Netherlands. jordivangestel@gmail.com', 'Netherlands|Netherlands|Netherlands', 0, 'Bacterial Physiological Phenomena|Biological Evolution|Cell Communication|Spores, Bacterial', 'Journal Article', '10.1371/journal.pcbi.1002818', '23284278', 'Traditionally microorganisms were considered to be autonomous organisms that could be studied in isolation. However, over the last decades cell-to-cell communication has been found to be ubiquitous. By secreting molecular signals in the extracellular environment microorganisms can indirectly assess the cell density and respond in accordance. In one of the best-studied microorganisms, Bacillus subtilis, the differentiation processes into a number of distinct cell types have been shown to depend on cell-to-cell communication. One of these cell types is the spore. Spores are metabolically inactive cells that are highly resistant against environmental stress. The onset of sporulation is dependent on cell-to-cell communication, as well as on a number of other environmental cues. By using individual-based simulations we examine when cell-to-cell communication that is involved in the onset of sporulation can evolve. We show that it evolves when three basic premises are satisfied. First, the population of cells has to affect the nutrient conditions. Second, there should be a time-lag between the moment that a cell decides to sporulate and the moment that it turns into a mature spore. Third, there has to be environmental variation. Cell-to-cell communication is a strategy to cope with environmental variation, by allowing cells to predict future environmental conditions. As a consequence, cells can anticipate environmental stress by initiating sporulation. Furthermore, signal production could be considered a cooperative trait and therefore evolves when it is not too costly to produce signal and when there are recurrent colony bottlenecks, which facilitate assortment. Finally, we also show that cell-to-cell communication can drive ecological diversification. Different ecotypes can evolve and be maintained due to frequency-dependent selection.'),
(85784, 2012, 'plos', 'Novel modeling of combinatorial miRNA targeting identifies SNP with potential role in bone density', 'Coronnello, Claudia|Hartmaier, Ryan|Arora, Arshi|Huleihel, Luai|Pandit, Kusum V|Bais, Abha S|Butterworth, Michael|Kaminski, Naftali|Stormo, Gary D|Oesterreich, Steffi|Benos, Panayiotis V', 'Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. clc196@pitt.edu|Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. clc196@pitt.edu|Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. clc196@pitt.edu|Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. clc196@pitt.edu|Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. clc196@pitt.edu|Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. clc196@pitt.edu|Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. clc196@pitt.edu|Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. clc196@pitt.edu|Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. clc196@pitt.edu|Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. clc196@pitt.edu|Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. clc196@pitt.edu', 'United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States', 0, 'Algorithms|Animals|Bone Density|Drosophila|Humans|MicroRNAs|Models, Theoretical|Polymorphism, Single Nucleotide', 'Journal Article', '10.1371/journal.pcbi.1002830', '23284279', 'MicroRNAs (miRNAs) are post-transcriptional regulators that bind to their target mRNAs through base complementarity. Predicting miRNA targets is a challenging task and various studies showed that existing algorithms suffer from high number of false predictions and low to moderate overlap in their predictions. Until recently, very few algorithms considered the dynamic nature of the interactions, including the effect of less specific interactions, the miRNA expression level, and the effect of combinatorial miRNA binding. Addressing these issues can result in a more accurate miRNA:mRNA modeling with many applications, including efficient miRNA-related SNP evaluation. We present a novel thermodynamic model based on the Fermi-Dirac equation that incorporates miRNA expression in the prediction of target occupancy and we show that it improves the performance of two popular single miRNA target finders. Modeling combinatorial miRNA targeting is a natural extension of this model. Two other algorithms show improved prediction efficiency when combinatorial binding models were considered. ComiR (Combinatorial miRNA targeting), a novel algorithm we developed, incorporates the improved predictions of the four target finders into a single probabilistic score using ensemble learning. Combining target scores of multiple miRNAs using ComiR improves predictions over the naïve method for target combination. ComiR scoring scheme can be used for identification of SNPs affecting miRNA binding. As proof of principle, ComiR identified rs17737058 as disruptive to the miR-488-5p:NCOA1 interaction, which we confirmed in vitro. We also found rs17737058 to be significantly associated with decreased bone mineral density (BMD) in two independent cohorts indicating that the miR-488-5p/NCOA1 regulatory axis is likely critical in maintaining BMD in women. With increasing availability of comprehensive high-throughput datasets from patients ComiR is expected to become an essential tool for miRNA-related studies.'),
(85785, 2012, 'plos', 'Phylogenetic diversity theory sheds light on the structure of microbial communities', 'ODwyer, James P|Kembel, Steven W|Green, Jessica L', 'Santa Fe Institute, Santa Fe, New Mexico, USA. jodwyer@santafe.edu|Santa Fe Institute, Santa Fe, New Mexico, USA. jodwyer@santafe.edu|Santa Fe Institute, Santa Fe, New Mexico, USA. jodwyer@santafe.edu', 'Mexico|Mexico|Mexico', 39, 'Humans|Metagenome|Models, Theoretical|Phylogeny', 'Journal Article', '10.1371/journal.pcbi.1002832', '23284280', 'Microbial communities are typically large, diverse, and complex, and identifying and understanding the processes driving their structure has implications ranging from ecosystem stability to human health and well-being. Phylogenetic data gives us a new insight into these processes, providing a more informative perspective on functional and trait diversity than taxonomic richness alone. But the sheer scale of high resolution phylogenetic data also presents a new challenge to ecological theory. We bring a sampling theory perspective to microbial communities, considering a local community of co-occuring organisms as a sample from a larger regional pool, and apply our framework to make analytical predictions for local phylogenetic diversity arising from a given metacommunity and community assembly process. We characterize community assembly in terms of quantitative descriptions of clustered, random and overdispersed sampling, which have been associated with hypotheses of environmental filtering and competition. Using our approach, we analyze large microbial communities from the human microbiome, uncovering significant variation in diversity across habitats relative to the null hypothesis of random sampling.'),
(85786, 2012, 'plos', 'Soft-bound synaptic plasticity increases storage capacity', 'van Rossum, Mark C W|Shippi, Maria|Barrett, Adam B', 'Institute for Adaptive and Neural Computation, School of Informatics, University of Edinburgh, Edinburgh, United Kingdom. mvanross@inf.ed.ac.uk|Institute for Adaptive and Neural Computation, School of Informatics, University of Edinburgh, Edinburgh, United Kingdom. mvanross@inf.ed.ac.uk|Institute for Adaptive and Neural Computation, School of Informatics, University of Edinburgh, Edinburgh, United Kingdom. mvanross@inf.ed.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Information Theory|Learning|Long-Term Potentiation|Memory|Models, Theoretical|Neuronal Plasticity', 'Journal Article', '10.1371/journal.pcbi.1002836', '23284281', 'Accurate models of synaptic plasticity are essential to understand the adaptive properties of the nervous system and for realistic models of learning and memory. Experiments have shown that synaptic plasticity depends not only on pre- and post-synaptic activity patterns, but also on the strength of the connection itself. Namely, weaker synapses are more easily strengthened than already strong ones. This so called soft-bound plasticity automatically constrains the synaptic strengths. It is known that this has important consequences for the dynamics of plasticity and the synaptic weight distribution, but its impact on information storage is unknown. In this modeling study we introduce an information theoretic framework to analyse memory storage in an online learning setting. We show that soft-bound plasticity increases a variety of performance criteria by about 18% over hard-bound plasticity, and likely maximizes the storage capacity of synapses.'),
(85787, 2012, 'plos', '3D reconstruction and standardization of the rat vibrissal cortex for precise registration of single neuron morphology', 'Egger, Robert|Narayanan, Rajeevan T|Helmstaedter, Moritz|de Kock, Christiaan P J|Oberlaender, Marcel', 'Digital Neuroanatomy, Max Planck Florida Institute, Jupiter, Florida, USA.|Digital Neuroanatomy, Max Planck Florida Institute, Jupiter, Florida, USA.|Digital Neuroanatomy, Max Planck Florida Institute, Jupiter, Florida, USA.|Digital Neuroanatomy, Max Planck Florida Institute, Jupiter, Florida, USA.|Digital Neuroanatomy, Max Planck Florida Institute, Jupiter, Florida, USA.', 'United States|United States|United States|United States|United States', 25, 'Animals|Cerebral Cortex|Imaging, Three-Dimensional|Neurons|Rats|Vibrissae', 'Journal Article', '10.1371/journal.pcbi.1002837', '23284282', 'The three-dimensional (3D) structure of neural circuits is commonly studied by reconstructing individual or small groups of neurons in separate preparations. Investigation of structural organization principles or quantification of dendritic and axonal innervation thus requires integration of many reconstructed morphologies into a common reference frame. Here we present a standardized 3D model of the rat vibrissal cortex and introduce an automated registration tool that allows for precise placement of single neuron reconstructions. We (1) developed an automated image processing pipeline to reconstruct 3D anatomical landmarks, i.e., the barrels in Layer 4, the pia and white matter surfaces and the blood vessel pattern from high-resolution images, (2) quantified these landmarks in 12 different rats, (3) generated an average 3D model of the vibrissal cortex and (4) used rigid transformations and stepwise linear scaling to register 94 neuron morphologies, reconstructed from in vivo stainings, to the standardized cortex model. We find that anatomical landmarks vary substantially across the vibrissal cortex within an individual rat. In contrast, the 3D layout of the entire vibrissal cortex remains remarkably preserved across animals. This allows for precise registration of individual neuron reconstructions with approximately 30 µm accuracy. Our approach could be used to reconstruct and standardize other anatomically defined brain areas and may ultimately lead to a precise digital reference atlas of the rat brain.'),
(85788, 2012, 'plos', 'PERT: a method for expression deconvolution of human blood samples from varied microenvironmental and developmental conditions', 'Qiao, Wenlian|Quon, Gerald|Csaszar, Elizabeth|Yu, Mei|Morris, Quaid|Zandstra, Peter W', 'Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.|Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.|Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.|Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.|Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.|Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.', 'Canada|Canada|Canada|Canada|Canada|Canada', 59, 'Algorithms|Fetal Blood|Flow Cytometry|Gene Expression Profiling|Humans|Least-Squares Analysis|Likelihood Functions|Oligonucleotide Array Sequence Analysis', 'Journal Article', '10.1371/journal.pcbi.1002838', '23284283', 'The cellular composition of heterogeneous samples can be predicted using an expression deconvolution algorithm to decompose their gene expression profiles based on pre-defined, reference gene expression profiles of the constituent populations in these samples. However, the expression profiles of the actual constituent populations are often perturbed from those of the reference profiles due to gene expression changes in cells associated with microenvironmental or developmental effects. Existing deconvolution algorithms do not account for these changes and give incorrect results when benchmarked against those measured by well-established flow cytometry, even after batch correction was applied. We introduce PERT, a new probabilistic expression deconvolution method that detects and accounts for a shared, multiplicative perturbation in the reference profiles when performing expression deconvolution. We applied PERT and three other state-of-the-art expression deconvolution methods to predict cell frequencies within heterogeneous human blood samples that were collected under several conditions (uncultured mono-nucleated and lineage-depleted cells, and culture-derived lineage-depleted cells). Only PERTs predicted proportions of the constituent populations matched those assigned by flow cytometry. Genes associated with cell cycle processes were highly enriched among those with the largest predicted expression changes between the cultured and uncultured conditions. We anticipate that PERT will be widely applicable to expression deconvolution strategies that use profiles from reference populations that vary from the corresponding constituent populations in cellular state but not cellular phenotypic identity.'),
(85789, 2012, 'plos', 'Nucleoid-associated proteins affect mutation dynamics in E coli in a growth phase-specific manner', 'Warnecke, Tobias|Supek, Fran|Lehner, Ben', 'Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), Barcelona, Spain. Tobias.Warnecke@crg.es|Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), Barcelona, Spain. Tobias.Warnecke@crg.es|Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), Barcelona, Spain. Tobias.Warnecke@crg.es', 'Spain|Spain|Spain', 0, 'DNA Repair|Escherichia coli|Escherichia coli Proteins|Evolution, Molecular|Mutation|Phylogeny|Protein Binding', 'Journal Article', '10.1371/journal.pcbi.1002846', '23284284', 'The binding of proteins can shield DNA from mutagenic processes but also interfere with efficient repair. How the presence of DNA-binding proteins shapes intra-genomic differences in mutability and, ultimately, sequence variation in natural populations, however, remains poorly understood. In this study, we examine sequence evolution in Escherichia coli in relation to the binding of four abundant nucleoid-associated proteins: Fis, H-NS, IhfA, and IhfB. We find that, for a subset of mutations, protein occupancy is associated with both increased and decreased mutability in the underlying sequence depending on when the protein is bound during the bacterial growth cycle. On average, protein-bound DNA exhibits reduced mutability compared to protein-free DNA. However, this net protective effect is weak and can be abolished or even reversed during stages of colony growth where binding coincides - and hence likely interferes with - DNA repair activity. We suggest that the four nucleoid-associated proteins analyzed here have played a minor but significant role in patterning extant sequence variation in E. coli.'),
(85790, 2012, 'plos', 'Teaching the fundamentals of biological data integration using classroom games', 'Schneider, Maria Victoria|Jimenez, Rafael C', 'Outreach and Training Team, European Molecular Biology Laboratory Outstation, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom. mvschneiderg@gmail.com|Outreach and Training Team, European Molecular Biology Laboratory Outstation, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom. mvschneiderg@gmail.com', 'United Kingdom|United Kingdom', 0, 'Biology|Education|Game Theory|Internet|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1002789', '23300402', 'This article aims to introduce the nature of data integration to life scientists. Generally, the subject of data integration is not discussed outside the field of computational science and is not covered in any detail, or even neglected, when teaching/training trainees. End users (hereby defined as wet-lab trainees, clinicians, lab researchers) will mostly interact with bioinformatics resources and tools through web interfaces that mask the user from the data integration processes. However, the lack of formal training or acquaintance with even simple database concepts and terminology often results in a real obstacle to the full comprehension of the resources and tools the end users wish to access. Understanding how data integration works is fundamental to empowering trainees to see the limitations as well as the possibilities when exploring, retrieving, and analysing biological data from databases. Here we introduce a game-based learning activity for training/teaching the topic of data integration that trainers/educators can adopt and adapt for their classroom. In particular we provide an example using DAS (Distributed Annotation Systems) as a method for data integration.'),
(85791, 2012, 'plos', 'A comparison of computational models for eukaryotic cell shape and motility', 'Holmes, William R|Edelstein-Keshet, Leah', 'Department of Mathematics, University of British Columbia, Vancouver, British Columbia, Canada. wrholmes@uci.edu|Department of Mathematics, University of British Columbia, Vancouver, British Columbia, Canada. wrholmes@uci.edu', 'Canada|Canada', 0, 'Animals|Cell Adhesion|Cell Movement|Cell Shape|Computer Simulation|Eukaryotic Cells|Humans', 'Comparative Study', '10.1371/journal.pcbi.1002793', '23300403', 'Eukaryotic cell motility involves complex interactions of signalling molecules, cytoskeleton, cell membrane, and mechanics interacting in space and time. Collectively, these components are used by the cell to interpret and respond to external stimuli, leading to polarization, protrusion, adhesion formation, and myosin-facilitated retraction. When these processes are choreographed correctly, shape change and motility results. A wealth of experimental data have identified numerous molecular constituents involved in these processes, but the complexity of their interactions and spatial organization make this a challenging problem to understand. This has motivated theoretical and computational approaches with simplified caricatures of cell structure and behaviour, each aiming to gain better understanding of certain kinds of cells and/or repertoire of behaviour. Reaction-diffusion (RD) equations as well as equations of viscoelastic flows have been used to describe the motility machinery. In this review, we describe some of the recent computational models for cell motility, concentrating on simulations of cell shape changes (mainly in two but also three dimensions). The problem is challenging not only due to the difficulty of abstracting and simplifying biological complexity but also because computing RD or fluid flow equations in deforming regions, known as a free-boundary problem, is an extremely challenging problem in applied mathematics. Here we describe the distinct approaches, comparing their strengths and weaknesses, and the kinds of biological questions that they have been able to address.'),
(85792, 2012, 'plos', 'Introduction to translational bioinformatics collection', 'Altman, Russ B', 'Department of Genetics, Stanford University, Stanford, California, United States of America. russ.altman@stanford.edu', 'United States', 9, 'Computational Biology|Humans|Translational Medical Research', 'Introductory Journal Article', '10.1371/journal.pcbi.1002796', '23300404', '-'),
(85793, 2012, 'plos', 'Chapter 3: Small molecules and disease', 'Wishart, David S', 'Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada. david.wishart@ualberta.ca', 'Canada', 0, 'Biomarkers|Computational Biology|Databases, Factual|Disease|Drug Discovery|Humans|Metabolomics|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1002805', '23300405', 'Big molecules such as proteins and genes still continue to capture the imagination of most biologists, biochemists and bioinformaticians. Small molecules, on the other hand, are the molecules that most biologists, biochemists and bioinformaticians prefer to ignore. However, it is becoming increasingly apparent that small molecules such as amino acids, lipids and sugars play a far more important role in all aspects of disease etiology and disease treatment than we realized. This particular chapter focuses on an emerging field of bioinformatics called chemical bioinformatics--a discipline that has evolved to help address the blended chemical and molecular biological needs of toxicogenomics, pharmacogenomics, metabolomics and systems biology. In the following pages we will cover several topics related to chemical bioinformatics. First, a brief overview of some of the most important or useful chemical bioinformatic resources will be given. Second, a more detailed overview will be given on those particular resources that allow researchers to connect small molecules to diseases. This section will focus on describing a number of recently developed databases or knowledgebases that explicitly relate small molecules--either as the treatment, symptom or cause--to disease. Finally a short discussion will be provided on newly emerging software tools that exploit these databases as a means to discover new biomarkers or even new treatments for disease.'),
(85794, 2012, 'plos', 'Chapter 12: Human microbiome analysis', 'Morgan, Xochitl C|Huttenhower, Curtis', 'Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America.|Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America.', 'United States|United States', 201, 'Bacteria|Genes, Bacterial|Host-Pathogen Interactions|Humans|Metagenome|Metagenomics|RNA, Ribosomal, 16S', 'Journal Article', '10.1371/journal.pcbi.1002808', '23300406', 'Humans are essentially sterile during gestation, but during and after birth, every body surface, including the skin, mouth, and gut, becomes host to an enormous variety of microbes, bacterial, archaeal, fungal, and viral. Under normal circumstances, these microbes help us to digest our food and to maintain our immune systems, but dysfunction of the human microbiota has been linked to conditions ranging from inflammatory bowel disease to antibiotic-resistant infections. Modern high-throughput sequencing and bioinformatic tools provide a powerful means of understanding the contribution of the human microbiome to health and its potential as a target for therapeutic interventions. This chapter will first discuss the historical origins of microbiome studies and methods for determining the ecological diversity of a microbial community. Next, it will introduce shotgun sequencing technologies such as metagenomics and metatranscriptomics, the computational challenges and methods associated with these data, and how they enable microbiome analysis. Finally, it will conclude with examples of the functional genomics of the human microbiome and its influences upon health and disease.'),
(85795, 2012, 'plos', 'Mechanics of undulatory swimming in a frictional fluid', 'Ding, Yang|Sharpe, Sarah S|Masse, Andrew|Goldman, Daniel I', 'School of Physics, Georgia Institute of Technology, Atlanta, Georgia, United States of America.|School of Physics, Georgia Institute of Technology, Atlanta, Georgia, United States of America.|School of Physics, Georgia Institute of Technology, Atlanta, Georgia, United States of America.|School of Physics, Georgia Institute of Technology, Atlanta, Georgia, United States of America.', 'Georgia|Georgia|Georgia|Georgia', 0, 'Animals|Biomechanical Phenomena|Lizards|Models, Biological|Swimming', 'Journal Article', '10.1371/journal.pcbi.1002810', '23300407', 'The sandfish lizard (Scincus scincus) swims within granular media (sand) using axial body undulations to propel itself without the use of limbs. In previous work we predicted average swimming speed by developing a numerical simulation that incorporated experimentally measured biological kinematics into a multibody sandfish model. The model was coupled to an experimentally validated soft sphere discrete element method simulation of the granular medium. In this paper, we use the simulation to study the detailed mechanics of undulatory swimming in a granular frictional fluid and compare the predictions to our previously developed resistive force theory (RFT) which models sand-swimming using empirically determined granular drag laws. The simulation reveals that the forward speed of the center of mass (CoM) oscillates about its average speed in antiphase with head drag. The coupling between overall body motion and body deformation results in a non-trivial pattern in the magnitude of lateral displacement of the segments along the body. The actuator torque and segment power are maximal near the center of the body and decrease to zero toward the head and the tail. Approximately 30% of the net swimming power is dissipated in head drag. The power consumption is proportional to the frequency in the biologically relevant range, which confirms that frictional forces dominate during sand-swimming by the sandfish. Comparison of the segmental forces measured in simulation with the force on a laterally oscillating rod reveals that a granular hysteresis effect causes the overestimation of the body thrust forces in the RFT. Our models provide detailed testable predictions for biological locomotion in a granular environment.'),
(85796, 2012, 'plos', 'Chapter 2: Data-driven view of disease biology', 'Greene, Casey S|Troyanskaya, Olga G', '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', 10, 'Bayes Theorem|Cell Line|Disease|Genome, Human|Humans', 'Journal Article', '10.1371/journal.pcbi.1002816', '23300408', 'Modern experimental strategies often generate genome-scale measurements of human tissues or cell lines in various physiological states. Investigators often use these datasets individually to help elucidate molecular mechanisms of human diseases. Here we discuss approaches that effectively weight and integrate hundreds of heterogeneous datasets to gene-gene networks that focus on a specific process or disease. Diverse and systematic genome-scale measurements provide such approaches both a great deal of power and a number of challenges. We discuss some such challenges as well as methods to address them. We also raise important considerations for the assessment and evaluation of such approaches. When carefully applied, these integrative data-driven methods can make novel high-quality predictions that can transform our understanding of the molecular-basis of human disease.'),
(85797, 2012, 'plos', 'Chapter 7: Pharmacogenomics', 'Karczewski, Konrad J|Daneshjou, Roxana|Altman, Russ B', 'Program in Biomedical Informatics, Stanford University, Stanford, California, United States of America.|Program in Biomedical Informatics, Stanford University, Stanford, California, United States of America.|Program in Biomedical Informatics, Stanford University, Stanford, California, United States of America.', 'United States|United States|United States', 0, 'Drug Discovery|Genome-Wide Association Study|Humans|Pharmacogenetics', 'Journal Article', '10.1371/journal.pcbi.1002817', '23300409', 'There is great variation in drug-response phenotypes, and a one size fits all paradigm for drug delivery is flawed. Pharmacogenomics is the study of how human genetic information impacts drug response, and it aims to improve efficacy and reduced side effects. In this article, we provide an overview of pharmacogenetics, including pharmacokinetics (PK), pharmacodynamics (PD), gene and pathway interactions, and off-target effects. We describe methods for discovering genetic factors in drug response, including genome-wide association studies (GWAS), expression analysis, and other methods such as chemoinformatics and natural language processing (NLP). We cover the practical applications of pharmacogenomics both in the pharmaceutical industry and in a clinical setting. In drug discovery, pharmacogenomics can be used to aid lead identification, anticipate adverse events, and assist in drug repurposing efforts. Moreover, pharmacogenomic discoveries show promise as important elements of physician decision support. Finally, we consider the ethical, regulatory, and reimbursement challenges that remain for the clinical implementation of pharmacogenomics.'),
(85798, 2012, 'plos', 'Chapter 4: Protein interactions and disease', 'Gonzalez, Mileidy W|Kann, Maricel G', 'National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America.|National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America.', 'United States|United States', 101, 'Disease|Humans|Mutation|Protein Binding', 'Journal Article', '10.1371/journal.pcbi.1002819', '23300410', 'Proteins do not function in isolation, it is their interactions with one another and also with other molecules (e.g. DNA, RNA) that mediate metabolic and signaling pathways, cellular processes, and organismal systems. Due to their central role in biological function, protein interactions also control the mechanisms leading to healthy and diseased states in organisms. Diseases are often caused by mutations affecting the binding interface or leading to biochemically dysfunctional allosteric changes in proteins. Therefore, protein interaction networks can elucidate the molecular basis of disease, which in turn can inform methods for prevention, diagnosis, and treatment. In this chapter, we will describe the computational approaches to predict and map networks of protein interactions and briefly review the experimental methods to detect protein interactions. We will describe the application of protein interaction networks as a translational approach to the study of human disease and evaluate the challenges faced by these approaches.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85799, 2012, 'plos', 'Chapter 5: Network biology approach to complex diseases', 'Cho, Dong-Yeon|Kim, Yoo-Ah|Przytycka, Teresa M', 'National Center for Biotechnology Information, NLM, NIH, Bethesda, Maryland, United States of America.|National Center for Biotechnology Information, NLM, NIH, Bethesda, Maryland, United States of America.|National Center for Biotechnology Information, NLM, NIH, Bethesda, Maryland, United States of America.', 'United States|United States|United States', 0, 'Disease|Humans', 'Journal Article', '10.1371/journal.pcbi.1002820', '23300411', 'Complex diseases are caused by a combination of genetic and environmental factors. Uncovering the molecular pathways through which genetic factors affect a phenotype is always difficult, but in the case of complex diseases this is further complicated since genetic factors in affected individuals might be different. In recent years, systems biology approaches and, more specifically, network based approaches emerged as powerful tools for studying complex diseases. These approaches are often built on the knowledge of physical or functional interactions between molecules which are usually represented as an interaction network. An interaction network not only reports the binary relationships between individual nodes but also encodes hidden higher level organization of cellular communication. Computational biologists were challenged with the task of uncovering this organization and utilizing it for the understanding of disease complexity, which prompted rich and diverse algorithmic approaches to be proposed. We start this chapter with a description of the general characteristics of complex diseases followed by a brief introduction to physical and functional networks. Next we will show how these networks are used to leverage genotype, gene expression, and other types of data to identify dysregulated pathways, infer the relationships between genotype and phenotype, and explain disease heterogeneity. We group the methods by common underlying principles and first provide a high level description of the principles followed by more specific examples. We hope that this chapter will give readers an appreciation for the wealth of algorithmic techniques that have been developed for the purpose of studying complex diseases as well as insight into their strengths and limitations.'),
(85800, 2012, 'plos', 'Chapter 6: Structural variation and medical genomics', 'Raphael, Benjamin J', 'Department of Computer Science and Center for Computational Molecular Biology, Brown University, Providence, Rhode Island, United States of America. braphael@brown.edu', 'United States', 0, 'Genome, Human|Humans|Oligonucleotide Array Sequence Analysis', 'Journal Article', '10.1371/journal.pcbi.1002821', '23300412', 'Differences between individual human genomes, or between human and cancer genomes, range in scale from single nucleotide variants (SNVs) through intermediate and large-scale duplications, deletions, and rearrangements of genomic segments. The latter class, called structural variants (SVs), have received considerable attention in the past several years as they are a previously under appreciated source of variation in human genomes. Much of this recent attention is the result of the availability of higher-resolution technologies for measuring these variants, including both microarray-based techniques, and more recently, high-throughput DNA sequencing. We describe the genomic technologies and computational techniques currently used to measure SVs, focusing on applications in human and cancer genomics.'),
(85801, 2012, 'plos', 'Chapter 11: Genome-wide association studies', 'Bush, William S|Moore, Jason H', 'Department of Biomedical Informatics, Center for Human Genetics Research, Vanderbilt University Medical School, Nashville, Tennessee, United States of America. william.s.bush@vanderbilt.edu|Department of Biomedical Informatics, Center for Human Genetics Research, Vanderbilt University Medical School, Nashville, Tennessee, United States of America. william.s.bush@vanderbilt.edu', 'United States|United States', 0, 'Electronic Health Records|Genetic Linkage|Genetic Variation|Genome-Wide Association Study|Haplotypes|Humans|Phenotype', 'Journal Article', '10.1371/journal.pcbi.1002822', '23300413', 'Genome-wide association studies (GWAS) have evolved over the last ten years into a powerful tool for investigating the genetic architecture of human disease. In this work, we review the key concepts underlying GWAS, including the architecture of common diseases, the structure of common human genetic variation, technologies for capturing genetic information, study designs, and the statistical methods used for data analysis. We also look forward to the future beyond GWAS.'),
(85802, 2012, 'plos', 'Chapter 13: Mining electronic health records in the genomics era', 'Denny, Joshua C', 'Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America. josh.denny@vanderbilt.edu', 'United States', 96, 'Continental Population Groups|Drug Therapy|Ethnic Groups|Genome, Human|Humans|Information Storage and Retrieval|Medical Records Systems, Computerized|Phenotype', 'Journal Article', '10.1371/journal.pcbi.1002823', '23300414', 'The combination of improved genomic analysis methods, decreasing genotyping costs, and increasing computing resources has led to an explosion of clinical genomic knowledge in the last decade. Similarly, healthcare systems are increasingly adopting robust electronic health record (EHR) systems that not only can improve health care, but also contain a vast repository of disease and treatment data that could be mined for genomic research. Indeed, institutions are creating EHR-linked DNA biobanks to enable genomic and pharmacogenomic research, using EHR data for phenotypic information. However, EHRs are designed primarily for clinical care, not research, so reuse of clinical EHR data for research purposes can be challenging. Difficulties in use of EHR data include: data availability, missing data, incorrect data, and vast quantities of unstructured narrative text data. Structured information includes billing codes, most laboratory reports, and other variables such as physiologic measurements and demographic information. Significant information, however, remains locked within EHR narrative text documents, including clinical notes and certain categories of test results, such as pathology and radiology reports. For relatively rare observations, combinations of simple free-text searches and billing codes may prove adequate when followed by manual chart review. However, to extract the large cohorts necessary for genome-wide association studies, natural language processing methods to process narrative text data may be needed. Combinations of structured and unstructured textual data can be mined to generate high-validity collections of cases and controls for a given condition. Once high-quality cases and controls are identified, EHR-derived cases can be used for genomic discovery and validation. Since EHR data includes a broad sampling of clinically-relevant phenotypic information, it may enable multiple genomic investigations upon a single set of genotyped individuals. This chapter reviews several examples of phenotype extraction and their application to genetic research, demonstrating a viable future for genomic discovery using EHR-linked data.'),
(85803, 2012, 'plos', 'Chapter 14: Cancer genome analysis', 'Vazquez, Miguel|de la Torre, Victor|Valencia, Alfonso', 'Structural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.|Structural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.|Structural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.', 'Spain|Spain|Spain', 0, 'Computational Biology|Databases, Genetic|Genes, Neoplasm|Genome, Human|Humans', 'Journal Article', '10.1371/journal.pcbi.1002824', '23300415', 'Although there is great promise in the benefits to be obtained by analyzing cancer genomes, numerous challenges hinder different stages of the process, from the problem of sample preparation and the validation of the experimental techniques, to the interpretation of the results. This chapter specifically focuses on the technical issues associated with the bioinformatics analysis of cancer genome data. The main issues addressed are the use of database and software resources, the use of analysis workflows and the presentation of clinically relevant action items. We attempt to aid new developers in the field by describing the different stages of analysis and discussing current approaches, as well as by providing practical advice on how to access and use resources, and how to implement recommendations. Real cases from cancer genome projects are used as examples.'),
(85804, 2012, 'plos', 'Chapter 1: Biomedical knowledge integration', 'Payne, Philip R O', 'The Ohio State University, Department of Biomedical Informatics, Columbus, Ohio, United States of America. philip.payne@osumc.edu', 'United States', 0, 'Biomedical Research|Knowledge', 'Journal Article', '10.1371/journal.pcbi.1002826', '23300416', 'The modern biomedical research and healthcare delivery domains have seen an unparalleled increase in the rate of innovation and novel technologies over the past several decades. Catalyzed by paradigm-shifting public and private programs focusing upon the formation and delivery of genomic and personalized medicine, the need for high-throughput and integrative approaches to the collection, management, and analysis of heterogeneous data sets has become imperative. This need is particularly pressing in the translational bioinformatics domain, where many fundamental research questions require the integration of large scale, multi-dimensional clinical phenotype and bio-molecular data sets. Modern biomedical informatics theory and practice has demonstrated the distinct benefits associated with the use of knowledge-based systems in such contexts. A knowledge-based system can be defined as an intelligent agent that employs a computationally tractable knowledge base or repository in order to reason upon data in a targeted domain and reproduce expert performance relative to such reasoning operations. The ultimate goal of the design and use of such agents is to increase the reproducibility, scalability, and accessibility of complex reasoning tasks. Examples of the application of knowledge-based systems in biomedicine span a broad spectrum, from the execution of clinical decision support, to epidemiologic surveillance of public data sets for the purposes of detecting emerging infectious diseases, to the discovery of novel hypotheses in large-scale research data sets. In this chapter, we will review the basic theoretical frameworks that define core knowledge types and reasoning operations with particular emphasis on the applicability of such conceptual models within the biomedical domain, and then go on to introduce a number of prototypical data integration requirements and patterns relevant to the conduct of translational bioinformatics that can be addressed via the design and use of knowledge-based systems.'),
(85805, 2012, 'plos', 'Chapter 9: Analyses using disease ontologies', 'Shah, Nigam H|Cole, Tyler|Musen, Mark A', 'Center for Biomedical Informatics Research, Stanford University, Stanford, California, United States of America. nigam@stanford.edu|Center for Biomedical Informatics Research, Stanford University, Stanford, California, United States of America. nigam@stanford.edu|Center for Biomedical Informatics Research, Stanford University, Stanford, California, United States of America. nigam@stanford.edu', 'United States|United States|United States', 16, 'Automation|Databases, Factual|Disease|Humans', 'Journal Article', '10.1371/journal.pcbi.1002827', '23300417', 'Advanced statistical methods used to analyze high-throughput data such as gene-expression assays result in long lists of significant genes. One way to gain insight into the significance of altered expression levels is to determine whether Gene Ontology (GO) terms associated with a particular biological process, molecular function, or cellular component are over- or under-represented in the set of genes deemed significant. This process, referred to as enrichment analysis, profiles a gene-set, and is widely used to makes sense of the results of high-throughput experiments. The canonical example of enrichment analysis is when the output dataset is a list of genes differentially expressed in some condition. To determine the biological relevance of a lengthy gene list, the usual solution is to perform enrichment analysis with the GO. We can aggregate the annotating GO concepts for each gene in this list, and arrive at a profile of the biological processes or mechanisms affected by the condition under study. While GO has been the principal target for enrichment analysis, the methods of enrichment analysis are generalizable. We can conduct the same sort of profiling along other ontologies of interest. Just as scientists can ask Which biological process is over-represented in my set of interesting genes or proteins? we can also ask Which disease (or class of diseases) is over-represented in my set of interesting genes or proteins?. For example, by annotating known protein mutations with disease terms from the ontologies in BioPortal, Mort et al. recently identified a class of diseases--blood coagulation disorders--that were associated with a 14-fold depletion in substitutions at O-linked glycosylation sites. With the availability of tools for automatic annotation of datasets with terms from disease ontologies, there is no reason to restrict enrichment analyses to the GO. In this chapter, we will discuss methods to perform enrichment analysis using any ontology available in the biomedical domain. We will review the general methodology of enrichment analysis, the associated challenges, and discuss the novel translational analyses enabled by the existence of public, national computational infrastructure and by the use of disease ontologies in such analyses.'),
(85806, 2012, 'plos', 'Chapter 10: Mining genome-wide genetic markers', 'Zhang, Xiang|Huang, Shunping|Zhang, Zhaojun|Wang, Wei', 'Department of Electrical Engineering and Computer Science, Case Western Reserve University, Ohio, United States of America.|Department of Electrical Engineering and Computer Science, Case Western Reserve University, Ohio, United States of America.|Department of Electrical Engineering and Computer Science, Case Western Reserve University, Ohio, United States of America.|Department of Electrical Engineering and Computer Science, Case Western Reserve University, Ohio, United States of America.', 'United States|United States|United States|United States', 8, 'Algorithms|Genetic Markers|Genome-Wide Association Study|Humans|Information Storage and Retrieval|Models, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002828', '23300418', 'Genome-wide association study (GWAS) aims to discover genetic factors underlying phenotypic traits. The large number of genetic factors poses both computational and statistical challenges. Various computational approaches have been developed for large scale GWAS. In this chapter, we will discuss several widely used computational approaches in GWAS. The following topics will be covered: (1) An introduction to the background of GWAS. (2) The existing computational approaches that are widely used in GWAS. This will cover single-locus, epistasis detection, and machine learning methods that have been recently developed in biology, statistic, and computer science communities. This part will be the main focus of this chapter. (3) The limitations of current approaches and future directions.'),
(85807, 2012, 'plos', 'Reliable B cell epitope predictions: impacts of method development and improved benchmarking', 'Kringelum, Jens Vindahl|Lundegaard, Claus|Lund, Ole|Nielsen, Morten', 'Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.|Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.|Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.|Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.', 'Denmark|Denmark|Denmark|Denmark', 0, 'B-Lymphocytes|Benchmarking|Epitopes|Humans|Models, Molecular|Odds Ratio', 'Journal Article', '10.1371/journal.pcbi.1002829', '23300419', 'The interaction between antibodies and antigens is one of the most important immune system mechanisms for clearing infectious organisms from the host. Antibodies bind to antigens at sites referred to as B-cell epitopes. Identification of the exact location of B-cell epitopes is essential in several biomedical applications such as, rational vaccine design, development of disease diagnostics and immunotherapeutics. However, experimental mapping of epitopes is resource intensive making in silico methods an appealing complementary approach. To date, the reported performance of methods for in silico mapping of B-cell epitopes has been moderate. Several issues regarding the evaluation data sets may however have led to the performance values being underestimated: Rarely, all potential epitopes have been mapped on an antigen, and antibodies are generally raised against the antigen in a given biological context not against the antigen monomer. Improper dealing with these aspects leads to many artificial false positive predictions and hence to incorrect low performance values. To demonstrate the impact of proper benchmark definitions, we here present an updated version of the DiscoTope method incorporating a novel spatial neighborhood definition and half-sphere exposure as surface measure. Compared to other state-of-the-art prediction methods, Discotope-2.0 displayed improved performance both in cross-validation and in independent evaluations. Using DiscoTope-2.0, we assessed the impact on performance when using proper benchmark definitions. For 13 proteins in the training data set where sufficient biological information was available to make a proper benchmark redefinition, the average AUC performance was improved from 0.791 to 0.824. Similarly, the average AUC performance on an independent evaluation data set improved from 0.712 to 0.727. Our results thus demonstrate that given proper benchmark definitions, B-cell epitope prediction methods achieve highly significant predictive performances suggesting these tools to be a powerful asset in rational epitope discovery. The updated version of DiscoTope is available at www.cbs.dtu.dk/services/DiscoTope-2.0.'),
(85808, 2012, 'plos', 'Phylodynamic inference and model assessment with approximate bayesian computation: influenza as a case study', 'Ratmann, Oliver|Donker, Gé|Meijer, Adam|Fraser, Christophe|Koelle, Katia', 'Department of Biology, Duke University, Durham, North Carolina, United States of America. oliver.ratmann@imperial.ac.uk|Department of Biology, Duke University, Durham, North Carolina, United States of America. oliver.ratmann@imperial.ac.uk|Department of Biology, Duke University, Durham, North Carolina, United States of America. oliver.ratmann@imperial.ac.uk|Department of Biology, Duke University, Durham, North Carolina, United States of America. oliver.ratmann@imperial.ac.uk|Department of Biology, Duke University, Durham, North Carolina, United States of America. oliver.ratmann@imperial.ac.uk', 'United States|United States|United States|United States|United States', 20, 'Bayes Theorem|Geography|Humans|Influenza A Virus, H3N2 Subtype|Influenza, Human|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1002835', '23300420', 'A key priority in infectious disease research is to understand the ecological and evolutionary drivers of viral diseases from data on disease incidence as well as viral genetic and antigenic variation. We propose using a simulation-based, Bayesian method known as Approximate Bayesian Computation (ABC) to fit and assess phylodynamic models that simulate pathogen evolution and ecology against summaries of these data. We illustrate the versatility of the method by analyzing two spatial models describing the phylodynamics of interpandemic human influenza virus subtype A(H3N2). The first model captures antigenic drift phenomenologically with continuously waning immunity, and the second epochal evolution model describes the replacement of major, relatively long-lived antigenic clusters. Combining features of long-term surveillance data from The Netherlands with features of influenza A (H3N2) hemagglutinin gene sequences sampled in northern Europe, key phylodynamic parameters can be estimated with ABC. Goodness-of-fit analyses reveal that the irregularity in interannual incidence and H3N2s ladder-like hemagglutinin phylogeny are quantitatively only reproduced under the epochal evolution model within a spatial context. However, the concomitant incidence dynamics result in a very large reproductive number and are not consistent with empirical estimates of H3N2s population level attack rate. These results demonstrate that the interactions between the evolutionary and ecological processes impose multiple quantitative constraints on the phylodynamic trajectories of influenza A(H3N2), so that sequence and surveillance data can be used synergistically. ABC, one of several data synthesis approaches, can easily interface a broad class of phylodynamic models with various types of data but requires careful calibration of the summaries and tolerance parameters.'),
(85809, 2012, 'plos', 'A universal trend among proteomes indicates an oily last common ancestor', 'Mannige, Ranjan V|Brooks, Charles L|Shakhnovich, Eugene I', 'Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America. rvmannige@lbl.gov|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America. rvmannige@lbl.gov|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America. rvmannige@lbl.gov', 'United States|United States|United States', 0, 'Evolution, Molecular|Gene Transfer, Horizontal|Oils|Phylogeny|Proteome|Recombination, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002839', '23300421', 'Despite progresses in ancestral protein sequence reconstruction, much needs to be unraveled about the nature of the putative last common ancestral proteome that served as the prototype of all extant lifeforms. Here, we present data that indicate a steady decline (oil escape) in proteome hydrophobicity over species evolvedness (node number) evident in 272 diverse proteomes, which indicates a highly hydrophobic (oily) last common ancestor (LCA). This trend, obtained from simple considerations (free from sequence reconstruction methods), was corroborated by regression studies within homologous and orthologous protein clusters as well as phylogenetic estimates of the ancestral oil content. While indicating an inherent irreversibility in molecular evolution, oil escape also serves as a rare and universal reaction-coordinate for evolution (reinforcing Darwins principle of Common Descent), and may prove important in matters such as (i) explaining the emergence of intrinsically disordered proteins, (ii) developing composition- and speciation-based global molecular clocks, and (iii) improving the statistical methods for ancestral sequence reconstruction.'),
(85810, 2012, 'plos', 'The two sides of complement C3d: evolution of electrostatics in a link between innate and adaptive immunity', 'Kieslich, Chris A|Morikis, Dimitrios', 'Department of Bioengineering, University of California, Riverside, Riverside, California, United States of America.|Department of Bioengineering, University of California, Riverside, Riverside, California, United States of America.', 'United States|United States', 19, 'Adaptive Immunity|Animals|Complement C3d|Humans|Immunity, Innate|Models, Molecular|Static Electricity', 'Journal Article', '10.1371/journal.pcbi.1002840', '23300422', 'The interaction between complement fragment C3d and complement receptor 2 (CR2) is a key aspect of complement immune system activation, and is a component in a link between innate and adaptive immunities. The complement immune system is an ancient mechanism for defense, and can be found in species that have been on Earth for the last 600 million years. However, the link between the complement system and adaptive immunity, which is formed through the association of the B-cell co-receptor complex, including the C3d-CR2 interaction, is a much more recent adaptation. Human C3d and CR2 have net charges of -1 and +7 respectively, and are believed to have evolved favoring the role of electrostatics in their functions. To investigate the role of electrostatics in the function and evolution of human C3d and CR2, we have applied electrostatic similarity methods to identify regions of evolutionarily conserved electrostatic potential based on 24 homologues of complement C3d and 4 homologues of CR2. We also examine the effects of structural perturbation, as introduced through molecular dynamics and mutations, on spatial distributions of electrostatic potential to identify perturbation resistant regions, generated by so-called electrostatic hot-spots. Distributions of electrostatic similarity based on families of perturbed structures illustrate the presence of electrostatic hot-spots at the two functional sites of C3d, while the surface of CR2 lacks electrostatic hot-spots despite its excessively positive nature. We propose that the electrostatic hot-spots of C3d have evolved to optimize its dual-functionality (covalently attaching to pathogen surfaces and interaction with CR2), which are both necessary for the formation B-cell co-receptor complexes. Comparison of the perturbation resistance of the electrostatic character of the homologues of C3d suggests that there was an emergence of a new role of electrostatics, and a transition in the function of C3d, after the divergence of jawless fish.'),
(85811, 2012, 'plos', 'Computational phenotyping of two-person interactions reveals differential neural response to depth-of-thought', 'Xiang, Ting|Ray, Debajyoti|Lohrenz, Terry|Dayan, Peter|Montague, P Read', 'Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.', 'United States|United States|United States|United States|United States', 32, 'Analysis of Variance|Biosensing Techniques|Central Nervous System|Computational Biology|Humans|Interpersonal Relations|Reference Values', 'Journal Article', '10.1371/journal.pcbi.1002841', '23300423', 'Reciprocating exchange with other humans requires individuals to infer the intentions of their partners. Despite the importance of this ability in healthy cognition and its impact in disease, the dimensions employed and computations involved in such inferences are not clear. We used a computational theory-of-mind model to classify styles of interaction in 195 pairs of subjects playing a multi-round economic exchange game. This classification produces an estimate of a subjects depth-of-thought in the game (low, medium, high), a parameter that governs the richness of the models they build of their partner. Subjects in each category showed distinct neural correlates of learning signals associated with different depths-of-thought. The model also detected differences in depth-of-thought between two groups of healthy subjects: one playing patients with psychiatric disease and the other playing healthy controls. The neural response categories identified by this computational characterization of theory-of-mind may yield objective biomarkers useful in the identification and characterization of pathologies that perturb the capacity to model and interact with other humans.'),
(85812, 2012, 'plos', 'Molecular mechanism of allosteric communication in Hsp70 revealed by molecular dynamics simulations', 'Chiappori, Federica|Merelli, Ivan|Colombo, Giorgio|Milanesi, Luciano|Morra, Giulia', 'Istituto di Tecnologie Biomediche-Consiglio Nazionale delle Ricerche (ITB-CNR), Segrate (Mi), Italy.|Istituto di Tecnologie Biomediche-Consiglio Nazionale delle Ricerche (ITB-CNR), Segrate (Mi), Italy.|Istituto di Tecnologie Biomediche-Consiglio Nazionale delle Ricerche (ITB-CNR), Segrate (Mi), Italy.|Istituto di Tecnologie Biomediche-Consiglio Nazionale delle Ricerche (ITB-CNR), Segrate (Mi), Italy.|Istituto di Tecnologie Biomediche-Consiglio Nazionale delle Ricerche (ITB-CNR), Segrate (Mi), Italy.', 'Italy|Italy|Italy|Italy|Italy', 43, 'Allosteric Regulation|Amino Acid Sequence|Binding Sites|HSP70 Heat-Shock Proteins|Hydrogen Bonding|Models, Molecular|Molecular Dynamics Simulation|Molecular Sequence Data|Protein Conformation|Sequence Homology, Amino Acid', 'Journal Article', '10.1371/journal.pcbi.1002844', '23300424', 'Investigating ligand-regulated allosteric coupling between protein domains is fundamental to understand cell-life regulation. The Hsp70 family of chaperones represents an example of proteins in which ATP binding and hydrolysis at the Nucleotide Binding Domain (NBD) modulate substrate recognition at the Substrate Binding Domain (SBD). Herein, a comparative analysis of an allosteric (Hsp70-DnaK) and a non-allosteric structural homolog (Hsp110-Sse1) of the Hsp70 family is carried out through molecular dynamics simulations, starting from different conformations and ligand-states. Analysis of ligand-dependent modulation of internal fluctuations and local deformation patterns highlights the structural and dynamical changes occurring at residue level upon ATP-ADP exchange, which are connected to the conformational transition between closed and open structures. By identifying the dynamically responsive protein regions and specific cross-domain hydrogen-bonding patterns that differentiate Hsp70 from Hsp110 as a function of the nucleotide, we propose a molecular mechanism for the allosteric signal propagation of the ATP-encoded conformational signal.'),
(85813, 2012, 'plos', 'Using molecular mechanics to predict bulk material properties of fibronectin fibers', 'Bradshaw, Mark J|Cheung, Man C|Ehrlich, Daniel J|Smith, Michael L', 'Department of Mechanical Engineering, Boston University, Boston, Massachusetts, United States of America.|Department of Mechanical Engineering, Boston University, Boston, Massachusetts, United States of America.|Department of Mechanical Engineering, Boston University, Boston, Massachusetts, United States of America.|Department of Mechanical Engineering, Boston University, Boston, Massachusetts, United States of America.', 'United States|United States|United States|United States', 18, 'Extracellular Matrix|Fibronectins|Microscopy|Models, Molecular|Protein Conformation|Protein Denaturation', 'Journal Article', '10.1371/journal.pcbi.1002845', '23300425', 'The structural proteins of the extracellular matrix (ECM) form fibers with finely tuned mechanical properties matched to the time scales of cell traction forces. Several proteins such as fibronectin (Fn) and fibrin undergo molecular conformational changes that extend the proteins and are believed to be a major contributor to the extensibility of bulk fibers. The dynamics of these conformational changes have been thoroughly explored since the advent of single molecule force spectroscopy and molecular dynamics simulations but remarkably, these data have not been rigorously applied to the understanding of the time dependent mechanics of bulk ECM fibers. Using measurements of protein density within fibers, we have examined the influence of dynamic molecular conformational changes and the intermolecular arrangement of Fn within fibers on the bulk mechanical properties of Fn fibers. Fibers were simulated as molecular strands with architectures that promote either equal or disparate molecular loading under conditions of constant extension rate. Measurements of protein concentration within micron scale fibers using deep ultraviolet transmission microscopy allowed the simulations to be scaled appropriately for comparison to in vitro measurements of fiber mechanics as well as providing estimates of fiber porosity and water content, suggesting Fn fibers are approximately 75% solute. Comparing the properties predicted by single molecule measurements to in vitro measurements of Fn fibers showed that domain unfolding is sufficient to predict the high extensibility and nonlinear stiffness of Fn fibers with surprising accuracy, with disparately loaded fibers providing the best fit to experiment. This work shows the promise of this microstructural modeling approach for understanding Fn fiber properties, which is generally applicable to other ECM fibers, and could be further expanded to tissue scale by incorporating these simulated fibers into three dimensional network models.'),
(85814, 2012, 'plos', 'Calcium wave propagation in networks of endothelial cells: model-based theoretical and experimental study', 'Long, Juexuan|Junkin, Michael|Wong, Pak Kin|Hoying, James|Deymier, Pierre', 'Material Science and Engineering, University of Arizona, Tucson, Arizona, United States of America. juexuanl@email.arizona.edu|Material Science and Engineering, University of Arizona, Tucson, Arizona, United States of America. juexuanl@email.arizona.edu|Material Science and Engineering, University of Arizona, Tucson, Arizona, United States of America. juexuanl@email.arizona.edu|Material Science and Engineering, University of Arizona, Tucson, Arizona, United States of America. juexuanl@email.arizona.edu|Material Science and Engineering, University of Arizona, Tucson, Arizona, United States of America. juexuanl@email.arizona.edu', 'United States|United States|United States|United States|United States', 19, 'Calcium|Cells, Cultured|Computer Simulation|Diffusion|Endothelium, Vascular|Gap Junctions|Humans|Microscopy, Fluorescence|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1002847', '23300426', 'In this paper, we present a combined theoretical and experimental study of the propagation of calcium signals in multicellular structures composed of human endothelial cells. We consider multicellular structures composed of a single chain of cells as well as a chain of cells with a side branch, namely a T structure. In the experiments, we investigate the result of applying mechano-stimulation to induce signaling in the form of calcium waves along the chain and the effect of single and dual stimulation of the multicellular structure. The experimental results provide evidence of an effect of architecture on the propagation of calcium waves. Simulations based on a model of calcium-induced calcium release and cell-to-cell diffusion through gap junctions shows that the propagation of calcium waves is dependent upon the competition between intracellular calcium regulation and architecture-dependent intercellular diffusion.'),
(85815, 2012, 'plos', 'Interconnected cavernous structure of bacterial fruiting bodies', 'Harvey, Cameron W|Du, Huijing|Xu, Zhiliang|Kaiser, Dale|Aranson, Igor|Alber, Mark', 'Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, Indiana, United States of America.|Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, Indiana, United States of America.|Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, Indiana, United States of America.|Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, Indiana, United States of America.|Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, Indiana, United States of America.|Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, Indiana, United States of America.', 'India|India|India|India|India|India', 7, 'Computer Simulation|Green Fluorescent Proteins|Microscopy, Electron, Scanning|Myxococcus xanthus|Spores, Bacterial|Tomography, Optical Coherence', 'Journal Article', '10.1371/journal.pcbi.1002850', '23300427', 'The formation of spore-filled fruiting bodies by myxobacteria is a fascinating case of multicellular self-organization by bacteria. The organization of Myxococcus xanthus into fruiting bodies has long been studied not only as an important example of collective motion of bacteria, but also as a simplified model for developmental morphogenesis. Sporulation within the nascent fruiting body requires signaling between moving cells in order that the rod-shaped self-propelled cells differentiate into spores at the appropriate time. Probing the three-dimensional structure of myxobacteria fruiting bodies has previously presented a challenge due to limitations of different imaging methods. A new technique using Infrared Optical Coherence Tomography (OCT) revealed previously unknown details of the internal structure of M. xanthus fruiting bodies consisting of interconnected pockets of relative high and low spore density regions. To make sense of the experimentally observed structure, modeling and computer simulations were used to test a hypothesized mechanism that could produce high-density pockets of spores. The mechanism consists of self-propelled cells aligning with each other and signaling by end-to-end contact to coordinate the process of differentiation resulting in a pattern of clusters observed in the experiment. The integration of novel OCT experimental techniques with computational simulations can provide new insight into the mechanisms that can give rise to the pattern formation seen in other biological systems such as dictyostelids, social amoeba known to form multicellular aggregates observed as slugs under starvation conditions.'),
(85816, 2012, 'plos', 'What is the role of motif D in the nucleotide incorporation catalyzed by the RNA-dependent RNA polymerase from poliovirus?', 'Shen, Hujun|Sun, Hui|Li, Guohui', 'Laboratory of Molecular Modeling and Design, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.|Laboratory of Molecular Modeling and Design, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.|Laboratory of Molecular Modeling and Design, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.', 'China|China|China', 43, 'Biocatalysis|Models, Molecular|Molecular Dynamics Simulation|Nucleotides|Poliovirus|Quantum Theory|RNA Replicase', 'Journal Article', '10.1371/journal.pcbi.1002851', '23300428', 'Poliovirus (PV) is a well-characterized RNA virus, and the RNA-dependent RNA polymerase (RdRp) from PV (3D(pol)) has been widely employed as an important model for understanding the structure-function relationships of RNA and DNA polymerases. Many experimental studies of the kinetics of nucleotide incorporation by RNA and DNA polymerases suggest that each nucleotide incorporation cycle basically consists of six sequential steps: (1) an incoming nucleotide binds to the polymerase-primer/template complex, (2) the ternary complex (nucleotide-polymerase-primer/template) undergoes a conformational change, (3) phosphoryl transfer occurs (the chemistry step), (4) a post-chemistry conformational change occurs, (5) pyrophosphate is released, (6) RNA or DNA translocation. Recently, the importance of structural motif D in nucleotide incorporation has been recognized, but the functions of motif D are less well explored so far. In this work, we used two computational techniques, molecular dynamics (MD) simulation and quantum mechanics (QM) method, to explore the roles of motif D in nucleotide incorporation catalyzed by PV 3D(pol). We discovered that the motif D, exhibiting high flexibility in either the presence or the absence of RNA primer/template, might facilitate the transportation of incoming nucleotide or outgoing pyrophosphate. We observed that the dynamic behavior of motif A, which should be essential to the polymerase function, was greatly affected by the motions of motif D. In the end, through QM calculations, we attempted to investigate the proton transfer in enzyme catalysis associated with a few amino acid residues of motifs F and D.'),
(85817, 2012, 'plos', 'Chapter 8: Biological knowledge assembly and interpretation', 'Kim, Ju Han', 'Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, Korea. juhan@snu.ac.kr', '-', 5, 'Gene Expression Profiling|Knowledge|Oligonucleotide Array Sequence Analysis|RNA, Messenger', 'Journal Article', '10.1371/journal.pcbi.1002858', '23300429', 'Most methods for large-scale gene expression microarray and RNA-Seq data analysis are designed to determine the lists of genes or gene products that show distinct patterns and/or significant differences. The most challenging and rate-liming step, however, is to determine what the resulting lists of genes and/or transcripts biologically mean. Biomedical ontology and pathway-based functional enrichment analysis is widely used to interpret the functional role of tightly correlated or differentially expressed genes. The groups of genes are assigned to the associated biological annotations using Gene Ontology terms or biological pathways and then tested if they are significantly enriched with the corresponding annotations. Unlike previous approaches, Gene Set Enrichment Analysis takes quite the reverse approach by using pre-defined gene sets. Differential co-expression analysis determines the degree of co-expression difference of paired gene sets across different conditions. Outcomes in DNA microarray and RNA-Seq data can be transformed into the graphical structure that represents biological semantics. A number of biomedical annotation and external repositories including clinical resources can be systematically integrated by biological semantics within the framework of concept lattice analysis. This array of methods for biological knowledge assembly and interpretation has been developed during the past decade and clearly improved our biological understanding of large-scale genomic data from the high-throughput technologies.'),
(85818, 2013, 'plos', 'Refractoriness in sustained visuo-manual control: is the refractory duration intrinsic or does it depend on external system properties?', 'van de Kamp, Cornelis|Gawthrop, Peter J|Gollee, Henrik|Loram, Ian D', 'Institute for Biomedical Research into Human Movement and Health, Manchester Metropolitan University, Manchester, United Kingdom. c.vandekamp@mmu.ac.uk|Institute for Biomedical Research into Human Movement and Health, Manchester Metropolitan University, Manchester, United Kingdom. c.vandekamp@mmu.ac.uk|Institute for Biomedical Research into Human Movement and Health, Manchester Metropolitan University, Manchester, United Kingdom. c.vandekamp@mmu.ac.uk|Institute for Biomedical Research into Human Movement and Health, Manchester Metropolitan University, Manchester, United Kingdom. c.vandekamp@mmu.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 32, 'Hand|Humans|Movement|Psychomotor Performance|Vision, Ocular', 'Journal Article', '10.1371/journal.pcbi.1002843', '23300430', 'Researchers have previously adopted the double stimulus paradigm to study refractoriness in human neuromotor control. Currently, refractoriness, such as the Psychological Refractory Period (PRP) has only been quantified in discrete movement conditions. Whether refractoriness and the associated serial ballistic hypothesis generalises to sustained control tasks has remained open for more than sixty years. Recently, a method of analysis has been presented that quantifies refractoriness in sustained control tasks and discriminates intermittent (serial ballistic) from continuous control. Following our recent demonstration that continuous control of an unstable second order system (i.e. balancing a virtual inverted pendulum through a joystick interface) is unnecessary, we ask whether refractoriness of substantial duration (~200 ms) is evident in sustained visual-manual control of external systems. We ask whether the refractory duration (i) is physiologically intrinsic, (ii) depends upon system properties like the order (0, 1(st), and 2(nd)) or stability, (iii) depends upon target jump direction (reversal, same direction). Thirteen participants used discrete movements (zero order system) as well as more sustained control activity (1(st) and 2(nd) order systems) to track unpredictable step-sequence targets. Results show a substantial refractory duration that depends upon system order (250, 350 and 550 ms for 0, 1(st) and 2(nd) order respectively, n=13, p<0.05), but not stability. In sustained control refractoriness was only found when the target reverses direction. In the presence of time varying actuators, systems and constraints, we propose that central refractoriness is an appropriate control mechanism for accommodating online optimization delays within the neural circuitry including the more variable processing times of higher order (complex) input-output relations.'),
(85819, 2013, 'plos', 'Network self-organization explains the statistics and dynamics of synaptic connection strengths in cortex', 'Zheng, Pengsheng|Dimitrakakis, Christos|Triesch, Jochen', 'Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany.|Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany.|Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany.', 'Germany|Germany|Germany', 0, 'Cerebral Cortex|Homeostasis|Humans|Learning|Memory|Nerve Net|Synapses', 'Journal Article', '10.1371/journal.pcbi.1002848', '23300431', 'The information processing abilities of neural circuits arise from their synaptic connection patterns. Understanding the laws governing these connectivity patterns is essential for understanding brain function. The overall distribution of synaptic strengths of local excitatory connections in cortex and hippocampus is long-tailed, exhibiting a small number of synaptic connections of very large efficacy. At the same time, new synaptic connections are constantly being created and individual synaptic connection strengths show substantial fluctuations across time. It remains unclear through what mechanisms these properties of neural circuits arise and how they contribute to learning and memory. In this study we show that fundamental characteristics of excitatory synaptic connections in cortex and hippocampus can be explained as a consequence of self-organization in a recurrent network combining spike-timing-dependent plasticity (STDP), structural plasticity and different forms of homeostatic plasticity. In the network, associative synaptic plasticity in the form of STDP induces a rich-get-richer dynamics among synapses, while homeostatic mechanisms induce competition. Under distinctly different initial conditions, the ensuing self-organization produces long-tailed synaptic strength distributions matching experimental findings. We show that this self-organization can take place with a purely additive STDP mechanism and that multiplicative weight dynamics emerge as a consequence of network interactions. The observed patterns of fluctuation of synaptic strengths, including elimination and generation of synaptic connections and long-term persistence of strong connections, are consistent with the dynamics of dendritic spines found in rat hippocampus. Beyond this, the model predicts an approximately power-law scaling of the lifetimes of newly established synaptic connection strengths during development. Our results suggest that the combined action of multiple forms of neuronal plasticity plays an essential role in the formation and maintenance of cortical circuits.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85820, 2013, 'plos', 'Identification of a functional connectome for long-term fear memory in mice', 'Wheeler, Anne L|Teixeira, Cátia M|Wang, Afra H|Xiong, Xuejian|Kovacevic, Natasa|Lerch, Jason P|McIntosh, Anthony R|Parkinson, John|Frankland, Paul W', 'Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.|Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.|Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.|Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.|Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.|Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.|Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.|Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.|Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.', 'Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada', 98, 'Animals|Brain|Fear|Immunohistochemistry|Memory|Mice|Mice, Mutant Strains|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.1002853', '23300432', 'Long-term memories are thought to depend upon the coordinated activation of a broad network of cortical and subcortical brain regions. However, the distributed nature of this representation has made it challenging to define the neural elements of the memory trace, and lesion and electrophysiological approaches provide only a narrow window into what is appreciated a much more global network. Here we used a global mapping approach to identify networks of brain regions activated following recall of long-term fear memories in mice. Analysis of Fos expression across 84 brain regions allowed us to identify regions that were co-active following memory recall. These analyses revealed that the functional organization of long-term fear memories depends on memory age and is altered in mutant mice that exhibit premature forgetting. Most importantly, these analyses indicate that long-term memory recall engages a network that has a distinct thalamic-hippocampal-cortical signature. This network is concurrently integrated and segregated and therefore has small-world properties, and contains hub-like regions in the prefrontal cortex and thalamus that may play privileged roles in memory expression.'),
(85821, 2013, 'plos', 'Adding protein context to the human protein-protein interaction network to reveal meaningful interactions', 'Schaefer, Martin H|Lopes, Tiago J S|Mah, Nancy|Shoemaker, Jason E|Matsuoka, Yukiko|Fontaine, Jean-Fred|Louis-Jeune, Caroline|Eisfeld, Amie J|Neumann, Gabriele|Perez-Iratxeta, Carol|Kawaoka, Yoshihiro|Kitano, Hiroaki|Andrade-Navarro, Miguel A', 'Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Berlin, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germ', 53, 'Alzheimer Disease|Biocatalysis|Humans|Phosphorylation|Protein Binding|Proteins|Proteome|Signal Transduction|Viral Proteins', 'Journal Article', '10.1371/journal.pcbi.1002860', '23300433', 'Interactions of proteins regulate signaling, catalysis, gene expression and many other cellular functions. Therefore, characterizing the entire human interactome is a key effort in current proteomics research. This challenge is complicated by the dynamic nature of protein-protein interactions (PPIs), which are conditional on the cellular context: both interacting proteins must be expressed in the same cell and localized in the same organelle to meet. Additionally, interactions underlie a delicate control of signaling pathways, e.g. by post-translational modifications of the protein partners - hence, many diseases are caused by the perturbation of these mechanisms. Despite the high degree of cell-state specificity of PPIs, many interactions are measured under artificial conditions (e.g. yeast cells are transfected with human genes in yeast two-hybrid assays) or even if detected in a physiological context, this information is missing from the common PPI databases. To overcome these problems, we developed a method that assigns context information to PPIs inferred from various attributes of the interacting proteins: gene expression, functional and disease annotations, and inferred pathways. We demonstrate that context consistency correlates with the experimental reliability of PPIs, which allows us to generate high-confidence tissue- and function-specific subnetworks. We illustrate how these context-filtered networks are enriched in bona fide pathways and disease proteins to prove the ability of context-filters to highlight meaningful interactions with respect to various biological questions. We use this approach to study the lung-specific pathways used by the influenza virus, pointing to IRAK1, BHLHE40 and TOLLIP as potential regulators of influenza virus pathogenicity, and to study the signalling pathways that play a role in Alzheimers disease, identifying a pathway involving the altered phosphorylation of the Tau protein. Finally, we provide the annotated human PPI network via a web frontend that allows the construction of context-specific networks in several ways.'),
(85822, 2013, 'plos', 'The underlying molecular and network level mechanisms in the evolution of robustness in gene regulatory networks', 'Pujato, Mario|MacCarthy, Thomas|Fiser, Andras|Bergman, Aviv', 'Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.', 'United States|United States|United States|United States', 0, 'DNA|Gene Regulatory Networks|Models, Molecular|Promoter Regions, Genetic|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002865', '23300434', 'Gene regulatory networks show robustness to perturbations. Previous works identified robustness as an emergent property of gene network evolution but the underlying molecular mechanisms are poorly understood. We used a multi-tier modeling approach that integrates molecular sequence and structure information with network architecture and population dynamics. Structural models of transcription factor-DNA complexes are used to estimate relative binding specificities. In this model, mutations in the DNA cause changes on two levels: (a) at the sequence level in individual binding sites (modulating binding specificity), and (b) at the network level (creating and destroying binding sites). We used this model to dissect the underlying mechanisms responsible for the evolution of robustness in gene regulatory networks. Results suggest that in sparse architectures (represented by short promoters), a mixture of local-sequence and network-architecture level changes are exploited. At the local-sequence level, robustness evolves by decreasing the probabilities of both the destruction of existent and generation of new binding sites. Meanwhile, in highly interconnected architectures (represented by long promoters), robustness evolves almost entirely via network level changes, deleting and creating binding sites that modify the network architecture.'),
(85823, 2013, 'plos', 'Phyletic profiling with cliques of orthologs is enhanced by signatures of paralogy relationships', 'Skunca, Nives|Boxc5xa1njak, Matko|Krixc5xa1ko, Anita|Panov, Panxc4x8de|Dxc5xbeeroski, Saxc5xa1o|Smuc, Tomislav|Supek, Fran', 'ETH Zurich, Computer Science, Zurich, Switzerland. skuncan@inf.ethz.ch|ETH Zurich, Computer Science, Zurich, Switzerland. skuncan@inf.ethz.ch|ETH Zurich, Computer Science, Zurich, Switzerland. skuncan@inf.ethz.ch|ETH Zurich, Computer Science, Zurich, Switzerland. skuncan@inf.ethz.ch|ETH Zurich, Computer Science, Zurich, Switzerland. skuncan@inf.ethz.ch|ETH Zurich, Computer Science, Zurich, Switzerland. skuncan@inf.ethz.ch|ETH Zurich, Computer Science, Zurich, Switzerland. skuncan@inf.ethz.ch', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 26, 'Escherichia coli|Gene Expression Profiling|Genes, Bacterial|Models, Theoretical|Phylogeny', 'Journal Article', '10.1371/journal.pcbi.1002852', '23308060', 'New microbial genomes are sequenced at a high pace, allowing insight into the genetics of not only cultured microbes, but a wide range of metagenomic collections such as the human microbiome. To understand the deluge of genomic data we face, computational approaches for gene functional annotation are invaluable. We introduce a novel model for computational annotation that refines two established concepts: annotation based on homology and annotation based on phyletic profiling. The phyletic profiling-based model that includes both inferred orthologs and paralogs-homologs separated by a speciation and a duplication event, respectively-provides more annotations at the same average Precision than the model that includes only inferred orthologs. For experimental validation, we selected 38 poorly annotated Escherichia coli genes for which the model assigned one of three GO terms with high confidence: involvement in DNA repair, protein translation, or cell wall synthesis. Results of antibiotic stress survival assays on E. coli knockout mutants showed high agreement with our models estimates of accuracy: out of 38 predictions obtained at the reported Precision of 60%, we confirmed 25 predictions, indicating that our confidence estimates can be used to make informed decisions on experimental validation. Our work will contribute to making experimental validation of computational predictions more approachable, both in cost and time. Our predictions for 998 prokaryotic genomes include ~400000 specific annotations with the estimated Precision of 90%, ~19000 of which are highly specific-e.g. penicillin binding, tRNA aminoacylation for protein translation, or pathogenesis-and are freely available at http://gorbi.irb.hr/.'),
(85824, 2013, 'plos', 'Integration of the transcriptome and glycome for identification of glycan cell signatures', 'Bennun, Sandra V|Yarema, Kevin J|Betenbaugh, Michael J|Krambeck, Frederick J', 'Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America. svbennun@gmail.com|Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America. svbennun@gmail.com|Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America. svbennun@gmail.com|Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America. svbennun@gmail.com', 'United States|United States|United States|United States', 34, 'Carbohydrates|Cell Line, Tumor|Glycosylation|Humans|Lymphatic Metastasis|Male|Polysaccharides|Prostatic Neoplasms|Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization|Transcriptome', 'Journal Article', '10.1371/journal.pcbi.1002813', '23326219', 'Abnormalities in glycan biosynthesis have been conclusively linked to many diseases but the complexity of glycosylation has hindered the analysis of glycan data in order to identify glycoforms contributing to disease. To overcome this limitation, we developed a quantitative N-glycosylation model that interprets and integrates mass spectral and transcriptomic data by incorporating key glycosylation enzyme activities. Using the cancer progression model of androgen-dependent to androgen-independent Lymph Node Carcinoma of the Prostate (LNCaP) cells, the N-glycosylation model identified and quantified glycan structural details not typically derived from single-stage mass spectral or gene expression data. Differences between the cell types uncovered include increases in H(II) and Le(y) epitopes, corresponding to greater activity of xcexb12-Fuc-transferase (FUT1) in the androgen-independent cells. The model further elucidated limitations in the two analytical platforms including a defect in the microarray for detecting the GnTV (MGAT5) enzyme. Our results demonstrate the potential of systems glycobiology tools for elucidating key glycan biomarkers and potential therapeutic targets. The integration of multiple data sets represents an important application of systems biology for understanding complex cellular processes.'),
(85825, 2013, 'plos', 'Computational analysis of Rho GTPase cycling', 'Falkenberg, Cibele Vieira|Loew, Leslie M', 'Center for Cell Analysis and Modeling, University of Connecticut Health Center, Farmington, Connecticut, United States of America.|Center for Cell Analysis and Modeling, University of Connecticut Health Center, Farmington, Connecticut, United States of America.', 'United States|United States', 10, 'Models, Theoretical|rho GTP-Binding Proteins', 'Journal Article', '10.1371/journal.pcbi.1002831', '23326220', 'The Rho family of GTPases control actin organization during diverse cellular responses (migration, cytokinesis and endocytosis). Although the primary members of this family (RhoA, Rac and Cdc42) have different downstream effects on actin remodeling, the basic mechanism involves targeting to the plasma membrane and activation by GTP binding. Our hypothesis is that the details of GTPase cycling between membrane and cytosol are key to the differential upstream regulation of these biochemical switches. Accordingly, we developed a modeling framework to analyze experimental data for these systems. This analysis can reveal details of GDI-mediated cycling and help distinguish between GDI-dependent and -independent mechanisms, including vesicle trafficking and direct association-dissociation of GTPase with membrane molecules. Analysis of experimental data for Rac membrane cycling reveals that the lower apparent affinity of GDI for RacGTP compared to RacGDP can be fully explained by the faster dissociation of the latter from the membrane. Non-dimensional steady-state solutions for membrane fraction of GTPase are presented in multidimensional charts. This methodology is then used to analyze glucose stimulated Rac cycling in pancreatic xcexb2-cells. The charts are used to illustrate the effects of GEFs/GAPs and regulated affinities between GTPases and membrane and/or GDI on the amount of membrane bound GTPase. In a similar fashion, the charts can be used as a guide in assessing how targeted modifications may compensate for altered GTPase-GDI balance in disease scenarios.'),
(85826, 2013, 'plos', 'Phosphorylation variation during the cell cycle scales with structural propensities of proteins', 'Tyanova, Stefka|Cox, Jürgen|Olsen, Jesper|Mann, Matthias|Frishman, Dmitrij', 'Genome-Oriented Bioinformatics Department, Technische Universität München, Freising, Germany.|Genome-Oriented Bioinformatics Department, Technische Universität München, Freising, Germany.|Genome-Oriented Bioinformatics Department, Technische Universität München, Freising, Germany.|Genome-Oriented Bioinformatics Department, Technische Universität München, Freising, Germany.|Genome-Oriented Bioinformatics Department, Technische Universität München, Freising, Germany.', 'Germany|Germany|Germany|Germany|Germany', 40, 'Amino Acids|Biological Evolution|Cell Cycle|Phosphorylation|Protein Structure, Secondary|Proteins', 'Journal Article', '10.1371/journal.pcbi.1002842', '23326221', 'Phosphorylation at specific residues can activate a protein, lead to its localization to particular compartments, be a trigger for protein degradation and fulfill many other biological functions. Protein phosphorylation is increasingly being studied at a large scale and in a quantitative manner that includes a temporal dimension. By contrast, structural properties of identified phosphorylation sites have so far been investigated in a static, non-quantitative way. Here we combine for the first time dynamic properties of the phosphoproteome with protein structural features. At six time points of the cell division cycle we investigate how the variation of the amount of phosphorylation correlates with the protein structure in the vicinity of the modified site. We find two distinct phosphorylation site groups: intrinsically disordered regions tend to contain sites with dynamically varying levels, whereas regions with predominantly regular secondary structures retain more constant phosphorylation levels. The two groups show preferences for different amino acids in their kinase recognition motifs - proline and other disorder-associated residues are enriched in the former group and charged residues in the latter. Furthermore, these preferences scale with the degree of disorderedness, from regular to irregular and to disordered structures. Our results suggest that the structural organization of the region in which a phosphorylation site resides may serve as an additional control mechanism. They also imply that phosphorylation sites are associated with different time scales that serve different functional needs.'),
(85827, 2013, 'plos', 'Modelling growth and form of the scleractinian coral Pocillopora verrucosa and the influence of hydrodynamics', 'Chindapol, Nol|Kaandorp, Jaap A|Cronemberger, Carolina|Mass, Tali|Genin, Amatzia', 'Section Computational Science, University of Amsterdam, Amsterdam, The Netherlands.|Section Computational Science, University of Amsterdam, Amsterdam, The Netherlands.|Section Computational Science, University of Amsterdam, Amsterdam, The Netherlands.|Section Computational Science, University of Amsterdam, Amsterdam, The Netherlands.|Section Computational Science, University of Amsterdam, Amsterdam, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 37, 'Animals|Anthozoa|Finite Element Analysis|Hydrodynamics|Models, Biological|Tomography, X-Ray Computed', 'Journal Article', '10.1371/journal.pcbi.1002849', '23326222', 'The growth of scleractinian corals is strongly influenced by the effect of water motion. Corals are known to have a high level of phenotypic variation and exhibit a diverse range of growth forms, which often contain a high level of geometric complexity. Due to their complex shape, simulation models represent an important option to complement experimental studies of growth and flow. In this work, we analyzed the impact of flow on corals morphology by an accretive growth model coupled with advection-diffusion equations. We performed simulations under no-flow and uni-directional flow setup with the Reynolds number constant. The relevant importance of diffusion to advection was investigated by varying the diffusion coefficient, rather than the flow speed in Péclet number. The flow and transport equations were coupled and solved using COMSOL Multiphysics. We then compared the simulated morphologies with a series of Computed Tomography (CT) scans of scleractinian corals Pocillopora verrucosa exposed to various flow conditions in the in situ controlled flume setup. As a result, we found a similar trend associated with the increasing Péclet for both simulated forms and in situ corals, that is uni-directional current tends to facilitate asymmetrical growth response resulting in colonies with branches predominantly developed in the upstream direction. A closer look at the morphological traits yielded an interesting property about colony symmetry and plasticity induced by uni-directional flow. Both simulated and in situ corals exhibit a tendency where the degree of symmetry decreases and compactification increases in conjunction with the augmented Péclet thus indicates the significant importance of hydrodynamics.'),
(85828, 2013, 'plos', 'The effects of temperature on the stability of a neuronal oscillator', 'Rinberg, Anatoly|Taylor, Adam L|Marder, Eve', 'Volen Center and Biology Department, Brandeis University, Waltham, Massachusetts, United States of America.|Volen Center and Biology Department, Brandeis University, Waltham, Massachusetts, United States of America.|Volen Center and Biology Department, Brandeis University, Waltham, Massachusetts, United States of America.', 'United States|United States|United States', 34, 'Animals|Crustacea|Models, Biological|Neurons|Temperature', 'Journal Article', '10.1371/journal.pcbi.1002857', '23326223', 'The crab Cancer borealis undergoes large daily fluctuations in environmental temperature (8-24°C) and must maintain appropriate neural function in the face of this perturbation. In the pyloric circuit of the crab stomatogastric ganglion, we pharmacologically isolated the pacemaker kernel (the AB and PD neurons) and characterized its behavior in response to temperature ramps from 7°C to 31°C. For moderate temperatures, the pacemaker displayed a frequency-temperature curve statistically indistinguishable from that of the intact circuit, and like the intact circuit maintained a constant duty cycle. At high temperatures (above 23°C), a variety of different behaviors were seen: in some preparations the pacemaker increased in frequency, in some it slowed, and in many preparations the pacemaker stopped oscillating (crashed). Furthermore, these crashes seemed to fall into two qualitatively different classes. Additionally, the animal-to-animal variability in frequency increased at high temperatures. We used a series of Morris-Lecar mathematical models to gain insight into these phenomena. The biophysical components of the final model have temperature sensitivities similar to those found in nature, and can crash via two qualitatively different mechanisms that resemble those observed experimentally. The crash type is determined by the precise parameters of the model at the reference temperature, 11°C, which could explain why some preparations seem to crash in one way and some in another. Furthermore, even models with very similar behavior at the reference temperature diverge greatly at high temperatures, resembling the experimental observations.'),
(85829, 2013, 'plos', 'Asymmetric PTEN distribution regulated by spatial heterogeneity in membrane-binding state transitions', 'Matsuoka, Satomi|Shibata, Tatsuo|Ueda, Masahiro', 'Laboratory for Cell Signaling Dynamics, RIKEN Quantitative Biology Center, Suita, Japan.|Laboratory for Cell Signaling Dynamics, RIKEN Quantitative Biology Center, Suita, Japan.|Laboratory for Cell Signaling Dynamics, RIKEN Quantitative Biology Center, Suita, Japan.', 'Japan|Japan|Japan', 17, 'Cell Membrane|Dictyostelium|Kinetics|Models, Theoretical|PTEN Phosphohydrolase|Protein Binding', 'Journal Article', '10.1371/journal.pcbi.1002862', '23326224', 'The molecular mechanisms that underlie asymmetric PTEN distribution at the posterior of polarized motile cells and regulate anterior pseudopod formation were addressed by novel single-molecule tracking analysis. Heterogeneity in the lateral mobility of PTEN on a membrane indicated the existence of three membrane-binding states with different diffusion coefficients and membrane-binding lifetimes. The stochastic state transition kinetics of PTEN among these three states were suggested to be regulated spatially along the cell polarity such that only the stable binding state is selectively suppressed at the anterior membrane to cause local PTEN depletion. By incorporating experimentally observed kinetic parameters into a simple mathematical model, the asymmetric PTEN distribution can be explained quantitatively to illustrate the regulatory mechanisms for cellular asymmetry based on an essential causal link between individual stochastic reactions and stable localizations of the ensemble.'),
(85830, 2013, 'plos', 'A guide to enterotypes across the human body: meta-analysis of microbial community structures in human microbiome datasets', 'Koren, Omry|Knights, Dan|Gonzalez, Antonio|Waldron, Levi|Segata, Nicola|Knight, Rob|Huttenhower, Curtis|Ley, Ruth E', 'Department of Microbiology, Cornell University, Ithaca, New York, United States of America.|Department of Microbiology, Cornell University, Ithaca, New York, United States of America.|Department of Microbiology, Cornell University, Ithaca, New York, United States of America.|Department of Microbiology, Cornell University, Ithaca, New York, United States of America.|Department of Microbiology, Cornell University, Ithaca, New York, United States of America.|Department of Microbiology, Cornell University, Ithaca, New York, United States of America.|Department of Microbiology, Cornell University, Ithaca, New York, United States of America.|Department of Microbiology, Cornell University, Ithaca, New York, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 284, 'Bacteria|Biodiversity|Humans|Metagenome|RNA, Ribosomal, 16S', 'Journal Article', '10.1371/journal.pcbi.1002863', '23326225', 'Recent analyses of human-associated bacterial diversity have categorized individuals into enterotypes or clusters based on the abundances of key bacterial genera in the gut microbiota. There is a lack of consensus, however, on the analytical basis for enterotypes and on the interpretation of these results. We tested how the following factors influenced the detection of enterotypes: clustering methodology, distance metrics, OTU-picking approaches, sequencing depth, data type (whole genome shotgun (WGS) vs.16S rRNA gene sequence data), and 16S rRNA region. We included 16S rRNA gene sequences from the Human Microbiome Project (HMP) and from 16 additional studies and WGS sequences from the HMP and MetaHIT. In most body sites, we observed smooth abundance gradients of key genera without discrete clustering of samples. Some body habitats displayed bimodal (e.g., gut) or multimodal (e.g., vagina) distributions of sample abundances, but not all clustering methods and workflows accurately highlight such clusters. Because identifying enterotypes in datasets depends not only on the structure of the data but is also sensitive to the methods applied to identifying clustering strength, we recommend that multiple approaches be used and compared when testing for enterotypes.'),
(85831, 2013, 'plos', 'The effects of city streets on an urban disease vector', 'Barbu, Corentin M|Hong, Andrew|Manne, Jennifer M|Small, Dylan S|Quintanilla Calderón, Javier E|Sethuraman, Karthik|Quispe-Machaca, Víctor|Ancca-Juárez, Jenny|Cornejo del Carpio, Juan G|Málaga Chavez, Fernando S|Náquira, César|Levy, Michael Z', 'Center for Clinical Epidemiology & Biostatistics - Department of Biostatistics & Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. corentin.barbu@gmail.com|Center for Clinical Epidemiology & Biostatistics - Department of Biostatistics & Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. corentin.barbu@gmail.com|Center for Clinical Epidemiology & Biostatistics - Department of Biostatistics & Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. corentin.barbu@gmail.com|Center for Clinical Epidemiology & Biostatistics - Department of Biostatistics & Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. corentin.barbu@gmail.com|Center for Clinical Epidemiology & Biostatistics - Department of Biostatistics & Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. corentin.barbu@gmail.com|Center for Clinical Epidemiology & Biostatistics - Department of Biostatistics & Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. corentin.barbu@gmail.com|Center for Clinical Epidemiology & Biostatistics - Department of Biostatistics & Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. corentin.barbu@gmail.com|Center for Clinical Epidemiology & Biostatistics - Department of Biostatistics & Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. corentin.barbu@gmail.com|Center for Clinical Epidemiology & Biostatistics - Department of Biostatistics & Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. corentin.barbu@gmail.com|Center for Clinical Epidemiology & Biostatistics - Department of Biostatistics & Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. corentin.barbu@gmail.com|Center for Clinical Epidemiology & Biostatistics - Department of Biostatistics & Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. corentin.barbu@gmail.com|Center for Clinical Epidemiology & Biostatistics - Department of Biostatistics & Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. corentin.barbu@gmail.com', 'United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States', 24, 'Animals|Chagas Disease|Disease Vectors|Humans|Peru|Urban Health', 'Journal Article', '10.1371/journal.pcbi.1002801', '23341756', 'With increasing urbanization vector-borne diseases are quickly developing in cities, and urban control strategies are needed. If streets are shown to be barriers to disease vectors, city blocks could be used as a convenient and relevant spatial unit of study and control. Unfortunately, existing spatial analysis tools do not allow for assessment of the impact of an urban grid on the presence of disease agents. Here, we first propose a method to test for the significance of the impact of streets on vector infestation based on a decomposition of Morans spatial autocorrelation index, and second, develop a Gaussian Field Latent Class model to finely describe the effect of streets while controlling for cofactors and imperfect detection of vectors. We apply these methods to cross-sectional data of infestation by the Chagas disease vector Triatoma infestans in the city of Arequipa, Peru. Our Morans decomposition test reveals that the distribution of T. infestans in this urban environment is significantly constrained by streets (p<0.05). With the Gaussian Field Latent Class model we confirm that streets provide a barrier against infestation and further show that greater than 90% of the spatial component of the probability of vector presence is explained by the correlation among houses within city blocks. The city block is thus likely to be an appropriate spatial unit to describe and control T. infestans in an urban context. Characteristics of the urban grid can influence the spatial dynamics of vector borne disease and should be considered when designing public health policies.'),
(85832, 2013, 'plos', 'Approximate Bayesian computation', 'Sunnåker, Mikael|Busetto, Alberto Giovanni|Numminen, Elina|Corander, Jukka|Foll, Matthieu|Dessimoz, Christophe', 'Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland. mikael.sunnaker@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland. mikael.sunnaker@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland. mikael.sunnaker@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland. mikael.sunnaker@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland. mikael.sunnaker@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland. mikael.sunnaker@bsse.ethz.ch', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 202, 'Algorithms|Bayes Theorem|Quality Control', 'Journal Article', '10.1371/journal.pcbi.1002803', '23341757', 'Approximate Bayesian computation (ABC) constitutes a class of computational methods rooted in Bayesian statistics. In all model-based statistical inference, the likelihood function is of central importance, since it expresses the probability of the observed data under a particular statistical model, and thus quantifies the support data lend to particular values of parameters and to choices among different models. For simple models, an analytical formula for the likelihood function can typically be derived. However, for more complex models, an analytical formula might be elusive or the likelihood function might be computationally very costly to evaluate. ABC methods bypass the evaluation of the likelihood function. In this way, ABC methods widen the realm of models for which statistical inference can be considered. ABC methods are mathematically well-founded, but they inevitably make assumptions and approximations whose impact needs to be carefully assessed. Furthermore, the wider application domain of ABC exacerbates the challenges of parameter estimation and model selection. ABC has rapidly gained popularity over the last years and in particular for the analysis of complex problems arising in biological sciences (e.g., in population genetics, ecology, epidemiology, and systems biology).'),
(85833, 2013, 'plos', 'How evolving heterogeneity distributions of resource allocation strategies shape mortality patterns', 'Le Cunff, Yann|Baudisch, Annette|Pakdaman, Khashayar', 'Institut Jacques Monod, CNRS UMR 7592, Univ Paris Diderot, Paris Cité Sorbonne, Paris, France. yann.lecunff@gmail.com|Institut Jacques Monod, CNRS UMR 7592, Univ Paris Diderot, Paris Cité Sorbonne, Paris, France. yann.lecunff@gmail.com|Institut Jacques Monod, CNRS UMR 7592, Univ Paris Diderot, Paris Cité Sorbonne, Paris, France. yann.lecunff@gmail.com', 'France|France|France', 10, 'Humans|Mortality|Mutation|Resource Allocation', 'Journal Article', '10.1371/journal.pcbi.1002825', '23341758', 'It is well established that individuals age differently. Yet the nature of these inter-individual differences is still largely unknown. For humans, two main hypotheses have been recently formulated: individuals may experience differences in aging rate or aging timing. This issue is central because it directly influences predictions for human lifespan and provides strong insights into the biological determinants of aging. In this article, we propose a model which lets population heterogeneity emerge from an evolutionary algorithm. We find that whether individuals differ in (i) aging rate or (ii) timing leads to different emerging population heterogeneity. Yet, in both cases, the same mortality patterns are observed at the population level. These patterns qualitatively reproduce those of yeasts, flies, worms and humans. Such findings, supported by an extensive parameter exploration, suggest that mortality patterns across species and their potential shapes belong to a limited and robust set of possible curves. In addition, we use our model to shed light on the notion of subpopulations, link population heterogeneity with the experimental results of stress induction experiments and provide predictions about the expected mortality patterns. As biology is moving towards the study of the distribution of individual-based measures, the model and framework we propose here paves the way for evolutionary interpretations of empirical and experimental data linking the individual level to the population level.'),
(85834, 2013, 'plos', 'Visual data mining of biological networks: one size does not fit all', 'Pastrello, Chiara|Otasek, David|Fortney, Kristen|Agapito, Giuseppe|Cannataro, Mario|Shirdel, Elize|Jurisica, Igor', 'CRO Aviano, National Cancer Institute, Aviano, Italy.|CRO Aviano, National Cancer Institute, Aviano, Italy.|CRO Aviano, National Cancer Institute, Aviano, Italy.|CRO Aviano, National Cancer Institute, Aviano, Italy.|CRO Aviano, National Cancer Institute, Aviano, Italy.|CRO Aviano, National Cancer Institute, Aviano, Italy.|CRO Aviano, National Cancer Institute, Aviano, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy|Italy', 16, 'Aging|Computational Biology|Humans|Information Storage and Retrieval|Neoplasms|Vision, Ocular', 'Journal Article', '10.1371/journal.pcbi.1002833', '23341759', 'High-throughput technologies produce massive amounts of data. However, individual methods yield data specific to the technique used and biological setup. The integration of such diverse data is necessary for the qualitative analysis of information relevant to hypotheses or discoveries. It is often useful to integrate these datasets using pathways and protein interaction networks to get a broader view of the experiment. The resulting network needs to be able to focus on either the large-scale picture or on the more detailed small-scale subsets, depending on the research question and goals. In this tutorial, we illustrate a workflow useful to integrate, analyze, and visualize data from different sources, and highlight important features of tools to support such analyses.'),
(85835, 2013, 'plos', 'Identifying transmission cycles at the human-animal interface: the role of animal reservoirs in maintaining gambiense human african trypanosomiasis', 'Funk, Sebastian|Nishiura, Hiroshi|Heesterbeek, Hans|Edmunds, W John|Checchi, Francesco', 'Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, USA. sf7@princeton.edu|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, USA. sf7@princeton.edu|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, USA. sf7@princeton.edu|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, USA. sf7@princeton.edu|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, USA. sf7@princeton.edu', 'Jersey|Jersey|Jersey|Jersey|Jersey', 0, 'Animals|Disease Reservoirs|Disease Vectors|Ecosystem|Humans|Models, Theoretical|Trypanosoma brucei gambiense|Trypanosomiasis, African', 'Journal Article', '10.1371/journal.pcbi.1002855', '23341760', 'Many infections can be transmitted between animals and humans. The epidemiological roles of different species can vary from important reservoirs to dead-end hosts. Here, we present a method to identify transmission cycles in different combinations of species from field data. We used this method to synthesise epidemiological and ecological data from Bipindi, Cameroon, a historical focus of gambiense Human African Trypanosomiasis (HAT, sleeping sickness), a disease that has often been considered to be maintained mainly by humans. We estimated the basic reproduction number [Formula: see text] of gambiense HAT in Bipindi and evaluated the potential for transmission in the absence of human cases. We found that under the assumption of random mixing between vectors and hosts, gambiense HAT could not be maintained in this focus without the contribution of animals. This result remains robust under extensive sensitivity analysis. When using the distributions of species among habitats to estimate the amount of mixing between those species, we found indications for an independent transmission cycle in wild animals. Stochastic simulation of the system confirmed that unless vectors moved between species very rarely, reintroduction would usually occur shortly after elimination of the infection from human populations. This suggests that elimination strategies may have to be reconsidered as targeting human cases alone would be insufficient for control, and reintroduction from animal reservoirs would remain a threat. Our approach is broadly applicable and could reveal animal reservoirs critical to the control of other infectious diseases.'),
(85836, 2013, 'plos', 'ADEMA: an algorithm to determine expected metabolite level alterations using mutual information', 'Cicek, A Ercument|Bederman, Ilya|Henderson, Leigh|Drumm, Mitchell L|Ozsoyoglu, Gultekin', 'Department of Electrical Engineering and Computer Science, Case Western Reserve University, Cleveland, Ohio, USA. aec51@case.edu|Department of Electrical Engineering and Computer Science, Case Western Reserve University, Cleveland, Ohio, USA. aec51@case.edu|Department of Electrical Engineering and Computer Science, Case Western Reserve University, Cleveland, Ohio, USA. aec51@case.edu|Department of Electrical Engineering and Computer Science, Case Western Reserve University, Cleveland, Ohio, USA. aec51@case.edu|Department of Electrical Engineering and Computer Science, Case Western Reserve University, Cleveland, Ohio, USA. aec51@case.edu', 'United States|United States|United States|United States|United States', 0, 'Algorithms|Animals|Lipogenesis|Metabolomics|Mice|Models, Theoretical|Multivariate Analysis', 'Journal Article', '10.1371/journal.pcbi.1002859', '23341761', 'Metabolomics is a relatively new omics platform, which analyzes a discrete set of metabolites detected in bio-fluids or tissue samples of organisms. It has been used in a diverse array of studies to detect biomarkers and to determine activity rates for pathways based on changes due to disease or drugs. Recent improvements in analytical methodology and large sample throughput allow for creation of large datasets of metabolites that reflect changes in metabolic dynamics due to disease or a perturbation in the metabolic network. However, current methods of comprehensive analyses of large metabolic datasets (metabolomics) are limited, unlike other omics approaches where complex techniques for analyzing coexpression/coregulation of multiple variables are applied. This paper discusses the shortcomings of current metabolomics data analysis techniques, and proposes a new multivariate technique (ADEMA) based on mutual information to identify expected metabolite level changes with respect to a specific condition. We show that ADEMA better predicts De Novo Lipogenesis pathway metabolite level changes in samples with Cystic Fibrosis (CF) than prediction based on the significance of individual metabolite level changes. We also applied ADEMAs classification scheme on three different cohorts of CF and wildtype mice. ADEMA was able to predict whether an unknown mouse has a CF or a wildtype genotype with 1.0, 0.84, and 0.9 accuracy for each respective dataset. ADEMA results had up to 31% higher accuracy as compared to other classification algorithms. In conclusion, ADEMA advances the state-of-the-art in metabolomics analysis, by providing accurate and interpretable classification results.'),
(85837, 2013, 'plos', 'Evolutionary optimization of protein folding', 'Debès, Cédric|Wang, Minglei|Caetano-Anollés, Gustavo|Gräter, Frauke', 'Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.|Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.|Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.|Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.', 'Germany|Germany|Germany|Germany', 26, 'Evolution, Molecular|Phylogeny|Protein Folding|Protein Structure, Secondary', 'Journal Article', '10.1371/journal.pcbi.1002861', '23341762', 'Nature has shaped the make up of proteins since their appearance, [Formula: see text]3.8 billion years ago. However, the fundamental drivers of structural change responsible for the extraordinary diversity of proteins have yet to be elucidated. Here we explore if protein evolution affects folding speed. We estimated folding times for the present-day catalog of protein domains directly from their size-modified contact order. These values were mapped onto an evolutionary timeline of domain appearance derived from a phylogenomic analysis of protein domains in 989 fully-sequenced genomes. Our results show a clear overall increase of folding speed during evolution, with known ultra-fast downhill folders appearing rather late in the timeline. Remarkably, folding optimization depends on secondary structure. While alpha-folds showed a tendency to fold faster throughout evolution, beta-folds exhibited a trend of folding time increase during the last [Formula: see text]1.5 billion years that began during the big bang of domain combinations. As a consequence, these domain structures are on average slow folders today. Our results suggest that fast and efficient folding of domains shaped the universe of protein structure. This finding supports the hypothesis that optimization of the kinetic and thermodynamic accessibility of the native fold reduces protein aggregation propensities that hamper cellular functions.'),
(85838, 2013, 'plos', 'Effects of ligand binding on the mechanical properties of ankyrin repeat protein gankyrin', 'Settanni, Giovanni|Serquera, David|Marszalek, Piotr E|Paci, Emanuele|Itzhaki, Laura S', 'Physics Department, Johannes Gutenberg University, Mainz, Germany. settani@uni-mainz.de|Physics Department, Johannes Gutenberg University, Mainz, Germany. settani@uni-mainz.de|Physics Department, Johannes Gutenberg University, Mainz, Germany. settani@uni-mainz.de|Physics Department, Johannes Gutenberg University, Mainz, Germany. settani@uni-mainz.de|Physics Department, Johannes Gutenberg University, Mainz, Germany. settani@uni-mainz.de', 'Germany|Germany|Germany|Germany|Germany', 8, 'Ligands|Models, Molecular|Molecular Dynamics Simulation|Proteasome Endopeptidase Complex|Protein Binding|Proto-Oncogene Proteins|Stress, Mechanical', 'Journal Article', '10.1371/journal.pcbi.1002864', '23341763', 'Ankyrin repeat proteins are elastic materials that unfold and refold sequentially, repeat by repeat, under force. Herein we use atomistic molecular dynamics to compare the mechanical properties of the 7-ankyrin-repeat oncoprotein Gankyrin in isolation and in complex with its binding partner S6-C. We show that the bound S6-C greatly increases the resistance of Gankyrin to mechanical stress. The effect is specific to those repeats of Gankyrin directly in contact with S6-C, and the mechanical hot spots of the interaction map to the same repeats as the thermodynamic hot spots. A consequence of stepwise nature of unfolding and the localized nature of ligand binding is that it impacts on all aspects of the proteins mechanical behavior, including the order of repeat unfolding, the diversity of unfolding pathways accessed, the nature of partially unfolded intermediates, the forces required and the work transferred to the system to unfold the whole protein and its parts. Stepwise unfolding thus provides the means to buffer repeat proteins and their binding partners from mechanical stress in the cell. Our results illustrate how ligand binding can control the mechanical response of proteins. The data also point to a cellular mechano-switching mechanism whereby binding between two partner macromolecules is regulated by mechanical stress.');
