INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84812, 2010, 'plos', 'Evaluating gene expression dynamics using pairwise RNA FISH data', 'Wyart, Matthieu|Botstein, David|Wingreen, Ned S', 'Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.|Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.|Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.', 'Jersey|Jersey|Jersey', 10, 'Algorithms|Cluster Analysis|Computational Biology|Computer Simulation|Gene Expression Profiling|Gene Expression Regulation, Fungal|In Situ Hybridization, Fluorescence|Principal Component Analysis|RNA, Fungal|RNA, Messenger|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins', 'Journal Article', '10.1371/journal.pcbi.1000979', '21079668', 'Recently, a novel approach has been developed to study gene expression in single cells with high time resolution using RNA Fluorescent In Situ Hybridization (FISH). The technique allows individual mRNAs to be counted with high accuracy in wild-type cells, but requires cells to be fixed, thus, each cell provides only a snapshot of gene expression. Here we show how and when RNA FISH data on pairs of genes can be used to reconstruct real-time dynamics from a collection of such snapshots. Using maximum-likelihood parameter estimation on synthetically generated, noisy FISH data, we show that dynamical programs of gene expression, such as cycles (e.g., the cell cycle) or switches between discrete states, can be accurately reconstructed. In the limit that mRNAs are produced in short-lived bursts, binary thresholding of the FISH data provides a robust way of reconstructing dynamics. In this regime, prior knowledge of the type of dynamics--cycle versus switch--is generally required and additional constraints, e.g., from triplet FISH measurements, may also be needed to fully constrain all parameters. As a demonstration, we apply the thresholding method to RNA FISH data obtained from single, unsynchronized cells of Saccharomyces cerevisiae. Our results support the existence of metabolic cycles and provide an estimate of global gene-expression noise. The approach to FISH data presented here can be applied in general to reconstruct dynamics from snapshots of pairs of correlated quantities including, for example, protein concentrations obtained from immunofluorescence assays.'),
(84813, 2010, 'plos', 'Scalable rule-based modelling of allosteric proteins and biochemical networks', 'Ollivier, Julien F|Shahrezaei, Vahid|Swain, Peter S', 'Department of Physiology, McGill University, Centre for Nonlinear Dynamics, Montreal, Québec, Canada. julien.ollivier@gmail.com|Department of Physiology, McGill University, Centre for Nonlinear Dynamics, Montreal, Québec, Canada. julien.ollivier@gmail.com|Department of Physiology, McGill University, Centre for Nonlinear Dynamics, Montreal, Québec, Canada. julien.ollivier@gmail.com', 'Canada|Canada|Canada', 34, 'Algorithms|Allosteric Regulation|Allosteric Site|Binding, Competitive|Computational Biology|Metabolic Networks and Pathways|Models, Biological|Proteins|Receptors, G-Protein-Coupled|Signal Transduction|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000975', '21079669', 'Much of the complexity of biochemical networks comes from the information-processing abilities of allosteric proteins, be they receptors, ion-channels, signalling molecules or transcription factors. An allosteric protein can be uniquely regulated by each combination of input molecules that it binds. This regulatory complexity causes a combinatorial increase in the number of parameters required to fit experimental data as the number of protein interactions increases. It therefore challenges the creation, updating, and re-use of biochemical models. Here, we propose a rule-based modelling framework that exploits the intrinsic modularity of protein structure to address regulatory complexity. Rather than treating proteins as black boxes, we model their hierarchical structure and, as conformational changes, internal dynamics. By modelling the regulation of allosteric proteins through these conformational changes, we often decrease the number of parameters required to fit data, and so reduce over-fitting and improve the predictive power of a model. Our method is thermodynamically grounded, imposes detailed balance, and also includes molecular cross-talk and the background activity of enzymes. We use our Allosteric Network Compiler to examine how allostery can facilitate macromolecular assembly and how competitive ligands can change the observed cooperativity of an allosteric protein. We also develop a parsimonious model of G protein-coupled receptors that explains functional selectivity and can predict the rank order of potency of agonists acting through a receptor. Our methodology should provide a basis for scalable, modular and executable modelling of biochemical networks in systems and synthetic biology.'),
(84814, 2010, 'plos', 'Intrinsic stability of temporally shifted spike-timing dependent plasticity', 'Babadi, Baktash|Abbott, L F', 'Department of Neuroscience, Columbia University, Center for Theoretical Neuroscience, New York, New York, United States of America. bb2280@columbia.edu|Department of Neuroscience, Columbia University, Center for Theoretical Neuroscience, New York, New York, United States of America. bb2280@columbia.edu', 'United States|United States', 45, 'Action Potentials|Algorithms|Computational Biology|Computer Simulation|Models, Neurological|Neuronal Plasticity|Neurons|Poisson Distribution|Synapses', 'Journal Article', '10.1371/journal.pcbi.1000961', '21079671', 'Spike-timing dependent plasticity (STDP), a widespread synaptic modification mechanism, is sensitive to correlations between presynaptic spike trains and it generates competition among synapses. However, STDP has an inherent instability because strong synapses are more likely to be strengthened than weak ones, causing them to grow in strength until some biophysical limit is reached. Through simulations and analytic calculations, we show that a small temporal shift in the STDP window that causes synchronous, or nearly synchronous, pre- and postsynaptic action potentials to induce long-term depression can stabilize synaptic strengths. Shifted STDP also stabilizes the postsynaptic firing rate and can implement both Hebbian and anti-Hebbian forms of competitive synaptic plasticity. Interestingly, the overall level of inhibition determines whether plasticity is Hebbian or anti-Hebbian. Even a random symmetric jitter of a few milliseconds in the STDP window can stabilize synaptic strengths while retaining these features. The same results hold for a shifted version of the more recent triplet model of STDP. Our results indicate that the detailed shape of the STDP window function near the transition from depression to potentiation is of the utmost importance in determining the consequences of STDP, suggesting that this region warrants further experimental study.'),
(84815, 2010, 'plos', 'The Mycobacterium tuberculosis drugome and its polypharmacological implications', 'Kinnings, Sarah L|Xie, Li|Fung, Kingston H|Jackson, Richard M|Xie, Lei|Bourne, Philip E', 'Institute of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.|Institute of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.|Institute of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.|Institute of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.|Institute of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.|Institute of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 79, 'Antitubercular Agents|Bacterial Proteins|Binding Sites|Cluster Analysis|Computational Biology|Computer Simulation|Databases, Factual|Humans|Models, Biological|Molecular Targeted Therapy|Mycobacterium tuberculosis|Reproducibility of Results|Tuberculosis', 'Journal Article', '10.1371/journal.pcbi.1000976', '21079673', 'We report a computational approach that integrates structural bioinformatics, molecular modelling and systems biology to construct a drug-target network on a structural proteome-wide scale. The approach has been applied to the genome of Mycobacterium tuberculosis (M.tb), the causative agent of one of todays most widely spread infectious diseases. The resulting drug-target interaction network for all structurally characterized approved drugs bound to putative M.tb receptors, we refer to as the TB-drugome. The TB-drugome reveals that approximately one-third of the drugs examined have the potential to be repositioned to treat tuberculosis and that many currently unexploited M.tb receptors may be chemically druggable and could serve as novel anti-tubercular targets. Furthermore, a detailed analysis of the TB-drugome has shed new light on the controversial issues surrounding drug-target networks [1]-[3]. Indeed, our results support the idea that drug-target networks are inherently modular, and further that any observed randomness is mainly caused by biased target coverage. The TB-drugome (http://funsite.sdsc.edu/drugome/TB) has the potential to be a valuable resource in the development of safe and efficient anti-tubercular drugs. More generally the methodology may be applied to other pathogens of interest with results improving as more of their structural proteomes are determined through the continued efforts of structural biology/genomics.'),
(84816, 2010, 'plos', 'Quantifying the impact of human immunodeficiency virus-1 escape from cytotoxic T-lymphocytes', 'Kadolsky, Ulrich D|Asquith, Becca', 'Department of Immunology, Division of Medicine, Imperial College London, London, United Kingdom. ulrich.kadolsky01@imperial.ac.uk|Department of Immunology, Division of Medicine, Imperial College London, London, United Kingdom. ulrich.kadolsky01@imperial.ac.uk', 'United Kingdom|United Kingdom', 0, 'Cluster Analysis|Cross-Sectional Studies|Epitopes|Genes, Viral|HIV Infections|HIV-1|Host-Pathogen Interactions|Humans|Linear Models|Models, Immunological|Mutation|T-Lymphocytes, Cytotoxic|Viral Load', 'Journal Article', '10.1371/journal.pcbi.1000981', '21079675', 'HIV-1 escape from the cytotoxic T-lymphocyte (CTL) response leads to a weakening of viral control and is likely to be detrimental to the patient. To date, the impact of escape on viral load and CD4(+) T cell count has not been quantified, primarily because of sparse longitudinal data and the difficulty of separating cause and effect in cross-sectional studies. We use two independent methods to quantify the impact of HIV-1 escape from CTLs in chronic infection: mathematical modelling of escape and statistical analysis of a cross-sectional cohort. Mathematical modelling revealed a modest increase in log viral load of 0.051 copies ml(-1) per escape event. Analysis of the cross-sectional cohort revealed a significant positive association between viral load and the number of escape events, after correcting for length of infection and rate of replication. We estimate that a single CTL escape event leads to a viral load increase of 0.11 log copies ml(-1) (95% confidence interval: 0.040-0.18), consistent with the predictions from the mathematical modelling. Overall, the number of escape events could only account for approximately 6% of the viral load variation in the cohort. Our findings indicate that although the loss of the CTL response for a single epitope results in a highly statistically significant increase in viral load, the biological impact is modest. We suggest that this small increase in viral load is explained by the small growth advantage of the variant relative to the wildtype virus. Escape from CTLs had a measurable, but unexpectedly low, impact on viral load in chronic infection.'),
(84817, 2010, 'plos', 'Shunting inhibition controls the gain modulation mediated by asynchronous neurotransmitter release in early development', 'Volman, Vladislav|Levine, Herbert|Sejnowski, Terrence J', 'Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California, United States of America. volman@salk.edu|Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California, United States of America. volman@salk.edu|Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California, United States of America. volman@salk.edu', 'United States|United States|United States', 11, 'Animals|Cells, Cultured|Hippocampus|Models, Neurological|Neuronal Plasticity|Neurons|Neurotransmitter Agents|Rats|Synaptic Membranes|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1000973', '21079676', 'The sensitivity of a neuron to its input can be modulated in several ways. Changes in the slope of the neuronal input-output curve depend on factors such as shunting inhibition, background noise, frequency-dependent synaptic excitation, and balanced excitation and inhibition. However, in early development GABAergic interneurons are excitatory and other mechanisms such as asynchronous transmitter release might contribute to regulating neuronal sensitivity. We modeled both phasic and asynchronous synaptic transmission in early development to study the impact of activity-dependent noise and short-term plasticity on the synaptic gain. Asynchronous release decreased or increased the gain depending on the membrane conductance. In the high shunt regime, excitatory input due to asynchronous release was divisive, whereas in the low shunt regime it had a nearly multiplicative effect on the firing rate. In addition, sensitivity to correlated inputs was influenced by shunting and asynchronous release in opposite ways. Thus, asynchronous release can regulate the information flow at synapses and its impact can be flexibly modulated by the membrane conductance.'),
(84818, 2010, 'plos', 'Exploring the universe of protein structures beyond the Protein Data Bank', 'Cossio, Pilar|Trovato, Antonio|Pietrucci, Fabio|Seno, Flavio|Maritan, Amos|Laio, Alessandro', 'International School for Advanced Studies SISSA, and CNR-INFM DEMOCRITOS, Trieste, Italy.|International School for Advanced Studies SISSA, and CNR-INFM DEMOCRITOS, Trieste, Italy.|International School for Advanced Studies SISSA, and CNR-INFM DEMOCRITOS, Trieste, Italy.|International School for Advanced Studies SISSA, and CNR-INFM DEMOCRITOS, Trieste, Italy.|International School for Advanced Studies SISSA, and CNR-INFM DEMOCRITOS, Trieste, Italy.|International School for Advanced Studies SISSA, and CNR-INFM DEMOCRITOS, Trieste, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy', 0, 'Algorithms|Computational Biology|Databases, Protein|Models, Molecular|Molecular Dynamics Simulation|Protein Conformation|Protein Folding|Proteins', 'Journal Article', '10.1371/journal.pcbi.1000957', '21079678', 'It is currently believed that the atlas of existing protein structures is faithfully represented in the Protein Data Bank. However, whether this atlas covers the full universe of all possible protein structures is still a highly debated issue. By using a sophisticated numerical approach, we performed an exhaustive exploration of the conformational space of a 60 amino acid polypeptide chain described with an accurate all-atom interaction potential. We generated a database of around 30,000 compact folds with at least of secondary structure corresponding to local minima of the potential energy. This ensemble plausibly represents the universe of protein folds of similar length, indeed, all the known folds are represented in the set with good accuracy. However, we discover that the known folds form a rather small subset, which cannot be reproduced by choosing random structures in the database. Rather, natural and possible folds differ by the contact order, on average significantly smaller in the former. This suggests the presence of an evolutionary bias, possibly related to kinetic accessibility, towards structures with shorter loops between contacting residues. Beside their conceptual relevance, the new structures open a range of practical applications such as the development of accurate structure prediction strategies, the optimization of force fields, and the identification and design of novel folds.'),
(84819, 2010, 'plos', 'Compensation for changing motor uncertainty', 'Hudson, Todd E|Tassinari, Hadley|Landy, Michael S', 'Department of Psychology, New York University, New York, New York, United States of America. hudson@cns.nyu.edu|Department of Psychology, New York University, New York, New York, United States of America. hudson@cns.nyu.edu|Department of Psychology, New York University, New York, New York, United States of America. hudson@cns.nyu.edu', 'United States|United States|United States', 0, 'Analysis of Variance|Anisotropy|Central Nervous System|Computational Biology|Computer Simulation|Humans|Linear Models|Models, Biological|Motor Activity|Psychomotor Performance', 'Journal Article', '10.1371/journal.pcbi.1000982', '21079679', 'When movement outcome differs consistently from the intended movement, errors are used to correct subsequent movements (e.g., adaptation to displacing prisms or force fields) by updating an internal model of motor and/or sensory systems. Here, we examine changes to an internal model of the motor system under changes in the variance structure of movement errors lacking an overall bias. We introduced a horizontal visuomotor perturbation to change the statistical distribution of movement errors anisotropically, while monetary gains/losses were awarded based on movement outcomes. We derive predictions for simulated movement planners, each differing in its internal model of the motor system. We find that humans optimally respond to the overall change in error magnitude, but ignore the anisotropy of the error distribution. Through comparison with simulated movement planners, we found that aimpoints corresponded quantitatively to an ideal movement planner that updates a strictly isotropic (circular) internal model of the error distribution. Aimpoints were planned in a manner that ignored the direction-dependence of error magnitudes, despite the continuous availability of unambiguous information regarding the anisotropic distribution of actual motor errors.'),
(84820, 2010, 'plos', 'Coding what and when in the Archer fish retina', 'Vasserman, Genadiy|Shamir, Maoz|Ben Simon, Avi|Segev, Ronen', 'Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.', 'Israel|Israel|Israel|Israel', 0, 'Animals|Computational Biology|Models, Animal|Perciformes|Photic Stimulation|Retinal Ganglion Cells', 'Journal Article', '10.1371/journal.pcbi.1000977', '21079682', 'Traditionally, the information content of the neural response is quantified using statistics of the responses relative to stimulus onset time with the assumption that the brain uses onset time to infer stimulus identity. However, stimulus onset time must also be estimated by the brain, making the utility of such an approach questionable. How can stimulus onset be estimated from the neural responses with sufficient accuracy to ensure reliable stimulus identification? We address this question using the framework of colour coding by the archer fish retinal ganglion cell. We found that stimulus identity, what, can be estimated from the responses of best single cells with an accuracy comparable to that of the animals psychophysical estimation. However, to extract this information, an accurate estimation of stimulus onset is essential. We show that stimulus onset time, when, can be estimated using a linear-nonlinear readout mechanism that requires the response of a population of 100 cells. Thus, stimulus onset time can be estimated using a relatively simple readout. However, large nerve cell populations are required to achieve sufficient accuracy.'),
(84821, 2010, 'plos', 'Systematic inference of copy-number genotypes from personal genome sequencing data reveals extensive olfactory receptor gene content diversity', 'Waszak, Sebastian M|Hasin, Yehudit|Zichner, Thomas|Olender, Tsviya|Keydar, Ifat|Khen, Miriam|Stütz, Adrian M|Schlattl, Andreas|Lancet, Doron|Korbel, Jan O', 'Department of Molecular Genetics, Crown Human Genome Center, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Crown Human Genome Center, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Crown Human Genome Center, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Crown Human Genome Center, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Crown Human Genome Center, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Crown Human Genome Center, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Crown Human Genome Center, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Crown Human Genome Center, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Crown Human Genome Center, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Crown Human Genome Center, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel|Israel|Israel|Israel|Israel|Israel|Israel|Israel|Israel', 0, 'Chromosome Mapping|DNA Copy Number Variations|Databases, Genetic|European Continental Ancestry Group|Genetic Variation|Genetics, Population|Genome|Genomics|Genotype|Humans|Oligonucleotide Array Sequence Analysis|Polymerase Chain Reaction|Polymorphism, Single Nucleotide|Principal Component Analysis|Receptors, Odorant|Reproducibility of Results|Sequence Analysis, DNA|Software', 'Journal Article', '10.1371/journal.pcbi.1000988', '21085617', 'Copy-number variations (CNVs) are widespread in the human genome, but comprehensive assignments of integer locus copy-numbers (i.e., copy-number genotypes) that, for example, enable discrimination of homozygous from heterozygous CNVs, have remained challenging. Here we present CopySeq, a novel computational approach with an underlying statistical framework that analyzes the depth-of-coverage of high-throughput DNA sequencing reads, and can incorporate paired-end and breakpoint junction analysis based CNV-analysis approaches, to infer locus copy-number genotypes. We benchmarked CopySeq by genotyping 500 chromosome 1 CNV regions in 150 personal genomes sequenced at low-coverage. The assessed copy-number genotypes were highly concordant with our performed qPCR experiments (Pearson correlation coefficient 0.94), and with the published results of two microarray platforms (95-99% concordance). We further demonstrated the utility of CopySeq for analyzing gene regions enriched for segmental duplications by comprehensively inferring copy-number genotypes in the CNV-enriched >800 olfactory receptor (OR) human gene and pseudogene loci. CopySeq revealed that OR loci display an extensive range of locus copy-numbers across individuals, with zero to two copies in some OR loci, and two to nine copies in others. Among genetic variants affecting OR loci we identified deleterious variants including CNVs and SNPs affecting ~15% and ~20% of the human OR gene repertoire, respectively, implying that genetic variants with a possible impact on smell perception are widespread. Finally, we found that for several OR loci the reference genome appears to represent a minor-frequency variant, implying a necessary revision of the OR repertoire for future functional studies. CopySeq can ascertain genomic structural variation in specific gene families as well as at a genome-wide scale, where it may enable the quantitative evaluation of CNVs in genome-wide association studies involving high-throughput sequencing.'),
(84822, 2010, 'plos', 'Lobe specific Ca2+-calmodulin nano-domain in neuronal spines: a single molecule level analysis', 'Kubota, Yoshihisa|Waxham, M Neal', 'Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, Texas, USA. Yoshihisa.Kubota@uth.tmc.edu|Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, Texas, USA. Yoshihisa.Kubota@uth.tmc.edu', 'United States|United States', 13, 'Algorithms|Animals|CA1 Region, Hippocampal|Calcium|Calmodulin|Dendritic Spines|Models, Biological|Models, Molecular|Monte Carlo Method|Pyramidal Cells|Rats', 'Journal Article', '10.1371/journal.pcbi.1000987', '21085618', 'Calmodulin (CaM) is a ubiquitous Ca(2+) buffer and second messenger that affects cellular function as diverse as cardiac excitability, synaptic plasticity, and gene transcription. In CA1 pyramidal neurons, CaM regulates two opposing Ca(2+)-dependent processes that underlie memory formation: long-term potentiation (LTP) and long-term depression (LTD). Induction of LTP and LTD require activation of Ca(2+)-CaM-dependent enzymes: Ca(2+)/CaM-dependent kinase II (CaMKII) and calcineurin, respectively. Yet, it remains unclear as to how Ca(2+) and CaM produce these two opposing effects, LTP and LTD. CaM binds 4 Ca(2+) ions: two in its N-terminal lobe and two in its C-terminal lobe. Experimental studies have shown that the N- and C-terminal lobes of CaM have different binding kinetics toward Ca(2+) and its downstream targets. This may suggest that each lobe of CaM differentially responds to Ca(2+) signal patterns. Here, we use a novel event-driven particle-based Monte Carlo simulation and statistical point pattern analysis to explore the spatial and temporal dynamics of lobe-specific Ca(2+)-CaM interaction at the single molecule level. We show that the N-lobe of CaM, but not the C-lobe, exhibits a nano-scale domain of activation that is highly sensitive to the location of Ca(2+) channels, and to the microscopic injection rate of Ca(2+) ions. We also demonstrate that Ca(2+) saturation takes place via two different pathways depending on the Ca(2+) injection rate, one dominated by the N-terminal lobe, and the other one by the C-terminal lobe. Taken together, these results suggest that the two lobes of CaM function as distinct Ca(2+) sensors that can differentially transduce Ca(2+) influx to downstream targets. We discuss a possible role of the N-terminal lobe-specific Ca(2+)-CaM nano-domain in CaMKII activation required for the induction of synaptic plasticity.'),
(84823, 2010, 'plos', 'Robustness of circadian clocks to daylight fluctuations: hints from the picoeucaryote Ostreococcus tauri', 'Thommen, Quentin|Pfeuty, Benjamin|Morant, Pierre-Emmanuel|Corellou, Florence|Bouget, François-Yves|Lefranc, Marc', 'Laboratoire de Physique des Lasers, Atomes, et Molécules, UFR de Physique, Université Lille 1, Villeneuve dAscq, France.|Laboratoire de Physique des Lasers, Atomes, et Molécules, UFR de Physique, Université Lille 1, Villeneuve dAscq, France.|Laboratoire de Physique des Lasers, Atomes, et Molécules, UFR de Physique, Université Lille 1, Villeneuve dAscq, France.|Laboratoire de Physique des Lasers, Atomes, et Molécules, UFR de Physique, Université Lille 1, Villeneuve dAscq, France.|Laboratoire de Physique des Lasers, Atomes, et Molécules, UFR de Physique, Université Lille 1, Villeneuve dAscq, France.|Laboratoire de Physique des Lasers, Atomes, et Molécules, UFR de Physique, Université Lille 1, Villeneuve dAscq, France.', 'France|France|France|France|France|France', 0, 'Algorithms|Chlorophyta|Circadian Clocks|Circadian Rhythm Signaling Peptides and Proteins|Feedback, Physiological|Gene Expression Regulation, Plant|Gene Regulatory Networks|Light|Normal Distribution|Oligonucleotide Array Sequence Analysis|RNA, Messenger', 'Journal Article', '10.1371/journal.pcbi.1000990', '21085637', 'The development of systemic approaches in biology has put emphasis on identifying genetic modules whose behavior can be modeled accurately so as to gain insight into their structure and function. However, most gene circuits in a cell are under control of external signals and thus, quantitative agreement between experimental data and a mathematical model is difficult. Circadian biology has been one notable exception: quantitative models of the internal clock that orchestrates biological processes over the 24-hour diurnal cycle have been constructed for a few organisms, from cyanobacteria to plants and mammals. In most cases, a complex architecture with interlocked feedback loops has been evidenced. Here we present the first modeling results for the circadian clock of the green unicellular alga Ostreococcus tauri. Two plant-like clock genes have been shown to play a central role in the Ostreococcus clock. We find that their expression time profiles can be accurately reproduced by a minimal model of a two-gene transcriptional feedback loop. Remarkably, best adjustment of data recorded under light/dark alternation is obtained when assuming that the oscillator is not coupled to the diurnal cycle. This suggests that coupling to light is confined to specific time intervals and has no dynamical effect when the oscillator is entrained by the diurnal cycle. This intriguing property may reflect a strategy to minimize the impact of fluctuations in daylight intensity on the core circadian oscillator, a type of perturbation that has been rarely considered when assessing the robustness of circadian clocks.'),
(84824, 2010, 'plos', 'PLoS Computational Biology conference postcards from ISMB 2010', 'Chalancon, Guilhem|Kosloff, Mickey|Osmanbeyoglu, Hatice Ulku|Saraswathi, Saras', 'MRC Laboratory of Molecular Biology, Cambridge, United Kingdom. guilhem@mrc-lmb.cam.ac.uk|MRC Laboratory of Molecular Biology, Cambridge, United Kingdom. guilhem@mrc-lmb.cam.ac.uk|MRC Laboratory of Molecular Biology, Cambridge, United Kingdom. guilhem@mrc-lmb.cam.ac.uk|MRC Laboratory of Molecular Biology, Cambridge, United Kingdom. guilhem@mrc-lmb.cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Animals|Computational Biology|Humans', 'Congress', '10.1371/journal.pcbi.1002000', '21085638', '-'),
(84825, 2010, 'plos', 'Local gene regulation details a recognition code within the LacI transcriptional factor family', 'Camas, Francisco M|Alm, Eric J|Poyatos, Juan F', 'Logic of Genomic Systems Laboratory, Spanish National Biotechnology Centre, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain. fmcamas@gmail.com|Logic of Genomic Systems Laboratory, Spanish National Biotechnology Centre, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain. fmcamas@gmail.com|Logic of Genomic Systems Laboratory, Spanish National Biotechnology Centre, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain. fmcamas@gmail.com', 'Spain|Spain|Spain', 17, 'Amino Acid Sequence|Binding Sites|Computational Biology|Consensus Sequence|Escherichia coli Proteins|Gene Expression Regulation, Bacterial|Genes, Bacterial|Lac Repressors|Models, Molecular|Molecular Sequence Annotation|Molecular Sequence Data|Mutation|Protein Binding|Protein Structure, Tertiary', 'Journal Article', '10.1371/journal.pcbi.1000989', '21085639', 'The specific binding of regulatory proteins to DNA sequences exhibits no clear patterns of association between amino acids (AAs) and nucleotides (NTs). This complexity of protein-DNA interactions raises the question of whether a simple set of wide-coverage recognition rules can ever be identified. Here, we analyzed this issue using the extensive LacI family of transcriptional factors (TFs). We searched for recognition patterns by introducing a new approach to phylogenetic footprinting, based on the pervasive presence of local regulation in prokaryotic transcriptional networks. We identified a set of specificity correlations--determined by two AAs of the TFs and two NTs in the binding sites--that is conserved throughout a dominant subgroup within the family regardless of the evolutionary distance, and that act as a relatively consistent recognition code. The proposed rules are confirmed with data of previous experimental studies and by events of convergent evolution in the phylogenetic tree. The presence of a code emphasizes the stable structural context of the LacI family, while defining a precise blueprint to reprogram TF specificity with many practical applications.'),
(84826, 2010, 'plos', 'Functional genomics complements quantitative genetics in identifying disease-gene associations', 'Guan, Yuanfang|Ackert-Bicknell, Cheryl L|Kell, Braden|Troyanskaya, Olga G|Hibbs, Matthew A', 'Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.|Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.|Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.|Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.|Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.', 'Jersey|Jersey|Jersey|Jersey|Jersey', 35, 'ATP Binding Cassette Transporter, Subfamily G, Member 8|ATP-Binding Cassette Transporters|Algorithms|Animals|Artificial Intelligence|Bayes Theorem|Bone Density|Chromosome Mapping|Cluster Analysis|Databases, Genetic|Disease Models, Animal|Genetic Predisposition to Disease|Genome-Wide Association Study|Genomics|Lipoproteins|Mice|Mice, Transgenic|Osteoporosis|Phenotype|Quantitative Trait Loci|Reproducibility of Results|Risk Factors|Tissue Inhibitor of Metalloproteinase-2', 'Journal Article', '10.1371/journal.pcbi.1000991', '21085640', 'An ultimate goal of genetic research is to understand the connection between genotype and phenotype in order to improve the diagnosis and treatment of diseases. The quantitative genetics field has developed a suite of statistical methods to associate genetic loci with diseases and phenotypes, including quantitative trait loci (QTL) linkage mapping and genome-wide association studies (GWAS). However, each of these approaches have technical and biological shortcomings. For example, the amount of heritable variation explained by GWAS is often surprisingly small and the resolution of many QTL linkage mapping studies is poor. The predictive power and interpretation of QTL and GWAS results are consequently limited. In this study, we propose a complementary approach to quantitative genetics by interrogating the vast amount of high-throughput genomic data in model organisms to functionally associate genes with phenotypes and diseases. Our algorithm combines the genome-wide functional relationship network for the laboratory mouse and a state-of-the-art machine learning method. We demonstrate the superior accuracy of this algorithm through predicting genes associated with each of 1157 diverse phenotype ontology terms. Comparison between our prediction results and a meta-analysis of quantitative genetic studies reveals both overlapping candidates and distinct, accurate predictions uniquely identified by our approach. Focusing on bone mineral density (BMD), a phenotype related to osteoporotic fracture, we experimentally validated two of our novel predictions (not observed in any previous GWAS/QTL studies) and found significant bone density defects for both Timp2 and Abcg8 deficient mice. Our results suggest that the integration of functional genomics data into networks, which itself is informative of protein function and interactions, can successfully be utilized as a complementary approach to quantitative genetics to predict disease risks. All supplementary material is available at http://cbfg.jax.org/phenotype.'),
(84827, 2010, 'plos', 'The role of oligomerization and cooperative regulation in protein function: the case of tryptophan synthase', 'Fatmi, M Qaiser|Chang, Chia-en A', 'Department of Chemistry, University of California, Riverside, Riverside, California, USA.|Department of Chemistry, University of California, Riverside, Riverside, California, USA.', 'United States|United States', 0, 'Allosteric Regulation|Amino Acids|Bacterial Proteins|Hydrogen Bonding|Indoles|Molecular Dynamics Simulation|Protein Binding|Protein Conformation|Protein Multimerization|Protein Subunits|Salmonella typhimurium|Thermodynamics|Tryptophan Synthase', 'Journal Article', '10.1371/journal.pcbi.1000994', '21085641', 'The oligomerization/co-localization of protein complexes and their cooperative regulation in protein function is a key feature in many biological systems. The synergistic regulation in different subunits often enhances the functional properties of the multi-enzyme complex. The present study used molecular dynamics and Brownian dynamics simulations to study the effects of allostery, oligomerization and intermediate channeling on enhancing the protein function of tryptophan synthase (TRPS). TRPS uses a set of xcexb1/xcexb2-dimeric units to catalyze the last two steps of L-tryptophan biosynthesis, and the rate is remarkably slower in the isolated monomers. Our work shows that without their binding partner, the isolated monomers are stable and more rigid. The substrates can form fairly stable interactions with the protein in both forms when the protein reaches the final ligand-bound conformations. Our simulations also revealed that the xcexb1/xcexb2-dimeric unit stabilizes the substrate-protein conformation in the ligand binding process, which lowers the conformation transition barrier and helps the protein conformations shift from an open/inactive form to a closed/active form. Brownian dynamics simulations with a coarse-grained model illustrate how protein conformations affect substrate channeling. The results highlight the complex roles of protein oligomerization and the fine balance between rigidity and dynamics in protein function.'),
(84828, 2010, 'plos', 'Solving navigational uncertainty using grid cells on robots', 'Milford, Michael J|Wiles, Janet|Wyeth, Gordon F', 'School of Engineering Systems, Queensland University of Technology, Brisbane, Australia. michael.milford@qut.edu.au|School of Engineering Systems, Queensland University of Technology, Brisbane, Australia. michael.milford@qut.edu.au|School of Engineering Systems, Queensland University of Technology, Brisbane, Australia. michael.milford@qut.edu.au', 'Australia|Australia|Australia', 51, 'Animals|Entorhinal Cortex|Homing Behavior|Models, Neurological|Neural Networks (Computer)|Rats|Robotics|Visual Fields', 'Journal Article', '10.1371/journal.pcbi.1000995', '21085643', 'To successfully navigate their habitats, many mammals use a combination of two mechanisms, path integration and calibration using landmarks, which together enable them to estimate their location and orientation, or pose. In large natural environments, both these mechanisms are characterized by uncertainty: the path integration process is subject to the accumulation of error, while landmark calibration is limited by perceptual ambiguity. It remains unclear how animals form coherent spatial representations in the presence of such uncertainty. Navigation research using robots has determined that uncertainty can be effectively addressed by maintaining multiple probabilistic estimates of a robots pose. Here we show how conjunctive grid cells in dorsocaudal medial entorhinal cortex (dMEC) may maintain multiple estimates of pose using a brain-based robot navigation system known as RatSLAM. Based both on rodent spatially-responsive cells and functional engineering principles, the cells at the core of the RatSLAM computational model have similar characteristics to rodent grid cells, which we demonstrate by replicating the seminal Moser experiments. We apply the RatSLAM model to a new experimental paradigm designed to examine the responses of a robot or animal in the presence of perceptual ambiguity. Our computational approach enables us to observe short-term population coding of multiple location hypotheses, a phenomenon which would not be easily observable in rodent recordings. We present behavioral and neural evidence demonstrating that the conjunctive grid cells maintain and propagate multiple estimates of pose, enabling the correct pose estimate to be resolved over time even without uniquely identifying cues. While recent research has focused on the grid-like firing characteristics, accuracy and representational capacity of grid cells, our results identify a possible critical and unique role for conjunctive grid cells in filtering sensory uncertainty. We anticipate our study to be a starting point for animal experiments that test navigation in perceptually ambiguous environments.'),
(84829, 2010, 'plos', 'A new integrated variable based on thermometry, actimetry and body position (TAP) to evaluate circadian system status in humans', 'Ortiz-Tudela, Elisabet|Martinez-Nicolas, Antonio|Campos, Manuel|Rol, Marxc3xada xc3x81ngeles|Madrid, Juan Antonio', 'Chronobiology Laboratory, Department of Physiology, University of Murcia, Murcia, Spain.|Chronobiology Laboratory, Department of Physiology, University of Murcia, Murcia, Spain.|Chronobiology Laboratory, Department of Physiology, University of Murcia, Murcia, Spain.|Chronobiology Laboratory, Department of Physiology, University of Murcia, Murcia, Spain.|Chronobiology Laboratory, Department of Physiology, University of Murcia, Murcia, Spain.', 'Spain|Spain|Spain|Spain|Spain', 0, 'Adolescent|Adult|Artifacts|Body Temperature|Circadian Rhythm|Female|Health Status Indicators|Humans|Male|Motor Activity|Posture|Sensitivity and Specificity|Signal Processing, Computer-Assisted|Sleep|Statistics, Nonparametric|Wrist', 'Journal Article', '10.1371/journal.pcbi.1000996', '21085644', 'The disruption of the circadian system in humans has been associated with the development of chronic illnesses and the worsening of pre-existing pathologies. Therefore, the assessment of human circadian system function under free living conditions using non-invasive techniques needs further research. Traditionally, overt rhythms such as activity and body temperature have been analyzed separately, however, a comprehensive index could reduce individual recording artifacts. Thus, a new variable (TAP), based on the integrated analysis of three simultaneous recordings: skin wrist temperature (T), motor activity (A) and body position (P) has been developed. Furthermore, we also tested the reliability of a single numerical index, the Circadian Function Index (CFI), to determine the circadian robustness. An actimeter and a temperature sensor were placed on the arm and wrist of the non-dominant hand, respectively, of 49 healthy young volunteers for a period of one week. T, A and P values were normalized for each subject. A non-parametric analysis was applied to both TAP and the separate variables to calculate their interdaily stability, intradaily variability and relative amplitude, and these values were then used for the CFI calculation. Modeling analyses were performed in order to determine TAP and CFI reliability. Each variable (T, A, P or TAP) was independently correlated with rest-activity logs kept by the volunteers. The highest correlation (r=xe2x80x8a-0.993, p<0.0001), along with highest specificity (0.870), sensitivity (0.740) and accuracy (0.904), were obtained when rest-activity records were compared to TAP. Furthermore, the CFI proved to be very sensitive to changes in circadian robustness. Our results demonstrate that the integrated TAP variable and the CFI calculation are powerful methods to assess circadian system status, improving sensitivity, specificity and accuracy in differentiating activity from rest over the analysis of wrist temperature, body position or activity alone.'),
(84830, 2010, 'plos', 'Vulnerabilities in the tau network and the role of ultrasensitive points in tau pathophysiology', 'Yuraszeck, Theresa M|Neveu, Pierre|Rodriguez-Fernandez, Maria|Robinson, Anne|Kosik, Kenneth S|Doyle, Francis J', 'Department of Chemical Engineering, University of California, Santa Barbara, Santa Barbara, California, USA.|Department of Chemical Engineering, University of California, Santa Barbara, Santa Barbara, California, USA.|Department of Chemical Engineering, University of California, Santa Barbara, Santa Barbara, California, USA.|Department of Chemical Engineering, University of California, Santa Barbara, Santa Barbara, California, USA.|Department of Chemical Engineering, University of California, Santa Barbara, Santa Barbara, California, USA.|Department of Chemical Engineering, University of California, Santa Barbara, Santa Barbara, California, USA.', 'United States|United States|United States|United States|United States|United States', 0, 'Alzheimer Disease|Animals|Brain Chemistry|COS Cells|Cercopithecus aethiops|Computer Simulation|Humans|Models, Biological|Protein Conformation|Reproducibility of Results|Signal Transduction|Systems Biology|tau Proteins', 'Journal Article', '10.1371/journal.pcbi.1000997', '21085645', 'The multifactorial nature of disease motivates the use of systems-level analyses to understand their pathology. We used a systems biology approach to study tau aggregation, one of the hallmark features of Alzheimers disease. A mathematical model was constructed to capture the current state of knowledge concerning taus behavior and interactions in cells. The model was implemented in silico in the form of ordinary differential equations. The identifiability of the model was assessed and parameters were estimated to generate two cellular states: a population of solutions that corresponds to normal tau homeostasis and a population of solutions that displays aggregation-prone behavior. The model of normal tau homeostasis was robust to perturbations, and disturbances in multiple processes were required to achieve an aggregation-prone state. The aggregation-prone state was ultrasensitive to perturbations in diverse subsets of networks. Tau aggregation requires that multiple cellular parameters are set coordinately to a set of values that drive pathological assembly of tau. This model provides a foundation on which to build and increase our understanding of the series of events that lead to tau aggregation and may ultimately be used to identify critical intervention points that can direct the cell away from tau aggregation to aid in the treatment of tau-mediated (or related) aggregation diseases including Alzheimers.'),
(84831, 2010, 'plos', 'Finding the way with a noisy brain', 'Cheung, Allen|Vickerstaff, Robert', 'Queensland Brain Institute and School of Information Technology and Electrical Engineering, The University of Queensland, Brisbane, Australia. a.cheung@uq.edu.au|Queensland Brain Institute and School of Information Technology and Electrical Engineering, The University of Queensland, Brisbane, Australia. a.cheung@uq.edu.au', 'Australia|Australia', 0, 'Algorithms|Animals|Ants|Brain|Computational Biology|Homing Behavior|Locomotion|Models, Neurological', 'Journal Article', '10.1371/journal.pcbi.1000992', '21085678', 'Successful navigation is fundamental to the survival of nearly every animal on earth, and achieved by nervous systems of vastly different sizes and characteristics. Yet surprisingly little is known of the detailed neural circuitry from any species which can accurately represent space for navigation. Path integration is one of the oldest and most ubiquitous navigation strategies in the animal kingdom. Despite a plethora of computational models, from equational to neural network form, there is currently no consensus, even in principle, of how this important phenomenon occurs neurally. Recently, all path integration models were examined according to a novel, unifying classification system. Here we combine this theoretical framework with recent insights from directed walk theory, and develop an intuitive yet mathematically rigorous proof that only one class of neural representation of space can tolerate noise during path integration. This result suggests many existing models of path integration are not biologically plausible due to their intolerance to noise. This surprising result imposes significant computational limitations on the neurobiological spatial representation of all successfully navigating animals, irrespective of species. Indeed, noise-tolerance may be an important functional constraint on the evolution of neuroarchitectural plans in the animal kingdom.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84832, 2010, 'plos', 'Analysis of stochastic strategies in bacterial competence: a master equation approach', 'Dandach, Sandra H|Khammash, Mustafa', 'Department of Mechanical and Industrial Engineering, University of California, Santa Barbara, Santa Barbara, California, USA.|Department of Mechanical and Industrial Engineering, University of California, Santa Barbara, Santa Barbara, California, USA.', 'United States|United States', 0, 'Algorithms|Bacillus subtilis|Bacterial Proteins|Gene Regulatory Networks|Models, Biological|Monte Carlo Method|Stochastic Processes|Systems Biology|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000985', '21085679', 'Competence is a transiently differentiated state that certain bacterial cells reach when faced with a stressful environment. Entrance into competence can be attributed to the excitability of the dynamics governing the genetic circuit that regulates this cellular behavior. Like many biological behaviors, entrance into competence is a stochastic event. In this case cellular noise is responsible for driving the cell from a vegetative state into competence and back. In this work we present a novel numerical method for the analysis of stochastic biochemical events and use it to study the excitable dynamics responsible for competence in Bacillus subtilis. Starting with a Finite State Projection (FSP) solution of the chemical master equation (CME), we develop efficient numerical tools for accurately computing competence probability. Additionally, we propose a new approach for the sensitivity analysis of stochastic events and utilize it to elucidate the robustness properties of the competence regulatory genetic circuit. We also propose and implement a numerical method to calculate the expected time it takes a cell to return from competence. Although this study is focused on an example of cell-differentiation in Bacillus subtilis, our approach can be applied to a wide range of stochastic phenomena in biological systems.'),
(84833, 2010, 'plos', 'Chromosome driven spatial patterning of proteins in bacteria', 'Saberi, Saeed|Emberly, Eldon', 'Physics, Simon Fraser University, Burnaby, British Columbia, Canada.|Physics, Simon Fraser University, Burnaby, British Columbia, Canada.', 'Canada|Canada', 0, 'Bacterial Proteins|Caulobacter crescentus|Chromosome Structures|Chromosomes, Bacterial|Computer Simulation|Escherichia coli|Intracellular Space|Models, Biological|Protein Multimerization|Protein Unfolding', 'Journal Article', '10.1371/journal.pcbi.1000986', '21085680', 'The spatial patterning of proteins in bacteria plays an important role in many processes, from cell division to chemotaxis. In the asymmetrically dividing bacteria Caulobacter crescentus, a scaffolding protein, PopZ, localizes to both poles and aids the differential patterning of proteins between mother and daughter cells during division. Polar patterning of misfolded proteins in Escherichia coli has also been shown, and likely plays an important role in cellular ageing. Recent experiments on both of the above systems suggest that the presence of chromosome free regions along with protein multimerization may be a mechanism for driving the polar localization of proteins. We have developed a simple physical model for protein localization using only these two driving mechanisms. Our model reproduces all the observed patterns of PopZ and misfolded protein localization--from diffuse, unipolar, and bipolar patterns and can also account for the observed patterns in a variety of mutants. The model also suggests new experiments to further test the role of the chromosome in driving protein patterning, and whether such a mechanism is responsible for helping to drive the differentiation of the cell poles.'),
(84834, 2010, 'plos', 'Spike-timing-based computation in sound localization', 'Goodman, Dan F M|Brette, Romain', 'Laboratoire Psychologie de la Perception, CNRS and Université Paris Descartes, Paris, France.|Laboratoire Psychologie de la Perception, CNRS and Université Paris Descartes, Paris, France.', 'France|France', 12, 'Action Potentials|Artificial Intelligence|Cochlea|Computational Biology|Computer Simulation|Evoked Potentials, Auditory|Hair Cells, Auditory|Humans|Models, Neurological|Neuronal Plasticity|Pyramidal Cells|Sound Localization|Synapses', 'Journal Article', '10.1371/journal.pcbi.1000993', '21085681', 'Spike timing is precise in the auditory system and it has been argued that it conveys information about auditory stimuli, in particular about the location of a sound source. However, beyond simple time differences, the way in which neurons might extract this information is unclear and the potential computational advantages are unknown. The computational difficulty of this task for an animal is to locate the source of an unexpected sound from two monaural signals that are highly dependent on the unknown source signal. In neuron models consisting of spectro-temporal filtering and spiking nonlinearity, we found that the binaural structure induced by spatialized sounds is mapped to synchrony patterns that depend on source location rather than on source signal. Location-specific synchrony patterns would then result in the activation of location-specific assemblies of postsynaptic neurons. We designed a spiking neuron model which exploited this principle to locate a variety of sound sources in a virtual acoustic environment using measured human head-related transfer functions. The model was able to accurately estimate the location of previously unknown sounds in both azimuth and elevation (including front/back discrimination) in a known acoustic environment. We found that multiple representations of different acoustic environments could coexist as sets of overlapping neural assemblies which could be associated with spatial locations by Hebbian learning. The model demonstrates the computational relevance of relative spike timing to extract spatial information about sources independently of the source signal.'),
(84835, 2010, 'plos', 'Modelling vesicular release at hippocampal synapses', 'Nadkarni, Suhita|Bartol, Thomas M|Sejnowski, Terrence J|Levine, Herbert', 'Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California, USA.|Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California, USA.|Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California, USA.|Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California, USA.', 'United States|United States|United States|United States', 35, 'CA1 Region, Hippocampal|CA3 Region, Hippocampal|Calcium|Computer Simulation|Exocytosis|Models, Neurological|Monte Carlo Method|Neuronal Plasticity|Reproducibility of Results|Stochastic Processes|Synapses|Synaptic Transmission|Synaptic Vesicles', 'Journal Article', '10.1371/journal.pcbi.1000983', '21085682', 'We study local calcium dynamics leading to a vesicle fusion in a stochastic, and spatially explicit, biophysical model of the CA3-CA1 presynaptic bouton. The kinetic model for vesicle release has two calcium sensors, a sensor for fast synchronous release that lasts a few tens of milliseconds and a separate sensor for slow asynchronous release that lasts a few hundred milliseconds. A wide range of data can be accounted for consistently only when a refractory period lasting a few milliseconds between releases is included. The inclusion of a second sensor for asynchronous release with a slow unbinding site, and thereby a long memory, affects short-term plasticity by facilitating release. Our simulations also reveal a third time scale of vesicle release that is correlated with the stimulus and is distinct from the fast and the slow releases. In these detailed Monte Carlo simulations all three time scales of vesicle release are insensitive to the spatial details of the synaptic ultrastructure. Furthermore, our simulations allow us to identify features of synaptic transmission that are universal and those that are modulated by structure.'),
(84836, 2010, 'plos', 'A new method to reconstruct recombination events at a genomic scale', 'Melé, Marta|Javed, Asif|Pybus, Marc|Calafell, Francesc|Parida, Laxmi|Bertranpetit, Jaume|Genographic Consortium Members', 'IBE, Institute of Evolutionary Biology (UPF-CSIC), CEXS-UPF-PRBB, Barcelona, Catalonia, Spain.|IBE, Institute of Evolutionary Biology (UPF-CSIC), CEXS-UPF-PRBB, Barcelona, Catalonia, Spain.|IBE, Institute of Evolutionary Biology (UPF-CSIC), CEXS-UPF-PRBB, Barcelona, Catalonia, Spain.|IBE, Institute of Evolutionary Biology (UPF-CSIC), CEXS-UPF-PRBB, Barcelona, Catalonia, Spain.|IBE, Institute of Evolutionary Biology (UPF-CSIC), CEXS-UPF-PRBB, Barcelona, Catalonia, Spain.|IBE, Institute of Evolutionary Biology (UPF-CSIC), CEXS-UPF-PRBB, Barcelona, Catalonia, Spain.|IBE, Institute of Evolutionary Biology (UPF-CSIC), CEXS-UPF-PRBB, Barcelona, Catalonia, Spain.', 'Spain|Spain|Spain|Spain|Spain|Spain|Spain', 11, 'Algorithms|Base Sequence|Calibration|Chromosomes, Human, X|Computer Simulation|Female|Genomics|Humans|Male|Molecular Sequence Data|Polymorphism, Single Nucleotide|Principal Component Analysis|Recombination, Genetic|Reproducibility of Results|Spermatozoa', 'Journal Article', '10.1371/journal.pcbi.1001010', '21124860', 'Recombination is one of the main forces shaping genome diversity, but the information it generates is often overlooked. A recombination event creates a junction between two parental sequences that may be transmitted to the subsequent generations. Just like mutations, these junctions carry evidence of the shared past of the sequences. We present the IRiS algorithm, which detects past recombination events from extant sequences and specifies the place of each recombination and which are the recombinants sequences. We have validated and calibrated IRiS for the human genome using coalescent simulations replicating standard human demographic history and a variable recombination rate model, and we have fine-tuned IRiS parameters to simultaneously optimize for false discovery rate, sensitivity, and accuracy in placing the recombination events in the sequence. Newer recombinations overwrite traces of past ones and our results indicate more recent recombinations are detected by IRiS with greater sensitivity. IRiS analysis of the MS32 region, previously studied using sperm typing, showed good concordance with estimated recombination rates. We also applied IRiS to haplotypes for 18 X-chromosome regions in HapMap Phase 3 populations. Recombination events detected for each individual were recoded as binary allelic states and combined into recotypes. Principal component analysis and multidimensional scaling based on recotypes reproduced the relationships between the eleven HapMap Phase III populations that can be expected from known human population history, thus further validating IRiS. We believe that our new method will contribute to the study of the distribution of recombination events across the genomes and, for the first time, it will allow the use of recombination as genetic marker to study human genetic variation.'),
(84837, 2010, 'plos', 'Deciphering the code for retroviral integration target site selection', 'Santoni, Federico Andrea|Hartley, Oliver|Luban, Jeremy', 'Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.|Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.|Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.', 'Switzerland|Switzerland|Switzerland', 0, 'Algorithms|Animals|Cell Line|Chi-Square Distribution|Chromatin|Chromatin Immunoprecipitation|Cluster Analysis|Computational Biology|CpG Islands|Databases, Genetic|Genetic Markers|Genome|Host-Pathogen Interactions|Humans|Mice|Retroviridae|STAT1 Transcription Factor|Sequence Analysis, DNA|Virus Integration', 'Journal Article', '10.1371/journal.pcbi.1001008', '21124862', 'Upon cell invasion, retroviruses generate a DNA copy of their RNA genome and integrate retroviral cDNA within host chromosomal DNA. Integration occurs throughout the host cell genome, but target site selection is not random. Each subgroup of retrovirus is distinguished from the others by attraction to particular features on chromosomes. Despite extensive efforts to identify host factors that interact with retrovirion components or chromosome features predictive of integration, little is known about how integration sites are selected. We attempted to identify markers predictive of retroviral integration by exploiting Precision-Recall methods for extracting information from highly skewed datasets to derive robust and discriminating measures of association. ChIPSeq datasets for more than 60 factors were compared with 14 retroviral integration datasets. When compared with MLV, PERV or XMRV integration sites, strong association was observed with STAT1, acetylation of H3 and H4 at several positions, and methylation of H2AZ, H3K4, and K9. By combining peaks from ChIPSeq datasets, a supermarker was identified that localized within 2 kB of 75% of MLV proviruses and detected differences in integration preferences among different cell types. The supermarker predicted the likelihood of integration within specific chromosomal regions in a cell-type specific manner, yielding probabilities for integration into proto-oncogene LMO2 identical to experimentally determined values. The supermarker thus identifies chromosomal features highly favored for retroviral integration, provides clues to the mechanism by which retrovirus integration sites are selected, and offers a tool for predicting cell-type specific proto-oncogene activation by retroviruses.'),
(84838, 2010, 'plos', 'Genome-wide association between branch point properties and alternative splicing', 'Corvelo, André|Hallegger, Martina|Smith, Christopher W J|Eyras, Eduardo', 'Computational Genomics, Universitat Pompeu Fabra, Barcelona, Spain.|Computational Genomics, Universitat Pompeu Fabra, Barcelona, Spain.|Computational Genomics, Universitat Pompeu Fabra, Barcelona, Spain.|Computational Genomics, Universitat Pompeu Fabra, Barcelona, Spain.', 'Spain|Spain|Spain|Spain', 100, 'Algorithms|Alternative Splicing|Animals|Databases, Genetic|Gene Expression Regulation|Genome-Wide Association Study|Genomics|Humans|Models, Genetic|Models, Statistical|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1001016', '21124863', 'The branch point (BP) is one of the three obligatory signals required for pre-mRNA splicing. In mammals, the degeneracy of the motif combined with the lack of a large set of experimentally verified BPs complicates the task of modeling it in silico, and therefore of predicting the location of natural BPs. Consequently, BPs have been disregarded in a considerable fraction of the genome-wide studies on the regulation of splicing in mammals. We present a new computational approach for mammalian BP prediction. Using sequence conservation and positional bias we obtained a set of motifs with good agreement with U2 snRNA binding stability. Using a Support Vector Machine algorithm, we created a model complemented with polypyrimidine tract features, which considerably improves the prediction accuracy over previously published methods. Applying our algorithm to human introns, we show that BP position is highly dependent on the presence of AG dinucleotides in the 3 end of introns, with distance to the 3 splice site and BP strength strongly correlating with alternative splicing. Furthermore, experimental BP mapping for five exons preceded by long AG-dinucleotide exclusion zones revealed that, for a given intron, more than one BP can be chosen throughout the course of splicing. Finally, the comparison between exons of different evolutionary ages and pseudo exons suggests a key role of the BP in the pathway of exon creation in human. Our computational and experimental analyses suggest that BP recognition is more flexible than previously assumed, and it appears highly dependent on the presence of downstream polypyrimidine tracts. The reported association between BP features and the splicing outcome suggests that this, so far disregarded but yet crucial, element buries information that can complement current acceptor site models.'),
(84839, 2010, 'plos', 'Simultaneous genome-wide inference of physical, genetic, regulatory, and functional pathway components', 'Park, Christopher Y|Hess, David C|Huttenhower, Curtis|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.|Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.|Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.', 'Jersey|Jersey|Jersey|Jersey', 20, 'Algorithms|Bayes Theorem|Cluster Analysis|Databases, Genetic|Gene Regulatory Networks|Glycolysis|High-Throughput Screening Assays|Metabolic Networks and Pathways|Protein Interaction Mapping|Reproducibility of Results|Saccharomyces cerevisiae|Signal Transduction|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1001009', '21124865', 'Biomolecular pathways are built from diverse types of pairwise interactions, ranging from physical protein-protein interactions and modifications to indirect regulatory relationships. One goal of systems biology is to bridge three aspects of this complexity: the growing body of high-throughput data assaying these interactions, the specific interactions in which individual genes participate, and the genome-wide patterns of interactions in a system of interest. Here, we describe methodology for simultaneously predicting specific types of biomolecular interactions using high-throughput genomic data. This results in a comprehensive compendium of whole-genome networks for yeast, derived from xe2x88xbc3,500 experimental conditions and describing 30 interaction types, which range from general (e.g. physical or regulatory) to specific (e.g. phosphorylation or transcriptional regulation). We used these networks to investigate molecular pathways in carbon metabolism and cellular transport, proposing a novel connection between glycogen breakdown and glucose utilization supported by recent publications. Additionally, 14 specific predicted interactions in DNA topological change and protein biosynthesis were experimentally validated. We analyzed the systems-level network features within all interactomes, verifying the presence of small-world properties and enrichment for recurring network motifs. This compendium of physical, synthetic, regulatory, and functional interaction networks has been made publicly available through an interactive web interface for investigators to utilize in future research at http://function.princeton.edu/bioweaver/.'),
(84840, 2010, 'plos', 'Treatment-mediated alterations in HIV fitness preserve CD4+ T cell counts but have minimal effects on viral load', 'Vaidya, Naveen K|Rong, Libin|Marconi, Vincent C|Kuritzkes, Daniel R|Deeks, Steven G|Perelson, Alan S', 'Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.', 'Mexico|Mexico|Mexico|Mexico|Mexico|Mexico', 0, 'CD4 Lymphocyte Count|CD4-Positive T-Lymphocytes|Drug Resistance, Viral|Enfuvirtide|HIV Envelope Protein gp41|HIV Fusion Inhibitors|HIV Infections|HIV-1|Host-Pathogen Interactions|Humans|Models, Biological|Peptide Fragments|Prognosis|Treatment Outcome|Viral Load', 'Journal Article', '10.1371/journal.pcbi.1001012', '21124866', 'For most HIV-infected patients, antiretroviral therapy controls viral replication. However, in some patients drug resistance can cause therapy to fail. Nonetheless, continued therapy with a failing regimen can preserve or even lead to increases in CD4+ T cell counts. To understand the biological basis of these observations, we used mathematical models to explain observations made in patients with drug-resistant HIV treated with enfuvirtide (ENF/T-20), an HIV-1 fusion inhibitor. Due to resistance emergence, ENF was removed from the drug regimen, drug-sensitive virus regrown, and ENF was re-administered. We used our model to study the dynamics of plasma-viral RNA and CD4+ T cell levels, and the competition between drug-sensitive and resistant viruses during therapy interruption and re-administration. Focusing on resistant viruses carrying the V38A mutation in gp41, we found ENF-resistant virus to be 17±3% less fit than ENF-sensitive virus in the absence of the drug, and that the loss of resistant virus during therapy interruption was primarily due to this fitness cost. Using viral dynamic parameters estimated from these patients, we show that although re-administration of ENF cannot suppress viral load, it can, in the presence of resistant virus, increase CD4+ T cell counts, which should yield clinical benefits. This study provides a framework to investigate HIV and T cell dynamics in patients who develop drug resistance to other antiretroviral agents and may help to develop more effective strategies for treatment.'),
(84841, 2010, 'plos', 'Reconstructing the three-dimensional GABAergic microcircuit of the striatum', 'Humphries, Mark D|Wood, Ric|Gurney, Kevin', 'Adaptive Behaviour Research Group, Department of Psychology, University of Sheffield, Sheffield, United Kingdom. m.d.humphries@shef.ac.uk|Adaptive Behaviour Research Group, Department of Psychology, University of Sheffield, Sheffield, United Kingdom. m.d.humphries@shef.ac.uk|Adaptive Behaviour Research Group, Department of Psychology, University of Sheffield, Sheffield, United Kingdom. m.d.humphries@shef.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 31, 'Action Potentials|Algorithms|Animals|Computational Biology|Computer Simulation|Corpus Striatum|Models, Neurological|Nerve Net|Neurons|Rats|gamma-Aminobutyric Acid', 'Journal Article', '10.1371/journal.pcbi.1001011', '21124867', 'A systems wiring constrains its dynamics, yet modelling of neural structures often overlooks the specific networks formed by their neurons. We developed an approach for constructing anatomically realistic networks and reconstructed the GABAergic microcircuit formed by the medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) of the adult rat striatum. We grew dendrite and axon models for these neurons and extracted probabilities for the presence of these neurites as a function of distance from the soma. From these, we found the probabilities of intersection between the neurites of two neurons given their inter-somatic distance, and used these to construct three-dimensional striatal networks. The MSN dendrite models predicted that half of all dendritic spines are within 100µm of the soma. The constructed networks predict distributions of gap junctions between FSI dendrites, synaptic contacts between MSNs, and synaptic inputs from FSIs to MSNs that are consistent with current estimates. The models predict that to achieve this, FSIs should be at most 1% of the striatal population. They also show that the striatum is sparsely connected: FSI-MSN and MSN-MSN contacts respectively form 7% and 1.7% of all possible connections. The models predict two striking network properties: the dominant GABAergic input to a MSN arises from neurons with somas at the edge of its dendritic field, and FSIs are inter-connected on two different spatial scales: locally by gap junctions and distally by synapses. We show that both properties influence striatal dynamics: the most potent inhibition of a MSN arises from a region of striatum at the edge of its dendritic field, and the combination of local gap junction and distal synaptic networks between FSIs sets a robust input-output regime for the MSN population. Our models thus intimately link striatal micro-anatomy to its dynamics, providing a biologically grounded platform for further study.'),
(84842, 2010, 'plos', 'Sequence motifs in MADS transcription factors responsible for specificity and diversification of protein-protein interaction', 'van Dijk, Aalt D J|Morabito, Giuseppa|Fiers, Martijn|van Ham, Roeland C H J|Angenent, Gerco C|Immink, Richard G H', 'Plant Research International, Bioscience, Wageningen, The Netherlands.|Plant Research International, Bioscience, Wageningen, The Netherlands.|Plant Research International, Bioscience, Wageningen, The Netherlands.|Plant Research International, Bioscience, Wageningen, The Netherlands.|Plant Research International, Bioscience, Wageningen, The Netherlands.|Plant Research International, Bioscience, Wageningen, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 39, 'Amino Acid Motifs|Amino Acid Sequence|Arabidopsis Proteins|Databases, Protein|Evolution, Molecular|MADS Domain Proteins|Models, Molecular|Models, Statistical|Molecular Sequence Data|Mutation|Protein Interaction Domains and Motifs|Protein Interaction Mapping|Reproducibility of Results|Sequence Alignment', 'Journal Article', '10.1371/journal.pcbi.1001017', '21124869', 'Protein sequences encompass tertiary structures and contain information about specific molecular interactions, which in turn determine biological functions of proteins. Knowledge about how protein sequences define interaction specificity is largely missing, in particular for paralogous protein families with high sequence similarity, such as the plant MADS domain transcription factor family. In comparison to the situation in mammalian species, this important family of transcription regulators has expanded enormously in plant species and contains over 100 members in the model plant species Arabidopsis thaliana. Here, we provide insight into the mechanisms that determine protein-protein interaction specificity for the Arabidopsis MADS domain transcription factor family, using an integrated computational and experimental approach. Plant MADS proteins have highly similar amino acid sequences, but their dimerization patterns vary substantially. Our computational analysis uncovered small sequence regions that explain observed differences in dimerization patterns with reasonable accuracy. Furthermore, we show the usefulness of the method for prediction of MADS domain transcription factor interaction networks in other plant species. Introduction of mutations in the predicted interaction motifs demonstrated that single amino acid mutations can have a large effect and lead to loss or gain of specific interactions. In addition, various performed bioinformatics analyses shed light on the way evolution has shaped MADS domain transcription factor interaction specificity. Identified protein-protein interaction motifs appeared to be strongly conserved among orthologs, indicating their evolutionary importance. We also provide evidence that mutations in these motifs can be a source for sub- or neo-functionalization. The analyses presented here take us a step forward in understanding protein-protein interactions and the interplay between protein sequences and network evolution.'),
(84843, 2010, 'plos', 'Pattern recognition software and techniques for biological image analysis', 'Shamir, Lior|Delaney, John D|Orlov, Nikita|Eckley, D Mark|Goldberg, Ilya G', 'Laboratory of Genetics, National Institute on Aging/National Institutes of Health, Baltimore, Maryland, United States of America.|Laboratory of Genetics, National Institute on Aging/National Institutes of Health, Baltimore, Maryland, United States of America.|Laboratory of Genetics, National Institute on Aging/National Institutes of Health, Baltimore, Maryland, United States of America.|Laboratory of Genetics, National Institute on Aging/National Institutes of Health, Baltimore, Maryland, United States of America.|Laboratory of Genetics, National Institute on Aging/National Institutes of Health, Baltimore, Maryland, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Computational Biology|Image Processing, Computer-Assisted|Pattern Recognition, Automated|Software', 'Journal Article', '10.1371/journal.pcbi.1000974', '21124870', 'The increasing prevalence of automated image acquisition systems is enabling new types of microscopy experiments that generate large image datasets. However, there is a perceived lack of robust image analysis systems required to process these diverse datasets. Most automated image analysis systems are tailored for specific types of microscopy, contrast methods, probes, and even cell types. This imposes significant constraints on experimental design, limiting their application to the narrow set of imaging methods for which they were designed. One of the approaches to address these limitations is pattern recognition, which was originally developed for remote sensing, and is increasingly being applied to the biology domain. This approach relies on training a computer to recognize patterns in images rather than developing algorithms or tuning parameters for specific image processing tasks. The generality of this approach promises to enable data mining in extensive image repositories, and provide objective and quantitative imaging assays for routine use. Here, we provide a brief overview of the technologies behind pattern recognition and its use in computer vision for biological and biomedical imaging. We list available software tools that can be used by biologists and suggest practical experimental considerations to make the best use of pattern recognition techniques for imaging assays.'),
(84844, 2010, 'plos', 'Network analysis of global influenza spread', 'Chan, Joseph|Holmes, Antony|Rabadan, Raul', 'Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University College of Physicians and Surgeons, New York, New York, United States of America.|Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University College of Physicians and Surgeons, New York, New York, United States of America.|Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University College of Physicians and Surgeons, New York, New York, United States of America.', 'United States|United States|United States', 40, 'Antigenic Variation|China|Cluster Analysis|Computational Biology|Genetic Drift|Geography|Hemagglutinin Glycoproteins, Influenza Virus|Hong Kong|Humans|Influenza A Virus, H1N1 Subtype|Influenza A Virus, H3N2 Subtype|Influenza, Human|Models, Statistical|Neuraminidase|Pandemics|Population Surveillance|Seasons|United States', 'Journal Article', '10.1371/journal.pcbi.1001005', '21124942', 'Although vaccines pose the best means of preventing influenza infection, strain selection and optimal implementation remain difficult due to antigenic drift and a lack of understanding global spread. Detecting viral movement by sequence analysis is complicated by skewed geographic and seasonal distributions in viral isolates. We propose a probabilistic method that accounts for sampling bias through spatiotemporal clustering and modeling regional and seasonal transmission as a binomial process. Analysis of H3N2 not only confirmed East-Southeast Asia as a source of new seasonal variants, but also increased the resolution of observed transmission to a country level. H1N1 data revealed similar viral spread from the tropics. Network analysis suggested China and Hong Kong as the origins of new seasonal H3N2 strains and the United States as a region where increased vaccination would maximally disrupt global spread of the virus. These techniques provide a promising methodology for the analysis of any seasonal virus, as well as for the continued surveillance of influenza.'),
(84845, 2010, 'plos', 'Using sequence-specific chemical and structural properties of DNA to predict transcription factor binding sites', 'Bauer, Amy L|Hlavacek, William S|Unkefer, Pat J|Mu, Fangping', 'Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.', 'Mexico|Mexico|Mexico|Mexico', 21, 'Algorithms|Artificial Intelligence|Binding Sites|Computational Biology|DNA, Bacterial|Escherichia coli|Escherichia coli Proteins|Molecular Dynamics Simulation|Nucleic Acid Conformation|Reproducibility of Results|Sequence Analysis, DNA|Transcription Factors', 'Comparative Study', '10.1371/journal.pcbi.1001007', '21124945', 'An important step in understanding gene regulation is to identify the DNA binding sites recognized by each transcription factor (TF). Conventional approaches to prediction of TF binding sites involve the definition of consensus sequences or position-specific weight matrices and rely on statistical analysis of DNA sequences of known binding sites. Here, we present a method called SiteSleuth in which DNA structure prediction, computational chemistry, and machine learning are applied to develop models for TF binding sites. In this approach, binary classifiers are trained to discriminate between true and false binding sites based on the sequence-specific chemical and structural features of DNA. These features are determined via molecular dynamics calculations in which we consider each base in different local neighborhoods. For each of 54 TFs in Escherichia coli, for which at least five DNA binding sites are documented in RegulonDB, the TF binding sites and portions of the non-coding genome sequence are mapped to feature vectors and used in training. According to cross-validation analysis and a comparison of computational predictions against ChIP-chip data available for the TF Fis, SiteSleuth outperforms three conventional approaches: Match, MATRIX SEARCH, and the method of Berg and von Hippel. SiteSleuth also outperforms QPMEME, a method similar to SiteSleuth in that it involves a learning algorithm. The main advantage of SiteSleuth is a lower false positive rate.'),
(84846, 2010, 'plos', 'How cations can assist DNase I in DNA binding and hydrolysis', 'Guéroult, Marc|Picot, Daniel|Abi-Ghanem, Joséphine|Hartmann, Brigitte|Baaden, Marc', 'CNRS UPR9080, Institut de Biologie Physico-Chimique, Paris, France.|CNRS UPR9080, Institut de Biologie Physico-Chimique, Paris, France.|CNRS UPR9080, Institut de Biologie Physico-Chimique, Paris, France.|CNRS UPR9080, Institut de Biologie Physico-Chimique, Paris, France.|CNRS UPR9080, Institut de Biologie Physico-Chimique, Paris, France.', 'France|France|France|France|France', 0, 'Amino Acid Sequence|Animals|Binding Sites|Calcium|Cations|Cattle|Crystallography, X-Ray|DNA|Deoxyribonuclease I|Hydrolysis|Magnesium|Molecular Dynamics Simulation|Molecular Sequence Annotation|Molecular Sequence Data|Poisson Distribution|Reproducibility of Results|Sequence Alignment', 'Journal Article', '10.1371/journal.pcbi.1001000', '21124947', 'DNase I requires Ca²+ and Mg²+ for hydrolyzing double-stranded DNA. However, the number and the location of DNase I ion-binding sites remain unclear, as well as the role of these counter-ions. Using molecular dynamics simulations, we show that bovine pancreatic (bp) DNase I contains four ion-binding pockets. Two of them strongly bind Ca²+ while the other two sites coordinate Mg²+. These theoretical results are strongly supported by revisiting crystallographic structures that contain bpDNase I. One Ca²+ stabilizes the functional DNase I structure. The presence of Mg²+ in close vicinity to the catalytic pocket of bpDNase I reinforces the idea of a cation-assisted hydrolytic mechanism. Importantly, Poisson-Boltzmann-type electrostatic potential calculations demonstrate that the divalent cations collectively control the electrostatic fit between bpDNase I and DNA. These results improve our understanding of the essential role of cations in the biological function of bpDNase I. The high degree of conservation of the amino acids involved in the identified cation-binding sites across DNase I and DNase I-like proteins from various species suggests that our findings generally apply to all DNase I-DNA interactions.'),
(84847, 2010, 'plos', 'A computational approach to analyze the mechanism of action of the kinase inhibitor bafetinib', 'Burkard, Thomas R|Rix, Uwe|Breitwieser, Florian P|Superti-Furga, Giulio|Colinge, Jacques', 'Research Center for Molecular Medicine of the Austrian Academy of Science, Vienna, Austria.|Research Center for Molecular Medicine of the Austrian Academy of Science, Vienna, Austria.|Research Center for Molecular Medicine of the Austrian Academy of Science, Vienna, Austria.|Research Center for Molecular Medicine of the Austrian Academy of Science, Vienna, Austria.|Research Center for Molecular Medicine of the Austrian Academy of Science, Vienna, Austria.', 'Austria|Austria|Austria|Austria|Austria', 27, 'Antineoplastic Agents|Apoptosis|ErbB Receptors|Humans|Leukemia, Myelogenous, Chronic, BCR-ABL Positive|Models, Biological|Protein Interaction Domains and Motifs|Protein Interaction Mapping|Protein Kinase Inhibitors|Proteomics|Pyrimidines|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1001001', '21124949', 'Prediction of drug action in human cells is a major challenge in biomedical research. Additionally, there is strong interest in finding new applications for approved drugs and identifying potential side effects. We present a computational strategy to predict mechanisms, risks and potential new domains of drug treatment on the basis of target profiles acquired through chemical proteomics. Functional protein-protein interaction networks that share one biological function are constructed and their crosstalk with the drug is scored regarding function disruption. We apply this procedure to the target profile of the second-generation BCR-ABL inhibitor bafetinib which is in development for the treatment of imatinib-resistant chronic myeloid leukemia. Beside the well known effect on apoptosis, we propose potential treatment of lung cancer and IGF1R expressing blast crisis.'),
(84848, 2010, 'plos', 'Untangling the Interplay between Epidemic Spread and Transmission Network Dynamics', 'Kamp, Christel', 'Biostatistics, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany. kamch@pei.de', 'Germany', 0, 'Algorithms|Computational Biology|Computer Simulation|Disease Transmission, Infectious|Epidemics|Epidemiologic Methods|HIV Infections|Humans|Models, Biological|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000984', '21124951', 'The epidemic spread of infectious diseases is ubiquitous and often has a considerable impact on public health and economic wealth. The large variability in the spatio-temporal patterns of epidemics prohibits simple interventions and requires a detailed analysis of each epidemic with respect to its infectious agent and the corresponding routes of transmission. To facilitate this analysis, we introduce a mathematical framework which links epidemic patterns to the topology and dynamics of the underlying transmission network. The evolution, both in disease prevalence and transmission network topology, is derived from a closed set of partial differential equations for infections without allowing for recovery. The predictions are in excellent agreement with complementarily conducted agent-based simulations. The capacity of this new method is demonstrated in several case studies on HIV epidemics in synthetic populations: it allows us to monitor the evolution of contact behavior among healthy and infected individuals and the contributions of different disease stages to the spreading of the epidemic. This gives both direction to and a test bed for targeted intervention strategies for epidemic control. In conclusion, this mathematical framework provides a capable toolbox for the analysis of epidemics from first principles. This allows for fast, in silico modeling--and manipulation--of epidemics and is especially powerful if complemented with adequate empirical data for parameterization.'),
(84849, 2010, 'plos', 'Environments that induce synthetic microbial ecosystems', 'Klitgord, Niels|Segrè, Daniel', 'Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America.|Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America.', 'United States|United States', 181, 'Algorithms|Culture Media|Desulfovibrio vulgaris|Ecosystem|Escherichia coli|Methanococcus|Microbial Interactions|Models, Biological|Saccharomyces cerevisiae|Synthetic Biology|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1001002', '21124952', 'Interactions between microbial species are sometimes mediated by the exchange of small molecules, secreted by one species and metabolized by another. Both one-way (commensal) and two-way (mutualistic) interactions may contribute to complex networks of interdependencies. Understanding these interactions constitutes an open challenge in microbial ecology, with applications ranging from the human microbiome to environmental sustainability. In parallel to natural communities, it is possible to explore interactions in artificial microbial ecosystems, e.g. pairs of genetically engineered mutualistic strains. Here we computationally generate artificial microbial ecosystems without re-engineering the microbes themselves, but rather by predicting their growth on appropriately designed media. We use genome-scale stoichiometric models of metabolism to identify media that can sustain growth for a pair of species, but fail to do so for one or both individual species, thereby inducing putative symbiotic interactions. We first tested our approach on two previously studied mutualistic pairs, and on a pair of highly curated model organisms, showing that our algorithms successfully recapitulate known interactions, robustly predict new ones, and provide novel insight on exchanged molecules. We then applied our method to all possible pairs of seven microbial species, and found that it is always possible to identify putative media that induce commensalism or mutualism. Our analysis also suggests that symbiotic interactions may arise more readily through environmental fluctuations than genetic modifications. We envision that our approach will help generate microbe-microbe interaction maps useful for understanding microbial consortia dynamics and evolution, and for exploring the full potential of natural metabolic pathways for metabolic engineering applications.'),
(84850, 2010, 'plos', 'On the origins of the weak folding cooperativity of a designed xcexb2xcexb2xcexb1 ultrafast protein FSD-1', 'Wu, Chun|Shea, Joan-Emma', 'Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, California, United States of America.|Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, California, United States of America.', 'United States|United States', 13, 'DNA-Binding Proteins|Kinetics|Molecular Dynamics Simulation|Nuclear Magnetic Resonance, Biomolecular|Protein Denaturation|Protein Folding|Protein Structure, Secondary|Protein Structure, Tertiary|Thermodynamics|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000998', '21124953', 'FSD-1, a designed small ultrafast folder with a xcexb2xcexb2xcexb1 fold, has been actively studied in the last few years as a model system for studying protein folding mechanisms and for testing of the accuracy of computational models. The suitability of this protein to describe the folding of naturally occurring xcexb1/xcexb2 proteins has recently been challenged based on the observation that the melting transition is very broad, with ill-resolved baselines. Using molecular dynamics simulations with the AMBER protein force field (ff96) coupled with the implicit solvent model (IGBxe2x80x8a=xe2x80x8a5), we shed new light into the nature of this transition and resolve the experimental controversies. We show that the melting transition corresponds to the melting of the protein as a whole, and not solely to the helix-coil transition. The breadth of the folding transition arises from the spread in the melting temperatures (from xe2x88xbc325 K to xe2x88xbc302 K) of the individual transitions: formation of the hydrophobic core, xcexb2-hairpin and tertiary fold, with the helix formed earlier. Our simulations initiated from an extended chain accurately predict the native structure, provide a reasonable estimate of the transition barrier height, and explicitly demonstrate the existence of multiple pathways and multiple transition states for folding. Our exhaustive sampling enables us to assess the quality of the Amber ff96/igb5 combination and reveals that while this force field can predict the correct native fold, it nonetheless overstabilizes the xcexb1-helix portion of the protein (Tmxe2x80x8a=xe2x80x8axe2x88xbc387K) as well as the denatured structures.'),
(84851, 2010, 'plos', 'Abnormal cortical networks in mild cognitive impairment and Alzheimers disease', 'Yao, Zhijun|Zhang, Yuanchao|Lin, Lei|Zhou, Yuan|Xu, Cunlu|Jiang, Tianzi|Alzheimers Disease Neuroimaging Initiative', 'Center for Computational Medicine, School of Information Science and Engineering, Lanzhou University, Lanzhou, China.|Center for Computational Medicine, School of Information Science and Engineering, Lanzhou University, Lanzhou, China.|Center for Computational Medicine, School of Information Science and Engineering, Lanzhou University, Lanzhou, China.|Center for Computational Medicine, School of Information Science and Engineering, Lanzhou University, Lanzhou, China.|Center for Computational Medicine, School of Information Science and Engineering, Lanzhou University, Lanzhou, China.|Center for Computational Medicine, School of Information Science and Engineering, Lanzhou University, Lanzhou, China.|Center for Computational Medicine, School of Information Science and Engineering, Lanzhou University, Lanzhou, China.', 'China|China|China|China|China|China|China', 0, 'Aged|Aged, 80 and over|Alzheimer Disease|Cerebral Cortex|Cluster Analysis|Cognition Disorders|Computational Biology|Female|Humans|Image Processing, Computer-Assisted|Magnetic Resonance Imaging|Male|Middle Aged|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.1001006', '21124954', 'Recently, many researchers have used graph theory to study the aberrant brain structures in Alzheimers disease (AD) and have made great progress. However, the characteristics of the cortical network in Mild Cognitive Impairment (MCI) are still largely unexplored. In this study, the gray matter volumes obtained from magnetic resonance imaging (MRI) for all brain regions except the cerebellum were parcellated into 90 areas using the automated anatomical labeling (AAL) template to construct cortical networks for 98 normal controls (NCs), 113 MCIs and 91 ADs. The measurements of the network properties were calculated for each of the three groups respectively. We found that all three cortical networks exhibited small-world properties and those strong interhemispheric correlations existed between bilaterally homologous regions. Among the three cortical networks, we found the greatest clustering coefficient and the longest absolute path length in AD, which might indicate that the organization of the cortical network was the least optimal in AD. The small-world measures of the MCI network exhibited intermediate values. This finding is logical given that MCI is considered to be the transitional stage between normal aging and AD. Out of all the between-group differences in the clustering coefficient and absolute path length, only the differences between the AD and normal control groups were statistically significant. Compared with the normal controls, the MCI and AD groups retained their hub regions in the frontal lobe but showed a loss of hub regions in the temporal lobe. In addition, altered interregional correlations were detected in the parahippocampus gyrus, medial temporal lobe, cingulum, fusiform, medial frontal lobe, and orbital frontal gyrus in groups with MCI and AD. Similar to previous studies of functional connectivity, we also revealed increased interregional correlations within the local brain lobes and disrupted long distance interregional correlations in groups with MCI and AD.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84852, 2010, 'plos', 'On the inverse problem of binocular 3D motion perception', 'Lages, Martin|Heron, Suzanne', 'School of Psychology, University of Glasgow, Glasgow, Scotland.|School of Psychology, University of Glasgow, Glasgow, Scotland.', '-|-', 0, 'Algorithms|Humans|Models, Biological|Motion Perception|Vision, Binocular', 'Journal Article', '10.1371/journal.pcbi.1000999', '21124957', 'It is shown that existing processing schemes of 3D motion perception such as interocular velocity difference, changing disparity over time, as well as joint encoding of motion and disparity, do not offer a general solution to the inverse optics problem of local binocular 3D motion. Instead we suggest that local velocity constraints in combination with binocular disparity and other depth cues provide a more flexible framework for the solution of the inverse problem. In the context of the aperture problem we derive predictions from two plausible default strategies: (1) the vector normal prefers slow motion in 3D whereas (2) the cyclopean average is based on slow motion in 2D. Predicting perceived motion directions for ambiguous line motion provides an opportunity to distinguish between these strategies of 3D motion processing. Our theoretical results suggest that velocity constraints and disparity from feature tracking are needed to solve the inverse problem of 3D motion perception. It seems plausible that motion and disparity input is processed in parallel and integrated late in the visual processing hierarchy.'),
(84853, 2010, 'plos', 'Sequence-based prediction for vaccine strain selection and identification of antigenic variability in foot-and-mouth disease virus', 'Reeve, Richard|Blignaut, Belinda|Esterhuysen, Jan J|Opperman, Pamela|Matthews, Louise|Fry, Elizabeth E|de Beer, Tjaart A P|Theron, Jacques|Rieder, Elizabeth|Vosloo, Wilna|ONeill, Hester G|Haydon, Daniel T|Maree, Francois F', 'Boyd Orr Centre for Population and Ecosystem Health, University of Glasgow, Glasgow, United Kingdom. richard.reeve@glasgow.ac.uk|Boyd Orr Centre for Population and Ecosystem Health, University of Glasgow, Glasgow, United Kingdom. richard.reeve@glasgow.ac.uk|Boyd Orr Centre for Population and Ecosystem Health, University of Glasgow, Glasgow, United Kingdom. richard.reeve@glasgow.ac.uk|Boyd Orr Centre for Population and Ecosystem Health, University of Glasgow, Glasgow, United Kingdom. richard.reeve@glasgow.ac.uk|Boyd Orr Centre for Population and Ecosystem Health, University of Glasgow, Glasgow, United Kingdom. richard.reeve@glasgow.ac.uk|Boyd Orr Centre for Population and Ecosystem Health, University of Glasgow, Glasgow, United Kingdom. richard.reeve@glasgow.ac.uk|Boyd Orr Centre for Population and Ecosystem Health, University of Glasgow, Glasgow, United Kingdom. richard.reeve@glasgow.ac.uk|Boyd Orr Centre for Population and Ecosystem Health, University of Glasgow, Glasgow, United Kingdom. richard.reeve@glasgow.ac.uk|Boyd Orr Centre for Population and Ecosystem Health, University of Glasgow, Glasgow, United Kingdom. richard.reeve@glasgow.ac.uk|Boyd Orr Centre for Population and Ecosystem Health, University of Glasgow, Glasgow, United Kingdom. richard.reeve@glasgow.ac.uk|Boyd Orr Centre for Population and Ecosystem Health, University of Glasgow, Glasgow, United Kingdom. richard.reeve@glasgow.ac.uk|Boyd Orr Centre for Population and Ecosystem Health, University of Glasgow, Glasgow, United Kingdom. richard.reeve@glasgow.ac.uk|Boyd Orr Centre for Population and Ecosystem Health, University of Glasgow, Glasgow, United Kingdom. richard.reeve@glasgow.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 49, 'Africa, Southern|Animals|Antibodies, Neutralizing|Antigenic Variation|Buffaloes|Capsid Proteins|Cattle|Cluster Analysis|Computational Biology|Computer Simulation|Epitopes|Foot-and-Mouth Disease|Foot-and-Mouth Disease Virus|Models, Immunological|Phylogeny|Sequence Alignment|Sequence Analysis, RNA|Viral Vaccines', 'Journal Article', '10.1371/journal.pcbi.1001027', '21151576', 'Identifying when past exposure to an infectious disease will protect against newly emerging strains is central to understanding the spread and the severity of epidemics, but the prediction of viral cross-protection remains an important unsolved problem. For foot-and-mouth disease virus (FMDV) research in particular, improved methods for predicting this cross-protection are critical for predicting the severity of outbreaks within endemic settings where multiple serotypes and subtypes commonly co-circulate, as well as for deciding whether appropriate vaccine(s) exist and how much they could mitigate the effects of any outbreak. To identify antigenic relationships and their predictors, we used linear mixed effects models to account for variation in pairwise cross-neutralization titres using only viral sequences and structural data. We identified those substitutions in surface-exposed structural proteins that are correlates of loss of cross-reactivity. These allowed prediction of both the best vaccine match for any single virus and the breadth of coverage of new vaccine candidates from their capsid sequences as effectively as or better than serology. Sub-sequences chosen by the model-building process all contained sites that are known epitopes on other serotypes. Furthermore, for the SAT1 serotype, for which epitopes have never previously been identified, we provide strong evidence--by controlling for phylogenetic structure--for the presence of three epitopes across a panel of viruses and quantify the relative significance of some individual residues in determining cross-neutralization. Identifying and quantifying the importance of sites that predict viral strain cross-reactivity not just for single viruses but across entire serotypes can help in the design of vaccines with better targeting and broader coverage. These techniques can be generalized to any infectious agents where cross-reactivity assays have been carried out. As the parameterization uses pre-existing datasets, this approach quickly and cheaply increases both our understanding of antigenic relationships and our power to control disease.'),
(84854, 2010, 'plos', 'Spatial pattern switching enables cyclic evolution in spatial epidemics', 'Boerlijst, Maarten Chris|van Ballegooijen, Willem Marijn', 'Theoretical Ecology, Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, Amsterdam, The Netherlands. m.c.boerlijst@uva.nl|Theoretical Ecology, Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, Amsterdam, The Netherlands. m.c.boerlijst@uva.nl', 'Netherlands|Netherlands', 0, 'Computational Biology|Disease Outbreaks|Evolution, Molecular|Host-Pathogen Interactions|Models, Biological|Mutation|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1001030', '21151577', 'Infectious diseases often spread as spatial epidemic outbreak waves. A number of model studies have shown that such spatial pattern formation can have important consequences for the evolution of pathogens. Here, we show that such spatial patterns can cause cyclic evolutionary dynamics in selection for the length of the infectious period. The necessary reversal in the direction of selection is enabled by a qualitative change in the spatial pattern from epidemic waves to irregular local outbreaks. The spatial patterns are an emergent property of the epidemic system, and they are robust against changes in specific model assumptions. Our results indicate that emergent spatial patterns can act as a rich source for complexity in pathogen evolution.'),
(84855, 2010, 'plos', 'Incremental mutual information: a new method for characterizing the strength and dynamics of connections in neuronal circuits', 'Singh, Abhinav|Lesica, Nicholas A', 'Ear Institute, University College London, London, United Kingdom.|Ear Institute, University College London, London, United Kingdom.', 'United Kingdom|United Kingdom', 9, 'Action Potentials|Algorithms|Animals|Computational Biology|Computer Simulation|Haplorhini|Models, Neurological|Neurons|Normal Distribution|Retinal Ganglion Cells|Thalamus', 'Journal Article', '10.1371/journal.pcbi.1001035', '21151578', 'Understanding the computations performed by neuronal circuits requires characterizing the strength and dynamics of the connections between individual neurons. This characterization is typically achieved by measuring the correlation in the activity of two neurons. We have developed a new measure for studying connectivity in neuronal circuits based on information theory, the incremental mutual information (IMI). By conditioning out the temporal dependencies in the responses of individual neurons before measuring the dependency between them, IMI improves on standard correlation-based measures in several important ways: 1) it has the potential to disambiguate statistical dependencies that reflect the connection between neurons from those caused by other sources (e.g. shared inputs or intrinsic cellular or network mechanisms) provided that the dependencies have appropriate timescales, 2) for the study of early sensory systems, it does not require responses to repeated trials of identical stimulation, and 3) it does not assume that the connection between neurons is linear. We describe the theory and implementation of IMI in detail and demonstrate its utility on experimental recordings from the primate visual system.'),
(84856, 2010, 'plos', 'Structure learning in human sequential decision-making', 'Acuña, Daniel E|Schrater, Paul', 'Department of Computer Science and Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America. acuna002@umn.edu|Department of Computer Science and Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America. acuna002@umn.edu', 'United States|United States', 27, 'Algorithms|Bayes Theorem|Decision Making|Humans|Learning|Models, Theoretical|Reward|Task Performance and Analysis', 'Journal Article', '10.1371/journal.pcbi.1001003', '21151963', 'Studies of sequential decision-making in humans frequently find suboptimal performance relative to an ideal actor that has perfect knowledge of the model of how rewards and events are generated in the environment. Rather than being suboptimal, we argue that the learning problem humans face is more complex, in that it also involves learning the structure of reward generation in the environment. We formulate the problem of structure learning in sequential decision tasks using Bayesian reinforcement learning, and show that learning the generative model for rewards qualitatively changes the behavior of an optimal learning agent. To test whether people exhibit structure learning, we performed experiments involving a mixture of one-armed and two-armed bandit reward models, where structure learning produces many of the qualitative behaviors deemed suboptimal in previous studies. Our results demonstrate humans can perform structure learning in a near-optimal manner.'),
(84857, 2010, 'plos', 'Modeling conformational ensembles of slow functional motions in Pin1-WW', 'Morcos, Faruck|Chatterjee, Santanu|McClendon, Christopher L|Brenner, Paul R|López-Rendón, Roberto|Zintsmaster, John|Ercsey-Ravasz, Maria|Sweet, Christopher R|Jacobson, Matthew P|Peng, Jeffrey W|Izaguirre, Jesús A', 'Interdisciplinary Center for Network Science and Applications, Notre Dame, Indiana, United States of America.|Interdisciplinary Center for Network Science and Applications, Notre Dame, Indiana, United States of America.|Interdisciplinary Center for Network Science and Applications, Notre Dame, Indiana, United States of America.|Interdisciplinary Center for Network Science and Applications, Notre Dame, Indiana, United States of America.|Interdisciplinary Center for Network Science and Applications, Notre Dame, Indiana, United States of America.|Interdisciplinary Center for Network Science and Applications, Notre Dame, Indiana, United States of America.|Interdisciplinary Center for Network Science and Applications, Notre Dame, Indiana, United States of America.|Interdisciplinary Center for Network Science and Applications, Notre Dame, Indiana, United States of America.|Interdisciplinary Center for Network Science and Applications, Notre Dame, Indiana, United States of America.|Interdisciplinary Center for Network Science and Applications, Notre Dame, Indiana, United States of America.|Interdisciplinary Center for Network Science and Applications, Notre Dame, Indiana, United States of America.', 'India|India|India|India|India|India|India|India|India|India|India', 0, 'Apoenzymes|Computational Biology|Humans|Hydrogen Bonding|Markov Chains|Molecular Dynamics Simulation|NIMA-Interacting Peptidylprolyl Isomerase|Nuclear Magnetic Resonance, Biomolecular|Peptidylprolyl Isomerase|Protein Conformation|Protein Interaction Mapping|Protein Structure, Tertiary', 'Journal Article', '10.1371/journal.pcbi.1001015', '21152000', 'Protein-protein interactions are often mediated by flexible loops that experience conformational dynamics on the microsecond to millisecond time scales. NMR relaxation studies can map these dynamics. However, defining the network of inter-converting conformers that underlie the relaxation data remains generally challenging. Here, we combine NMR relaxation experiments with simulation to visualize networks of inter-converting conformers. We demonstrate our approach with the apo Pin1-WW domain, for which NMR has revealed conformational dynamics of a flexible loop in the millisecond range. We sample and cluster the free energy landscape using Markov State Models (MSM) with major and minor exchange states with high correlation with the NMR relaxation data and low NOE violations. These MSM are hierarchical ensembles of slowly interconverting, metastable macrostates and rapidly interconverting microstates. We found a low population state that consists primarily of holo-like conformations and is a hub visited by most pathways between macrostates. These results suggest that conformational equilibria between holo-like and alternative conformers pre-exist in the intrinsic dynamics of apo Pin1-WW. Analysis using MutInf, a mutual information method for quantifying correlated motions, reveals that WW dynamics not only play a role in substrate recognition, but also may help couple the substrate binding site on the WW domain to the one on the catalytic domain. Our work represents an important step towards building networks of inter-converting conformational states and is generally applicable.'),
(84858, 2010, 'plos', 'Axial and radial forces of cross-bridges depend on lattice spacing', 'Williams, C David|Regnier, Michael|Daniel, Thomas L', 'Department of Physiology and Biophysics, University of Washington, Seattle, Washington, United States of America.|Department of Physiology and Biophysics, University of Washington, Seattle, Washington, United States of America.|Department of Physiology and Biophysics, University of Washington, Seattle, Washington, United States of America.', 'United States|United States|United States', 25, 'Actins|Adenosine Diphosphate|Adenosine Triphosphate|Biomechanical Phenomena|Computational Biology|Models, Biological|Molecular Dynamics Simulation|Myosins|Protein Binding|Protein Structure, Quaternary|Sarcomeres|Torque', 'Journal Article', '10.1371/journal.pcbi.1001018', '21152002', 'Nearly all mechanochemical models of the cross-bridge treat myosin as a simple linear spring arranged parallel to the contractile filaments. These single-spring models cannot account for the radial force that muscle generates (orthogonal to the long axis of the myofilaments) or the effects of changes in filament lattice spacing. We describe a more complex myosin cross-bridge model that uses multiple springs to replicate myosins force-generating power stroke and account for the effects of lattice spacing and radial force. The four springs which comprise this model (the 4sXB) correspond to the mechanically relevant portions of myosins structure. As occurs in vivo, the 4sXBs state-transition kinetics and force-production dynamics vary with lattice spacing. Additionally, we describe a simpler two-spring cross-bridge (2sXB) model which produces results similar to those of the 4sXB model. Unlike the 4sXB model, the 2sXB model requires no iterative techniques, making it more computationally efficient. The rate at which both multi-spring cross-bridges bind and generate force decreases as lattice spacing grows. The axial force generated by each cross-bridge as it undergoes a power stroke increases as lattice spacing grows. The radial force that a cross-bridge produces as it undergoes a power stroke varies from expansive to compressive as lattice spacing increases. Importantly, these results mirror those for intact, contracting muscle force production.'),
(84859, 2010, 'plos', 'Assessing computational methods of cis-regulatory module prediction', 'Su, Jing|Teichmann, Sarah A|Down, Thomas A', 'MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.|MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.|MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 56, 'Algorithms|Animals|Area Under Curve|Cluster Analysis|Computational Biology|Databases, Genetic|Drosophila|Genome, Human|Genome, Insect|Humans|Models, Genetic|Phylogeny|ROC Curve|Regulatory Elements, Transcriptional|Transcription Factors', 'Comparative Study', '10.1371/journal.pcbi.1001020', '21152003', 'Computational methods attempting to identify instances of cis-regulatory modules (CRMs) in the genome face a challenging problem of searching for potentially interacting transcription factor binding sites while knowledge of the specific interactions involved remains limited. Without a comprehensive comparison of their performance, the reliability and accuracy of these tools remains unclear. Faced with a large number of different tools that address this problem, we summarized and categorized them based on search strategy and input data requirements. Twelve representative methods were chosen and applied to predict CRMs from the Drosophila CRM database REDfly, and across the human ENCODE regions. Our results show that the optimal choice of method varies depending on species and composition of the sequences in question. When discriminating CRMs from non-coding regions, those methods considering evolutionary conservation have a stronger predictive power than methods designed to be run on a single genome. Different CRM representations and search strategies rely on different CRM properties, and different methods can complement one another. For example, some favour homotypical clusters of binding sites, while others perform best on short CRMs. Furthermore, most methods appear to be sensitive to the composition and structure of the genome to which they are applied. We analyze the principal features that distinguish the methods that performed well, identify weaknesses leading to poor performance, and provide a guide for users. We also propose key considerations for the development and evaluation of future CRM-prediction methods.'),
(84860, 2010, 'plos', 'Little Italy: an agent-based approach to the estimation of contact patterns- fitting predicted matrices to serological data', 'Iozzi, Fabrizio|Trusiano, Francesco|Chinazzi, Matteo|Billari, Francesco C|Zagheni, Emilio|Merler, Stefano|Ajelli, Marco|Del Fava, Emanuele|Manfredi, Piero', 'Department of Decision Sciences, Bocconi University, Milan, Italy.|Department of Decision Sciences, Bocconi University, Milan, Italy.|Department of Decision Sciences, Bocconi University, Milan, Italy.|Department of Decision Sciences, Bocconi University, Milan, Italy.|Department of Decision Sciences, Bocconi University, Milan, Italy.|Department of Decision Sciences, Bocconi University, Milan, Italy.|Department of Decision Sciences, Bocconi University, Milan, Italy.|Department of Decision Sciences, Bocconi University, Milan, Italy.|Department of Decision Sciences, Bocconi University, Milan, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy|Italy|Italy|Italy', 43, 'Adolescent|Adult|Aged|Chickenpox|Child|Child, Preschool|Computational Biology|Contact Tracing|Databases, Factual|Herpesvirus 3, Human|Humans|Infant|Middle Aged|Models, Theoretical|Parvoviridae Infections|Parvovirus B19, Human|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1001021', '21152004', 'Knowledge of social contact patterns still represents the most critical step for understanding the spread of directly transmitted infections. Data on social contact patterns are, however, expensive to obtain. A major issue is then whether the simulation of synthetic societies might be helpful to reliably reconstruct such data. In this paper, we compute a variety of synthetic age-specific contact matrices through simulation of a simple individual-based model (IBM). The model is informed by Italian Time Use data and routine socio-demographic data (e.g., school and workplace attendance, household structure, etc.). The model is named Little Italy because each artificial agent is a clone of a real person. In other words, each agents daily diary is the one observed in a corresponding real individual sampled in the Italian Time Use Survey. We also generated contact matrices from the socio-demographic model underlying the Italian IBM for pandemic prediction. These synthetic matrices are then validated against recently collected Italian serological data for Varicella (VZV) and ParvoVirus (B19). Their performance in fitting sero-profiles are compared with other matrices available for Italy, such as the Polymod matrix. Synthetic matrices show the same qualitative features of the ones estimated from sample surveys: for example, strong assortativeness and the presence of super- and sub-diagonal stripes related to contacts between parents and children. Once validated against serological data, Little Italy matrices fit worse than the Polymod one for VZV, but better than concurrent matrices for B19. This is the first occasion where synthetic contact matrices are systematically compared with real ones, and validated against epidemiological data. The results suggest that simple, carefully designed, synthetic matrices can provide a fruitful complementary approach to questionnaire-based matrices. The paper also supports the idea that, depending on the transmissibility level of the infection, either the number of different contacts, or repeated exposure, may be the key factor for transmission.'),
(84861, 2010, 'plos', 'Modeling mechanisms of in vivo variability in methotrexate accumulation and folate pathway inhibition in acute lymphoblastic leukemia cells', 'Panetta, John C|Sparreboom, Alex|Pui, Ching-Hon|Relling, Mary V|Evans, William E', 'Department of Pharmaceutical Sciences, St. Jude Childrens Research Hospital, Memphis, Tennessee, United States of America. carl.panetta@stjude.org|Department of Pharmaceutical Sciences, St. Jude Childrens Research Hospital, Memphis, Tennessee, United States of America. carl.panetta@stjude.org|Department of Pharmaceutical Sciences, St. Jude Childrens Research Hospital, Memphis, Tennessee, United States of America. carl.panetta@stjude.org|Department of Pharmaceutical Sciences, St. Jude Childrens Research Hospital, Memphis, Tennessee, United States of America. carl.panetta@stjude.org|Department of Pharmaceutical Sciences, St. Jude Childrens Research Hospital, Memphis, Tennessee, United States of America. carl.panetta@stjude.org', 'United States|United States|United States|United States|United States', 34, 'Cell Division|Cohort Studies|Computational Biology|Computer Simulation|Drug Resistance, Neoplasm|Female|Folic Acid|Gene Expression Regulation, Neoplastic|Humans|Male|Metabolic Networks and Pathways|Methotrexate|Polyglutamic Acid|Polymorphism, Genetic|Precursor Cell Lymphoblastic Leukemia-Lymphoma', 'Journal Article', '10.1371/journal.pcbi.1001019', '21152005', 'Methotrexate (MTX) is widely used for the treatment of childhood acute lymphoblastic leukemia (ALL). The accumulation of MTX and its active metabolites, methotrexate polyglutamates (MTXPG), in ALL cells is an important determinant of its antileukemic effects. We studied 194 of 356 patients enrolled on St. Jude Total XV protocol for newly diagnosed ALL with the goal of characterizing the intracellular pharmacokinetics of MTXPG in leukemia cells, relating these pharmacokinetics to ALL lineage, ploidy and molecular subtype, and using a folate pathway model to simulate optimal treatment strategies. Serial MTX concentrations were measured in plasma and intracellular MTXPG concentrations were measured in circulating leukemia cells. A pharmacokinetic model was developed which accounted for the plasma disposition of MTX along with the transport and metabolism of MTXPG. In addition, a folate pathway model was adapted to simulate the effects of treatment strategies on the inhibition of de novo purine synthesis (DNPS). The intracellular MTXPG pharmacokinetic model parameters differed significantly by lineage, ploidy, and molecular subtypes of ALL. Folylpolyglutamate synthetase (FPGS) activity was higher in B vs T lineage ALL (p<0.005), MTX influx and FPGS activity were higher in hyperdiploid vs non-hyperdiploid ALL (p<0.03), MTX influx and FPGS activity were lower in the t(12,21) (ETV6-RUNX1) subtype (p<0.05), and the ratio of FPGS to xcexb3-glutamyl hydrolase (GGH) activity was lower in the t(1,19) (TCF3-PBX1) subtype (p<0.03) than other genetic subtypes. In addition, the folate pathway model showed differential inhibition of DNPS relative to MTXPG accumulation, MTX dose, and schedule. This study has provided new insights into the intracellular disposition of MTX in leukemia cells and how it affects treatment efficacy.'),
(84862, 2010, 'plos', 'A systems model for immune cell interactions unravels the mechanism of inflammation in human skin', 'Valeyev, Najl V|Hundhausen, Christian|Umezawa, Yoshinori|Kotov, Nikolay V|Williams, Gareth|Clop, Alex|Ainali, Crysanthi|Ouzounis, Christos|Tsoka, Sophia|Nestle, Frank O', 'St Johns Institute of Dermatology, Kings College London, London, United Kingdom. N.Valeyev@kent.ac.uk|St Johns Institute of Dermatology, Kings College London, London, United Kingdom. N.Valeyev@kent.ac.uk|St Johns Institute of Dermatology, Kings College London, London, United Kingdom. N.Valeyev@kent.ac.uk|St Johns Institute of Dermatology, Kings College London, London, United Kingdom. N.Valeyev@kent.ac.uk|St Johns Institute of Dermatology, Kings College London, London, United Kingdom. N.Valeyev@kent.ac.uk|St Johns Institute of Dermatology, Kings College London, London, United Kingdom. N.Valeyev@kent.ac.uk|St Johns Institute of Dermatology, Kings College London, London, United Kingdom. N.Valeyev@kent.ac.uk|St Johns Institute of Dermatology, Kings College London, London, United Kingdom. N.Valeyev@kent.ac.uk|St Johns Institute of Dermatology, Kings College London, London, United Kingdom. N.Valeyev@kent.ac.uk|St Johns Institute of Dermatology, Kings College London, London, United Kingdom. N.Valeyev@kent.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Cytokines|Dose-Response Relationship, Immunologic|Gene Expression Profiling|Genome-Wide Association Study|Histocytochemistry|Homeostasis|Humans|Inflammation|Leukocytes|Models, Biological|Phenotype|Psoriasis|Signal Transduction|Skin|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1001024', '21152006', 'Inflammation is characterized by altered cytokine levels produced by cell populations in a highly interdependent manner. To elucidate the mechanism of an inflammatory reaction, we have developed a mathematical model for immune cell interactions via the specific, dose-dependent cytokine production rates of cell populations. The model describes the criteria required for normal and pathological immune system responses and suggests that alterations in the cytokine production rates can lead to various stable levels which manifest themselves in different disease phenotypes. The model predicts that pairs of interacting immune cell populations can maintain homeostatic and elevated extracellular cytokine concentration levels, enabling them to operate as an immune system switch. The concept described here is developed in the context of psoriasis, an immune-mediated disease, but it can also offer mechanistic insights into other inflammatory pathologies as it explains how interactions between immune cell populations can lead to disease phenotypes.'),
(84863, 2010, 'plos', 'Gambling in the visual periphery: a conjoint-measurement analysis of human ability to judge visual uncertainty', 'Zhang, Hang|Morvan, Camille|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', 'United States|United States|United States', 11, 'Computational Biology|Decision Making|Female|Humans|Male|Photic Stimulation|Psychomotor Performance|Retina|Saccades|Visual Fields', 'Journal Article', '10.1371/journal.pcbi.1001023', '21152007', 'Recent work in motor control demonstrates that humans take their own motor uncertainty into account, adjusting the timing and goals of movement so as to maximize expected gain. Visual sensitivity varies dramatically with retinal location and target, and models of optimal visual search typically assume that the visual system takes retinal inhomogeneity into account in planning eye movements. Such models can then use the entire retina rather than just the fovea to speed search. Using a simple decision task, we evaluated human ability to compensate for retinal inhomogeneity. We first measured observers sensitivity for targets, varying contrast and eccentricity. Observers then repeatedly chose between targets differing in eccentricity and contrast, selecting the one they would prefer to attempt: e.g., a low contrast target at 2° versus a high contrast target at 10°. Observers knew they would later attempt some of their chosen targets and receive rewards for correct classifications. We evaluated performance in three ways. Equivalence: Do observers judgments agree with their actual performance? Do they correctly trade off eccentricity and contrast and select the more discriminable target in each pair? Transitivity: Are observers choices self-consistent? Dominance: Do observers understand that increased contrast improves performance? Decreased eccentricity? All observers exhibited patterned failures of equivalence, and seven out of eight observers failed transitivity. There were significant but small failures of dominance. All these failures together reduced their winnings by 10%-18%.'),
(84864, 2010, 'plos', 'Self-organized criticality in developing neuronal networks', 'Tetzlaff, Christian|Okujeni, Samora|Egert, Ulrich|Wxc3xb6rgxc3xb6tter, Florentin|Butz, Markus', 'Bernstein Center for Computational Neuroscience, Institute of Physics III - Biophysics, Georg-August Universitxc3xa4t, Gxc3xb6ttingen, Germany. tetzlaff@physik3.gwdg.de|Bernstein Center for Computational Neuroscience, Institute of Physics III - Biophysics, Georg-August Universitxc3xa4t, Gxc3xb6ttingen, Germany. tetzlaff@physik3.gwdg.de|Bernstein Center for Computational Neuroscience, Institute of Physics III - Biophysics, Georg-August Universitxc3xa4t, Gxc3xb6ttingen, Germany. tetzlaff@physik3.gwdg.de|Bernstein Center for Computational Neuroscience, Institute of Physics III - Biophysics, Georg-August Universitxc3xa4t, Gxc3xb6ttingen, Germany. tetzlaff@physik3.gwdg.de|Bernstein Center for Computational Neuroscience, Institute of Physics III - Biophysics, Georg-August Universitxc3xa4t, Gxc3xb6ttingen, Germany. tetzlaff@physik3.gwdg.de', 'Germany|Germany|Germany|Germany|Germany', 102, 'Action Potentials|Algorithms|Analysis of Variance|Animals|Cerebral Cortex|Computational Biology|Dendrites|Homeostasis|Models, Neurological|Nerve Net|Neurites|Neurons|Rats|Rats, Wistar|Synapses', 'Journal Article', '10.1371/journal.pcbi.1001013', '21152008', 'Recently evidence has accumulated that many neural networks exhibit self-organized criticality. In this state, activity is similar across temporal scales and this is beneficial with respect to information flow. If subcritical, activity can die out, if supercritical epileptiform patterns may occur. Little is known about how developing networks will reach and stabilize criticality. Here we monitor the development between 13 and 95 days in vitro (DIV) of cortical cell cultures (n = 20) and find four different phases, related to their morphological maturation: An initial low-activity state (xe2x89x8819 DIV) is followed by a supercritical (xe2x89x8820 DIV) and then a subcritical one (xe2x89x8836 DIV) until the network finally reaches stable criticality (xe2x89x8858 DIV). Using network modeling and mathematical analysis we describe the dynamics of the emergent connectivity in such developing systems. Based on physiological observations, the synaptic development in the model is determined by the drive of the neurons to adjust their connectivity for reaching on average firing rate homeostasis. We predict a specific time course for the maturation of inhibition, with strong onset and delayed pruning, and that total synaptic connectivity should be strongly linked to the relative levels of excitation and inhibition. These results demonstrate that the interplay between activity and connectivity guides developing networks into criticality suggesting that this may be a generic and stable state of many networks in vivo and in vitro.'),
(84865, 2010, 'plos', 'Identifying a high fraction of the human genome to be under selective constraint using GERP++', 'Davydov, Eugene V|Goode, David L|Sirota, Marina|Cooper, Gregory M|Sidow, Arend|Batzoglou, Serafim', 'Department of Computer Science, Stanford University, Stanford, California, United States of America.|Department of Computer Science, Stanford University, Stanford, California, United States of America.|Department of Computer Science, Stanford University, Stanford, California, United States of America.|Department of Computer Science, Stanford University, Stanford, California, United States of America.|Department of Computer Science, Stanford University, Stanford, California, United States of America.|Department of Computer Science, Stanford University, Stanford, California, United States of America.', 'United States|United States|United States|United States|United States|United States', 0, 'Algorithms|Animals|Genome, Human|Genomics|Humans|Mammals|Models, Genetic|Phylogeny|Sequence Alignment|Sequence Analysis, DNA|Software|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1001025', '21152010', 'Computational efforts to identify functional elements within genomes leverage comparative sequence information by looking for regions that exhibit evidence of selective constraint. One way of detecting constrained elements is to follow a bottom-up approach by computing constraint scores for individual positions of a multiple alignment and then defining constrained elements as segments of contiguous, highly scoring nucleotide positions. Here we present GERP++, a new tool that uses maximum likelihood evolutionary rate estimation for position-specific scoring and, in contrast to previous bottom-up methods, a novel dynamic programming approach to subsequently define constrained elements. GERP++ evaluates a richer set of candidate element breakpoints and ranks them based on statistical significance, eliminating the need for biased heuristic extension techniques. Using GERP++ we identify over 1.3 million constrained elements spanning over 7% of the human genome. We predict a higher fraction than earlier estimates largely due to the annotation of longer constrained elements, which improves one to one correspondence between predicted elements with known functional sequences. GERP++ is an efficient and effective tool to provide both nucleotide- and element-level constraint scores within deep multiple sequence alignments.'),
(84866, 2010, 'plos', 'Gene expression network reconstruction by convex feature selection when incorporating genetic perturbations', 'Logsdon, Benjamin A|Mezey, Jason', 'Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.|Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.', 'United States|United States', 0, 'Algorithms|Gene Expression Regulation, Fungal|Gene Regulatory Networks|Genome, Fungal|Metabolic Networks and Pathways|Models, Genetic|Phenotype|Quantitative Trait Loci|Saccharomyces cerevisiae|Signal Transduction|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1001014', '21152011', 'Cellular gene expression measurements contain regulatory information that can be used to discover novel network relationships. Here, we present a new algorithm for network reconstruction powered by the adaptive lasso, a theoretically and empirically well-behaved method for selecting the regulatory features of a network. Any algorithms designed for network discovery that make use of directed probabilistic graphs require perturbations, produced by either experiments or naturally occurring genetic variation, to successfully infer unique regulatory relationships from gene expression data. Our approach makes use of appropriately selected cis-expression Quantitative Trait Loci (cis-eQTL), which provide a sufficient set of independent perturbations for maximum network resolution. We compare the performance of our network reconstruction algorithm to four other approaches: the PC-algorithm, QTLnet, the QDG algorithm, and the NEO algorithm, all of which have been used to reconstruct directed networks among phenotypes leveraging QTL. We show that the adaptive lasso can outperform these algorithms for networks of ten genes and ten cis-eQTL, and is competitive with the QDG algorithm for networks with thirty genes and thirty cis-eQTL, with rich topologies and hundreds of samples. Using this novel approach, we identify unique sets of directed relationships in Saccharomyces cerevisiae when analyzing genome-wide gene expression data for an intercross between a wild strain and a lab strain. We recover novel putative network relationships between a tyrosine biosynthesis gene (TYR1), and genes involved in endocytosis (RCY1), the spindle checkpoint (BUB2), sulfonate catabolism (JLP1), and cell-cell communication (PRM7). Our algorithm provides a synthesis of feature selection methods and graphical model theory that has the potential to reveal new directed regulatory relationships from the analysis of population level genetic and gene expression data.'),
(84867, 2010, 'plos', 'A scalable approach for discovering conserved active subnetworks across species', 'Deshpande, Raamesh|Sharma, Shikha|Verfaillie, Catherine M|Hu, Wei-Shou|Myers, Chad L', 'Department of Computer Science and Engineering, University of Minnesota-Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Computer Science and Engineering, University of Minnesota-Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Computer Science and Engineering, University of Minnesota-Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Computer Science and Engineering, University of Minnesota-Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Computer Science and Engineering, University of Minnesota-Twin Cities, Minneapolis, Minnesota, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Algorithms|Animals|Computational Biology|Databases, Genetic|Gene Expression Profiling|Gene Regulatory Networks|Humans|Mice|Oligonucleotide Array Sequence Analysis|Protein Interaction Mapping|Reproducibility of Results|Signal Transduction|Species Specificity|Stem Cells', 'Journal Article', '10.1371/journal.pcbi.1001028', '21170309', 'Overlaying differential changes in gene expression on protein interaction networks has proven to be a useful approach to interpreting the cells dynamic response to a changing environment. Despite successes in finding active subnetworks in the context of a single species, the idea of overlaying lists of differentially expressed genes on networks has not yet been extended to support the analysis of multiple species interaction networks. To address this problem, we designed a scalable, cross-species network search algorithm, neXus (Network-cross(X)-species-Search), that discovers conserved, active subnetworks based on parallel differential expression studies in multiple species. Our approach leverages functional linkage networks, which provide more comprehensive coverage of functional relationships than physical interaction networks by combining heterogeneous types of genomic data. We applied our cross-species approach to identify conserved modules that are differentially active in stem cells relative to differentiated cells based on parallel gene expression studies and functional linkage networks from mouse and human. We find hundreds of conserved active subnetworks enriched for stem cell-associated functions such as cell cycle, DNA repair, and chromatin modification processes. Using a variation of this approach, we also find a number of species-specific networks, which likely reflect mechanisms of stem cell function that have diverged between mouse and human. We assess the statistical significance of the subnetworks by comparing them with subnetworks discovered on random permutations of the differential expression data. We also describe several case examples that illustrate the utility of comparative analysis of active subnetworks.'),
(84868, 2010, 'plos', 'A minimal model of metabolism-based chemotaxis', 'Egbert, Matthew D|Barandiaran, Xabier E|Di Paolo, Ezequiel A', 'Centre for Computational Neuroscience and Robotics, University of Sussex, Brighton, United Kingdom. mde@matthewegbert.com|Centre for Computational Neuroscience and Robotics, University of Sussex, Brighton, United Kingdom. mde@matthewegbert.com|Centre for Computational Neuroscience and Robotics, University of Sussex, Brighton, United Kingdom. mde@matthewegbert.com', 'United Kingdom|United Kingdom|United Kingdom', 41, 'Bacterial Physiological Phenomena|Chemotaxis|Escherichia coli|Flagella|Fumarates|Metabolism|Models, Biological|Salmonella typhimurium|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1001004', '21170312', 'Since the pioneering work by Julius Adler in the 1960s, bacterial chemotaxis has been predominantly studied as metabolism-independent. All available simulation models of bacterial chemotaxis endorse this assumption. Recent studies have shown, however, that many metabolism-dependent chemotactic patterns occur in bacteria. We hereby present the simplest artificial protocell model capable of performing metabolism-based chemotaxis. The model serves as a proof of concept to show how even the simplest metabolism can sustain chemotactic patterns of varying sophistication. It also reproduces a set of phenomena that have recently attracted attention on bacterial chemotaxis and provides insights about alternative mechanisms that could instantiate them. We conclude that relaxing the metabolism-independent assumption provides important theoretical advances, forces us to rethink some established pre-conceptions and may help us better understand unexplored and poorly understood aspects of bacterial chemotaxis.'),
(84869, 2010, 'plos', 'Cholera- and anthrax-like toxins are among several new ADP-ribosyltransferases', 'Fieldhouse, Robert J|Turgeon, Zachari|White, Dawn|Merrill, A Rod', 'Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada.|Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada.|Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada.|Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada.', 'Canada|Canada|Canada|Canada', 0, 'ADP Ribose Transferases|Amino Acid Sequence|Bacillus cereus|Bacterial Proteins|Bacterial Toxins|Computational Biology|Data Mining|Enterococcus faecalis|Models, Molecular|Molecular Sequence Data|Mycobacterium avium|Photorhabdus|Phylogeny|Protein Conformation|Reproducibility of Results|Sequence Alignment|Sequence Analysis, DNA|Structure-Activity Relationship|Vibrio|Vibrio cholerae', 'Journal Article', '10.1371/journal.pcbi.1001029', '21170356', 'Chelt, a cholera-like toxin from Vibrio cholerae, and Certhrax, an anthrax-like toxin from Bacillus cereus, are among six new bacterial protein toxins we identified and characterized using in silico and cell-based techniques. We also uncovered medically relevant toxins from Mycobacterium avium and Enterococcus faecalis. We found agriculturally relevant toxins in Photorhabdus luminescens and Vibrio splendidus. These toxins belong to the ADP-ribosyltransferase family that has conserved structure despite low sequence identity. Therefore, our search for new toxins combined fold recognition with rules for filtering sequences--including a primary sequence pattern--to reduce reliance on sequence identity and identify toxins using structure. We used computers to build models and analyzed each new toxin to understand features including: structure, secretion, cell entry, activation, NAD+ substrate binding, intracellular target binding and the reaction mechanism. We confirmed activity using a yeast growth test. In this era where an expanding protein structure library complements abundant protein sequence data--and we need high-throughput validation--our approach provides insight into the newest toxin ADP-ribosyltransferases.'),
(84870, 2010, 'plos', 'Modeling the evolution of regulatory elements by simultaneous detection and alignment with phylogenetic pair HMMs', 'Majoros, William H|Ohler, Uwe', 'Institute for Genome Sciences & Policy, Duke University, Durham, North Carolina, United States of America. bmajoros@duke.edu|Institute for Genome Sciences & Policy, Duke University, Durham, North Carolina, United States of America. bmajoros@duke.edu', 'United States|United States', 0, 'Animals|Base Sequence|Computational Biology|Computer Simulation|Drosophila melanogaster|Evolution, Molecular|Gene Expression Regulation|Markov Chains|Molecular Sequence Data|Phylogeny|ROC Curve|Regulatory Elements, Transcriptional|Sequence Alignment|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1001037', '21187896', 'The computational detection of regulatory elements in DNA is a difficult but important problem impacting our progress in understanding the complex nature of eukaryotic gene regulation. Attempts to utilize cross-species conservation for this task have been hampered both by evolutionary changes of functional sites and poor performance of general-purpose alignment programs when applied to non-coding sequence. We describe a new and flexible framework for modeling binding site evolution in multiple related genomes, based on phylogenetic pair hidden Markov models which explicitly model the gain and loss of binding sites along a phylogeny. We demonstrate the value of this framework for both the alignment of regulatory regions and the inference of precise binding-site locations within those regions. As the underlying formalism is a stochastic, generative model, it can also be used to simulate the evolution of regulatory elements. Our implementation is scalable in terms of numbers of species and sequence lengths and can produce alignments and binding-site predictions with accuracy rivaling or exceeding current systems that specialize in only alignment or only binding-site prediction. We demonstrate the validity and power of various model components on extensive simulations of realistic sequence data and apply a specific model to study Drosophila enhancers in as many as ten related genomes and in the presence of gain and loss of binding sites. Different models and modeling assumptions can be easily specified, thus providing an invaluable tool for the exploration of biological hypotheses that can drive improvements in our understanding of the mechanisms and evolution of gene regulation.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84871, 2010, 'plos', 'Encoding of spatio-temporal input characteristics by a CA1 pyramidal neuron model', 'Pissadaki, Eleftheria Kyriaki|Sidiropoulou, Kyriaki|Reczko, Martin|Poirazi, Panayiota', 'Department of Biology, University of Crete, Heraklion, Crete, Greece. eleftheria.pissadaki@pharm.ox.ac.uk|Department of Biology, University of Crete, Heraklion, Crete, Greece. eleftheria.pissadaki@pharm.ox.ac.uk|Department of Biology, University of Crete, Heraklion, Crete, Greece. eleftheria.pissadaki@pharm.ox.ac.uk|Department of Biology, University of Crete, Heraklion, Crete, Greece. eleftheria.pissadaki@pharm.ox.ac.uk', 'Greece|Greece|Greece|Greece', 17, 'Algorithms|Animals|CA1 Region, Hippocampal|Cluster Analysis|Computational Biology|Models, Neurological|Pyramidal Cells|Reproducibility of Results|Synapses|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1001038', '21187899', 'The in vivo activity of CA1 pyramidal neurons alternates between regular spiking and bursting, but how these changes affect information processing remains unclear. Using a detailed CA1 pyramidal neuron model, we investigate how timing and spatial arrangement variations in synaptic inputs to the distal and proximal dendritic layers influence the information content of model responses. We find that the temporal delay between activation of the two layers acts as a switch between excitability modes: short delays induce bursting while long delays decrease firing. For long delays, the average firing frequency of the model response discriminates spatially clustered from diffused inputs to the distal dendritic tree. For short delays, the onset latency and inter-spike-interval succession of model responses can accurately classify input signals as temporally close or distant and spatially clustered or diffused across different stimulation protocols. These findings suggest that a CA1 pyramidal neuron may be capable of encoding and transmitting presynaptic spatiotemporal information about the activity of the entorhinal cortex-hippocampal network to higher brain regions via the selective use of either a temporal or a rate code.'),
(84872, 2010, 'plos', 'How noisy adaptation of neurons shapes interspike interval histograms and correlations', 'Schwalger, Tilo|Fisch, Karin|Benda, Jan|Lindner, Benjamin', 'Max-Planck Institute for the Physics of Complex Systems, Dresden, Germany. tilo@pks.mpg.de|Max-Planck Institute for the Physics of Complex Systems, Dresden, Germany. tilo@pks.mpg.de|Max-Planck Institute for the Physics of Complex Systems, Dresden, Germany. tilo@pks.mpg.de|Max-Planck Institute for the Physics of Complex Systems, Dresden, Germany. tilo@pks.mpg.de', 'Germany|Germany|Germany|Germany', 43, 'Action Potentials|Algorithms|Computational Biology|Computer Simulation|Models, Neurological|Neurons|Normal Distribution|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1001026', '21187900', 'Channel noise is the dominant intrinsic noise source of neurons causing variability in the timing of action potentials and interspike intervals (ISI). Slow adaptation currents are observed in many cells and strongly shape response properties of neurons. These currents are mediated by finite populations of ionic channels and may thus carry a substantial noise component. Here we study the effect of such adaptation noise on the ISI statistics of an integrate-and-fire model neuron by means of analytical techniques and extensive numerical simulations. We contrast this stochastic adaptation with the commonly studied case of a fast fluctuating current noise and a deterministic adaptation current (corresponding to an infinite population of adaptation channels). We derive analytical approximations for the ISI density and ISI serial correlation coefficient for both cases. For fast fluctuations and deterministic adaptation, the ISI density is well approximated by an inverse Gaussian (IG) and the ISI correlations are negative. In marked contrast, for stochastic adaptation, the density is more peaked and has a heavier tail than an IG density and the serial correlations are positive. A numerical study of the mixed case where both fast fluctuations and adaptation channel noise are present reveals a smooth transition between the analytically tractable limiting cases. Our conclusions are furthermore supported by numerical simulations of a biophysically more realistic Hodgkin-Huxley type model. Our results could be used to infer the dominant source of noise in neurons from their ISI statistics.'),
(84873, 2010, 'plos', 'Combining network modeling and gene expression microarray analysis to explore the dynamics of Th1 and Th2 cell regulation', 'Pedicini, Marco|Barrenäs, Fredrik|Clancy, Trevor|Castiglione, Filippo|Hovig, Eivind|Kanduri, Kartiek|Santoni, Daniele|Benson, Mikael', 'Istituto per le Applicazioni del Calcolo Mauro Picone, Consiglio Nazionale delle Ricerche, Rome, Italy.|Istituto per le Applicazioni del Calcolo Mauro Picone, Consiglio Nazionale delle Ricerche, Rome, Italy.|Istituto per le Applicazioni del Calcolo Mauro Picone, Consiglio Nazionale delle Ricerche, Rome, Italy.|Istituto per le Applicazioni del Calcolo Mauro Picone, Consiglio Nazionale delle Ricerche, Rome, Italy.|Istituto per le Applicazioni del Calcolo Mauro Picone, Consiglio Nazionale delle Ricerche, Rome, Italy.|Istituto per le Applicazioni del Calcolo Mauro Picone, Consiglio Nazionale delle Ricerche, Rome, Italy.|Istituto per le Applicazioni del Calcolo Mauro Picone, Consiglio Nazionale delle Ricerche, Rome, Italy.|Istituto per le Applicazioni del Calcolo Mauro Picone, Consiglio Nazionale delle Ricerche, Rome, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy|Italy|Italy', 20, 'Algorithms|Computational Biology|Computer Simulation|Databases, Genetic|Gene Expression Profiling|Gene Knockout Techniques|Gene Regulatory Networks|Humans|Oligonucleotide Array Sequence Analysis|Phenotype|Th1 Cells|Th2 Cells', 'Journal Article', '10.1371/journal.pcbi.1001032', '21187905', 'Two T helper (Th) cell subsets, namely Th1 and Th2 cells, play an important role in inflammatory diseases. The two subsets are thought to counter-regulate each other, and alterations in their balance result in different diseases. This paradigm has been challenged by recent clinical and experimental data. Because of the large number of genes involved in regulating Th1 and Th2 cells, assessment of this paradigm by modeling or experiments is difficult. Novel algorithms based on formal methods now permit the analysis of large gene regulatory networks. By combining these algorithms with in silico knockouts and gene expression microarray data from human T cells, we examined if the results were compatible with a counter-regulatory role of Th1 and Th2 cells. We constructed a directed network model of genes regulating Th1 and Th2 cells through text mining and manual curation. We identified four attractors in the network, three of which included genes that corresponded to Th0, Th1 and Th2 cells. The fourth attractor contained a mixture of Th1 and Th2 genes. We found that neither in silico knockouts of the Th1 and Th2 attractor genes nor gene expression microarray data from patients with immunological disorders and healthy subjects supported a counter-regulatory role of Th1 and Th2 cells. By combining network modeling with transcriptomic data analysis and in silico knockouts, we have devised a practical way to help unravel complex regulatory network topology and to increase our understanding of how network actions may differ in health and disease.'),
(84874, 2010, 'plos', 'Rhythmic dynamics and synchronization via dimensionality reduction: application to human gait', 'Zhang, Jie|Zhang, Kai|Feng, Jianfeng|Small, Michael', 'Center for Computational Systems Biology, Fudan University, Shanghai, Peoples Republic of China. jzhang080@gmail.com|Center for Computational Systems Biology, Fudan University, Shanghai, Peoples Republic of China. jzhang080@gmail.com|Center for Computational Systems Biology, Fudan University, Shanghai, Peoples Republic of China. jzhang080@gmail.com|Center for Computational Systems Biology, Fudan University, Shanghai, Peoples Republic of China. jzhang080@gmail.com', 'China|China|China|China', 30, 'Ankle|Biomechanical Phenomena|Computational Biology|Gait|Humans|Knee|Models, Biological|Walking', 'Journal Article', '10.1371/journal.pcbi.1001033', '21187907', 'Reliable characterization of locomotor dynamics of human walking is vital to understanding the neuromuscular control of human locomotion and disease diagnosis. However, the inherent oscillation and ubiquity of noise in such non-strictly periodic signals pose great challenges to current methodologies. To this end, we exploit the state-of-the-art technology in pattern recognition and, specifically, dimensionality reduction techniques, and propose to reconstruct and characterize the dynamics accurately on the cycle scale of the signal. This is achieved by deriving a low-dimensional representation of the cycles through global optimization, which effectively preserves the topology of the cycles that are embedded in a high-dimensional Euclidian space. Our approach demonstrates a clear advantage in capturing the intrinsic dynamics and probing the subtle synchronization patterns from uni/bivariate oscillatory signals over traditional methods. Application to human gait data for healthy subjects and diabetics reveals a significant difference in the dynamics of ankle movements and ankle-knee coordination, but not in knee movements. These results indicate that the impaired sensory feedback from the feet due to diabetes does not influence the knee movement in general, and that normal human walking is not critically dependent on the feedback from the peripheral nervous system.'),
(84875, 2010, 'plos', 'The evolutionary analysis of emerging low frequency HIV-1 CXCR4 using variants through time--an ultra-deep approach', 'Archer, John|Rambaut, Andrew|Taillon, Bruce E|Harrigan, P Richard|Lewis, Marilyn|Robertson, David L', 'Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.|Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.|Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.|Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.|Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.|Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 61, 'Algorithms|Computational Biology|Cyclohexanes|Genetic Variation|HIV Fusion Inhibitors|HIV Infections|HIV-1|Humans|Maraviroc|Receptors, CXCR4|Sequence Alignment|Sequence Analysis, RNA|Software|Triazoles|Viral Tropism', 'Journal Article', '10.1371/journal.pcbi.1001022', '21187908', 'Large-scale parallel pyrosequencing produces unprecedented quantities of sequence data. However, when generated from viral populations current mapping software is inadequate for dealing with the high levels of variation present, resulting in the potential for biased data loss. In order to apply the 454 Life Sciences pyrosequencing system to the study of viral populations, we have developed software for the processing of highly variable sequence data. Here we demonstrate our software by analyzing two temporally sampled HIV-1 intra-patient datasets from a clinical study of maraviroc. This drug binds the CCR5 coreceptor, thus preventing HIV-1 infection of the cell. The objective is to determine viral tropism (CCR5 versus CXCR4 usage) and track the evolution of minority CXCR4-using variants that may limit the response to a maraviroc-containing treatment regimen. Five time points (two prior to treatment) were available from each patient. We first quantify the effects of divergence on initial read k-mer mapping and demonstrate the importance of utilizing population-specific template sequences in relation to the analysis of next-generation sequence data. Then, in conjunction with coreceptor prediction algorithms that infer HIV tropism, our software was used to quantify the viral population structure pre- and post-treatment. In both cases, low frequency CXCR4-using variants (2.5-15%) were detected prior to treatment. Following phylogenetic inference, these variants were observed to exist as distinct lineages that were maintained through time. Our analysis, thus confirms the role of pre-existing CXCR4-using virus in the emergence of maraviroc-insensitive HIV. The software will have utility for the study of intra-host viral diversity and evolution of other fast evolving viruses, and is available from http://www.bioinf.manchester.ac.uk/segminator/.'),
(84876, 2010, 'plos', 'Mapping dynamic histone acetylation patterns to gene expression in nanog-depleted murine embryonic stem cells', 'Markowetz, Florian|Mulder, Klaas W|Airoldi, Edoardo M|Lemischka, Ihor R|Troyanskaya, Olga G', 'Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom. florian.markowetz@cancer.org.uk|Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom. florian.markowetz@cancer.org.uk|Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom. florian.markowetz@cancer.org.uk|Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom. florian.markowetz@cancer.org.uk|Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom. florian.markowetz@cancer.org.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 18, 'Acetylation|Animals|Cluster Analysis|Computational Biology|Embryonic Stem Cells|Gene Expression Profiling|Gene Expression Regulation|Gene Silencing|Genome-Wide Association Study|Histones|Homeodomain Proteins|Mice|Nanog Homeobox Protein|Phenotype', 'Journal Article', '10.1371/journal.pcbi.1001034', '21187909', 'Embryonic stem cells (ESC) have the potential to self-renew indefinitely and to differentiate into any of the three germ layers. The molecular mechanisms for self-renewal, maintenance of pluripotency and lineage specification are poorly understood, but recent results point to a key role for epigenetic mechanisms. In this study, we focus on quantifying the impact of histone 3 acetylation (H3K9,14ac) on gene expression in murine embryonic stem cells. We analyze genome-wide histone acetylation patterns and gene expression profiles measured over the first five days of cell differentiation triggered by silencing Nanog, a key transcription factor in ESC regulation. We explore the temporal and spatial dynamics of histone acetylation data and its correlation with gene expression using supervised and unsupervised statistical models. On a genome-wide scale, changes in acetylation are significantly correlated to changes in mRNA expression and, surprisingly, this coherence increases over time. We quantify the predictive power of histone acetylation for gene expression changes in a balanced cross-validation procedure. In an in-depth study we focus on genes central to the regulatory network of Mouse ESC, including those identified in a recent genome-wide RNAi screen and in the PluriNet, a computationally derived stem cell signature. We find that compared to the rest of the genome, ESC-specific genes show significantly more acetylation signal and a much stronger decrease in acetylation over time, which is often not reflected in a concordant expression change. These results shed light on the complexity of the relationship between histone acetylation and gene expression and are a step forward to dissect the multilayer regulatory mechanisms that determine stem cell fate.'),
(84877, 2010, 'plos', 'Mathematical model of a cell size checkpoint', 'Vilela, Marco|Morgan, Jeffrey J|Lindahl, Paul A', 'Department of Chemistry, Texas A&M University, College Station, Texas, United States of America.|Department of Chemistry, Texas A&M University, College Station, Texas, United States of America.|Department of Chemistry, Texas A&M University, College Station, Texas, United States of America.', 'United States|United States|United States', 19, 'Algorithms|Cell Cycle|Cell Cycle Proteins|Cell Enlargement|Computational Biology|Computer Simulation|Microtubules|Models, Biological|Nuclear Proteins|Phosphorylation|Protein Kinases|Protein-Serine-Threonine Kinases|Protein-Tyrosine Kinases|Schizosaccharomyces|Schizosaccharomyces pombe Proteins', 'Journal Article', '10.1371/journal.pcbi.1001036', '21187911', 'How cells regulate their size from one generation to the next has remained an enigma for decades. Recently, a molecular mechanism that links cell size and cell cycle was proposed in fission yeast. This mechanism involves changes in the spatial cellular distribution of two proteins, Pom1 and Cdr2, as the cell grows. Pom1 inhibits Cdr2 while Cdr2 promotes the G2 xe2x86x92 M transition. Cdr2 is localized in the middle cell region (midcell) whereas the concentration of Pom1 is highest at the cell tips and declines towards the midcell. In short cells, Pom1 efficiently inhibits Cdr2. However, as cells grow, the Pom1 concentration at midcell decreases such that Cdr2 becomes activated at some critical size. In this study, the chemistry of Pom1 and Cdr2 was modeled using a deterministic reaction-diffusion-convection system interacting with a deterministic model describing microtubule dynamics. Simulations mimicked experimental data from wild-type (WT) fission yeast growing at normal and reduced rates, they also mimicked the behavior of a Pom1 overexpression mutant and WT yeast exposed to a microtubule depolymerizing drug. A mechanism linking cell size and cell cycle, involving the downstream action of Cdr2 on Wee1 phosphorylation, is proposed.'),
(84878, 2010, 'plos', 'Kinetics of rhodopsin deactivation and its role in regulating recovery and reproducibility of rod photoresponse', 'Caruso, Giovanni|Bisegna, Paolo|Lenoci, Leonardo|Andreucci, Daniele|Gurevich, Vsevolod V|Hamm, Heidi E|DiBenedetto, Emmanuele', 'Construction Technologies Institute, National Research Council, Rome, Italy.|Construction Technologies Institute, National Research Council, Rome, Italy.|Construction Technologies Institute, National Research Council, Rome, Italy.|Construction Technologies Institute, National Research Council, Rome, Italy.|Construction Technologies Institute, National Research Council, Rome, Italy.|Construction Technologies Institute, National Research Council, Rome, Italy.|Construction Technologies Institute, National Research Council, Rome, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy|Italy', 16, 'Animals|Arrestin|Computational Biology|G-Protein-Coupled Receptor Kinase 1|Kinetics|Markov Chains|Mice|Mice, Transgenic|Models, Neurological|Phosphorylation|Photons|Reproducibility of Results|Retinal Rod Photoreceptor Cells|Rhodopsin', 'Journal Article', '10.1371/journal.pcbi.1001031', '21200415', 'The single photon response (SPR) in vertebrate phototransduction is regulated by the dynamics of R* during its lifetime, including the random number of phosphorylations, the catalytic activity and the random sojourn time at each phosphorylation level. Because of this randomness the electrical responses are expected to be inherently variable. However the SPR is highly reproducible. The mechanisms that confer to the SPR such a low variability are not completely understood. The kinetics of rhodopsin deactivation is investigated by a Continuous Time Markov Chain (CTMC) based on the biochemistry of rhodopsin activation and deactivation, interfaced with a spatio-temporal model of phototransduction. The model parameters are extracted from the photoresponse data of both wild type and mutant mice, having variable numbers of phosphorylation sites and, with the same set of parameters, the model reproduces both WT and mutant responses. The sources of variability are dissected into its components, by asking whether a random number of turnoff steps, a random sojourn time between steps, or both, give rise to the known variability. The model shows that only the randomness of the sojourn times in each of the phosphorylated states contributes to the Coefficient of Variation (CV) of the response, whereas the randomness of the number of R* turnoff steps has a negligible effect. These results counter the view that the larger the number of decay steps of R*, the more stable the photoresponse is. Our results indicate that R* shutoff is responsible for the variability of the photoresponse, while the diffusion of the second messengers acts as a variability suppressor.'),
(84879, 2010, 'plos', 'Phase-locked signals elucidate circuit architecture of an oscillatory pathway', 'Jovic, Andreja|Howell, Bryan|Cote, Michelle|Wade, Susan M|Mehta, Khamir|Miyawaki, Atsushi|Neubig, Richard R|Linderman, Jennifer J|Takayama, Shuichi', 'Biomedical Engineering Department, University of Michigan, Ann Arbor, Michigan, United States of America.|Biomedical Engineering Department, University of Michigan, Ann Arbor, Michigan, United States of America.|Biomedical Engineering Department, University of Michigan, Ann Arbor, Michigan, United States of America.|Biomedical Engineering Department, University of Michigan, Ann Arbor, Michigan, United States of America.|Biomedical Engineering Department, University of Michigan, Ann Arbor, Michigan, United States of America.|Biomedical Engineering Department, University of Michigan, Ann Arbor, Michigan, United States of America.|Biomedical Engineering Department, University of Michigan, Ann Arbor, Michigan, United States of America.|Biomedical Engineering Department, University of Michigan, Ann Arbor, Michigan, United States of America.|Biomedical Engineering Department, University of Michigan, Ann Arbor, Michigan, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 33, 'Calcium Signaling|Carbachol|Computational Biology|HEK293 Cells|Humans|Models, Biological|Receptor, Muscarinic M3|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1001040', '21203481', 'This paper introduces the concept of phase-locking analysis of oscillatory cellular signaling systems to elucidate biochemical circuit architecture. Phase-locking is a physical phenomenon that refers to a response mode in which system output is synchronized to a periodic stimulus, in some instances, the number of responses can be fewer than the number of inputs, indicative of skipped beats. While the observation of phase-locking alone is largely independent of detailed mechanism, we find that the properties of phase-locking are useful for discriminating circuit architectures because they reflect not only the activation but also the recovery characteristics of biochemical circuits. Here, this principle is demonstrated for analysis of a G-protein coupled receptor system, the M3 muscarinic receptor-calcium signaling pathway, using microfluidic-mediated periodic chemical stimulation of the M3 receptor with carbachol and real-time imaging of resulting calcium transients. Using this approach we uncovered the potential importance of basal IP3 production, a finding that has important implications on calcium response fidelity to periodic stimulation. Based upon our analysis, we also negated the notion that the Gq-PLC interaction is switch-like, which has a strong influence upon how extracellular signals are filtered and interpreted downstream. Phase-locking analysis is a new and useful tool for model revision and mechanism elucidation, the method complements conventional genetic and chemical tools for analysis of cellular signaling circuitry and should be broadly applicable to other oscillatory pathways.'),
(84880, 2010, 'plos', 'Determinants of heterogeneity, excitation and conduction in the sinoatrial node: a model study', 'Oren, Ronit V|Clancy, Colleen E', 'Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, United States of America.|Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, United States of America.', 'United States|United States', 29, 'Animals|Cell Count|Computational Biology|Computer Simulation|Fibroblasts|Heart Atria|Models, Cardiovascular|Rabbits|Sinoatrial Node|Sodium Channels|Time Factors|Vagus Nerve Stimulation', 'Journal Article', '10.1371/journal.pcbi.1001041', '21203483', 'The sinoatrial node (SAN) is a complex structure that exhibits anatomical and functional heterogeneity which may depend on: 1) The existence of distinct cell populations, 2) electrotonic influences of the surrounding atrium, 3) the presence of a high density of fibroblasts, and 4) atrial cells intermingled within the SAN. Our goal was to utilize a computer model to predict critical determinants and modulators of excitation and conduction in the SAN. We built a theoretical non-uniform model composed of distinct central and peripheral SAN cells and a uniform model containing only central cells connected to the atrium. We tested the effects of coupling strength between SAN cells in the models, as well as the effects of fibroblasts and interspersed atrial cells. Although we could simulate single cell experimental data supporting the multiple cell type hypothesis, 2D non-uniform models did not simulate expected tissue behavior, such as central pacemaking. When we considered the atrial effects alone in a simple homogeneous uniform model, central pacemaking initiation and impulse propagation in simulations were consistent with experiments. Introduction of fibroblasts in our simulated tissue resulted in various effects depending on the density, distribution, and fibroblast-myocyte coupling strength. Incorporation of atrial cells in our simulated SAN tissue had little effect on SAN electrophysiology. Our tissue model simulations suggest atrial electrotonic effects as plausible to account for SAN heterogeneity, sequence, and rate of propagation. Fibroblasts can act as obstacles, current sinks or shunts to conduction in the SAN depending on their orientation, density, and coupling.'),
(84881, 2010, 'plos', 'Widespread compensatory evolution conserves DNA-encoded nucleosome organization in yeast', 'Kenigsberg, Ephraim|Bar, Amir|Segal, Eran|Tanay, Amos', 'Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.|Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.|Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.|Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel|Israel|Israel', 0, 'Base Composition|Computational Biology|DNA, Fungal|Evolution, Molecular|Gene Frequency|Models, Genetic|Mutation|Nucleosomes|Polymorphism, Single Nucleotide|Saccharomyces cerevisiae|Sequence Alignment|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1001039', '21203484', 'Evolution maintains organismal fitness by preserving genomic information. This is widely assumed to involve conservation of specific genomic loci among species. Many genomic encodings are now recognized to integrate small contributions from multiple genomic positions into quantitative dispersed codes, but the evolutionary dynamics of such codes are still poorly understood. Here we show that in yeast, sequences that quantitatively affect nucleosome occupancy evolve under compensatory dynamics that maintain heterogeneous levels of A+T content through spatially coupled A/T-losing and A/T-gaining substitutions. Evolutionary modeling combined with data on yeast polymorphisms supports the idea that these substitution dynamics are a consequence of weak selection. This shows that compensatory evolution, so far believed to affect specific groups of epistatically linked loci like paired RNA bases, is a widespread phenomenon in the yeast genome, affecting the majority of intergenic sequences in it. The model thus derived suggests that compensation is inevitable when evolution conserves quantitative and dispersed genomic functions.'),
(84882, 2011, 'plos', 'Benchmarking ontologies: bigger or better?', 'Yao, Lixia|Divoli, Anna|Mayzus, Ilya|Evans, James A|Rzhetsky, Andrey', 'Department of Biomedical Informatics, Columbia University, New York, New York, USA.|Department of Biomedical Informatics, Columbia University, New York, New York, USA.|Department of Biomedical Informatics, Columbia University, New York, New York, USA.|Department of Biomedical Informatics, Columbia University, New York, New York, USA.|Department of Biomedical Informatics, Columbia University, New York, New York, USA.', 'United States|United States|United States|United States|United States', 0, 'Information Storage and Retrieval', 'Journal Article', '10.1371/journal.pcbi.1001055', '21249231', 'A scientific ontology is a formal representation of knowledge within a domain, typically including central concepts, their properties, and relations. With the rise of computers and high-throughput data collection, ontologies have become essential to data mining and sharing across communities in the biomedical sciences. Powerful approaches exist for testing the internal consistency of an ontology, but not for assessing the fidelity of its domain representation. We introduce a family of metrics that describe the breadth and depth with which an ontology represents its knowledge domain. We then test these metrics using (1) four of the most common medical ontologies with respect to a corpus of medical documents and (2) seven of the most popular English thesauri with respect to three corpora that sample language from medicine, news, and novels. Here we show that our approach captures the quality of ontological representation and guides efforts to narrow the breach between ontology and collective discourse within a domain. Our results also demonstrate key features of medical ontologies, English thesauri, and discourse from different domains. Medical ontologies have a small intersection, as do English thesauri. Moreover, dialects characteristic of distinct domains vary strikingly as many of the same words are used quite differently in medicine, news, and novels. As ontologies are intended to mirror the state of knowledge, our methods to tighten the fit between ontology and domain will increase their relevance for new areas of biomedical science and improve the accuracy and power of inferences computed across them.'),
(84883, 2011, 'plos', 'Measuring the evolutionary rewiring of biological networks', 'Shou, Chong|Bhardwaj, Nitin|Lam, Hugo Y K|Yan, Koon-Kiu|Kim, Philip M|Snyder, Michael|Gerstein, Mark B', 'Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 72, 'Biological Evolution|Genomics|Proteomics', 'Journal Article', '10.1371/journal.pcbi.1001050', '21253555', 'We have accumulated a large amount of biological network data and expect even more to come. Soon, we anticipate being able to compare many different biological networks as we commonly do for molecular sequences. It has long been believed that many of these networks change, or rewire, at different rates. It is therefore important to develop a framework to quantify the differences between networks in a unified fashion. We developed such a formalism based on analogy to simple models of sequence evolution, and used it to conduct a systematic study of network rewiring on all the currently available biological networks. We found that, similar to sequences, biological networks show a decreased rate of change at large time divergences, because of saturation in potential substitutions. However, different types of biological networks consistently rewire at different rates. Using comparative genomics and proteomics data, we found a consistent ordering of the rewiring rates: transcription regulatory, phosphorylation regulatory, genetic interaction, miRNA regulatory, protein interaction, and metabolic pathway network, from fast to slow. This ordering was found in all comparisons we did of matched networks between organisms. To gain further intuition on network rewiring, we compared our observed rewirings with those obtained from simulation. We also investigated how readily our formalism could be mapped to other network contexts, in particular, we showed how it could be applied to analyze changes in a range of commonplace networks such as family trees, co-authorships and linux-kernel function dependencies.'),
(84884, 2011, 'plos', 'Relationships between gene expression and brain wiring in the adult rodent brain', 'French, Leon|Pavlidis, Paul', 'Bioinformatics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.|Bioinformatics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.', 'Canada|Canada', 82, 'Animals|Brain|Gene Expression|Mice|Rats', 'Journal Article', '10.1371/journal.pcbi.1001049', '21253556', 'We studied the global relationship between gene expression and neuroanatomical connectivity in the adult rodent brain. We utilized a large data set of the rat brain connectome from the Brain Architecture Management System (942 brain regions and over 5000 connections) and used statistical approaches to relate the data to the gene expression signatures of 17,530 genes in 142 anatomical regions from the Allen Brain Atlas. Our analysis shows that adult gene expression signatures have a statistically significant relationship to connectivity. In particular, brain regions that have similar expression profiles tend to have similar connectivity profiles, and this effect is not entirely attributable to spatial correlations. In addition, brain regions which are connected have more similar expression patterns. Using a simple optimization approach, we identified a set of genes most correlated with neuroanatomical connectivity, and find that this set is enriched for genes involved in neuronal development and axon guidance. A number of the genes have been implicated in neurodevelopmental disorders such as autistic spectrum disorder. Our results have the potential to shed light on the role of gene expression patterns in influencing neuronal activity and connectivity, with potential applications to our understanding of brain disorders. Supplementary data are available at http://www.chibi.ubc.ca/ABAMS.'),
(84885, 2011, 'plos', 'Predicting novel binding modes of agonists to xcexb2 adrenergic receptors using all-atom molecular dynamics simulations', 'Vanni, Stefano|Neri, Marilisa|Tavernelli, Ivano|Rothlisberger, Ursula', 'Laboratory of Computational Chemistry and Biochemistry, Ecole Polytechnique Fxc3xa9dxc3xa9rale de Lausanne, Lausanne, Switzerland.|Laboratory of Computational Chemistry and Biochemistry, Ecole Polytechnique Fxc3xa9dxc3xa9rale de Lausanne, Lausanne, Switzerland.|Laboratory of Computational Chemistry and Biochemistry, Ecole Polytechnique Fxc3xa9dxc3xa9rale de Lausanne, Lausanne, Switzerland.|Laboratory of Computational Chemistry and Biochemistry, Ecole Polytechnique Fxc3xa9dxc3xa9rale de Lausanne, Lausanne, Switzerland.', 'Switzerland|Switzerland|Switzerland|Switzerland', 0, 'Adrenergic beta-Agonists|Binding Sites|Models, Molecular|Molecular Dynamics Simulation', 'Journal Article', '10.1371/journal.pcbi.1001053', '21253557', 'Understanding the binding mode of agonists to adrenergic receptors is crucial to enabling improved rational design of new therapeutic agents. However, so far the high conformational flexibility of G protein-coupled receptors has been an obstacle to obtaining structural information on agonist binding at atomic resolution. In this study, we report microsecond classical molecular dynamics simulations of xcexb2(1) and xcexb2(2) adrenergic receptors bound to the full agonist isoprenaline and in their unliganded form. These simulations show a novel agonist binding mode that differs from the one found for antagonists in the crystal structures and from the docking poses reported by in silico docking studies performed on rigid receptors. Internal water molecules contribute to the stabilization of novel interactions between ligand and receptor, both at the interface of helices V and VI with the catechol group of isoprenaline as well as at the interface of helices III and VII with the ethanolamine moiety of the ligand. Despite the fact that the characteristic N-C-C-OH motif is identical in the co-crystallized ligands and in the full agonist isoprenaline, the interaction network between this group and the anchor site formed by Asp(3.32) and Asn(7.39) is substantially different between agonists and inverse agonists/antagonists due to two water molecules that enter the cavity and contribute to the stabilization of a novel network of interactions. These new binding poses, together with observed conformational changes in the extracellular loops, suggest possible determinants of receptor specificity.'),
(84886, 2011, 'plos', 'Thermodynamic stability of histone H3 is a necessary but not sufficient driving force for its evolutionary conservation', 'Ramachandran, Srinivas|Vogel, Lisa|Strahl, Brian D|Dokholyan, Nikolay V', 'Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.|Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.|Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.|Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.', 'United States|United States|United States|United States', 8, 'Biological Evolution|Histones|Models, Molecular|Protein Processing, Post-Translational|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1001042', '21253558', 'Determining the forces that conserve amino acid positions in proteins across species is a fundamental pursuit of molecular evolution. Evolutionary conservation is driven by either a proteins function or its thermodynamic stability. Highly conserved histone proteins offer a platform to evaluate these driving forces. While the conservation of histone H3 and H4 tail domains and surface residues are driven by functional importance, the driving force behind the conservation of buried histone residues has not been examined. Using a computational approach, we determined the thermodynamically preferred amino acids at each buried position in H3 and H4. In agreement with what is normally observed in proteins, we find a significant correlation between thermodynamic stability and evolutionary conservation in the buried residues in H4. In striking contrast, we find that thermodynamic stability of buried H3 residues does not correlate with evolutionary conservation. Given that these H3 residues are not post-translationally modified and only regulate H3-H3 and H3-H4 stabilizing interactions, our data imply an unknown function responsible for driving conservation of these buried H3 residues.'),
(84887, 2011, 'plos', 'A novel approach to pharmacodynamic assessment of antimicrobial agents: new insights to dosing regimen design', 'Tam, Vincent H|Nikolaou, Michael', 'Department of Clinical Sciences and Administration, College of Pharmacy, University of Houston, Houston, Texas, United States of America. vtam@uh.edu|Department of Clinical Sciences and Administration, College of Pharmacy, University of Houston, Houston, Texas, United States of America. vtam@uh.edu', 'United States|United States', 25, 'Anti-Infective Agents|Area Under Curve|Dose-Response Relationship, Drug|Drug Design|Microbial Sensitivity Tests|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1001043', '21253559', 'Pharmacodynamic modeling has been increasingly used as a decision support tool to guide dosing regimen selection, both in the drug development and clinical settings. Killing by antimicrobial agents has been traditionally classified categorically as concentration-dependent (which would favor less fractionating regimens) or time-dependent (for which more frequent dosing is preferred). While intuitive and useful to explain empiric data, a more informative approach is necessary to provide a robust assessment of pharmacodynamic profiles in situations other than the extremes of the spectrum (e.g., agents which exhibit partial concentration-dependent killing). A quantitative approach to describe the interaction of an antimicrobial agent and a pathogen is proposed to fill this unmet need. A hypothetic antimicrobial agent with linear pharmacokinetics is used for illustrative purposes. A non-linear functional form (sigmoid Emax) of killing consisted of 3 parameters is used. Using different parameter values in conjunction with the relative growth rate of the pathogen and antimicrobial agent concentration ranges, various conventional pharmacodynamic surrogate indices (e.g., AUC/MIC, Cmax/MIC, %T>MIC) could be satisfactorily linked to outcomes. In addition, the dosing intensity represented by the average kill rate of a dosing regimen can be derived, which could be used for quantitative comparison. The relevance of our approach is further supported by experimental data from our previous investigations using a variety of gram-negative bacteria and antimicrobial agents (moxifloxacin, levofloxacin, gentamicin, amikacin and meropenem). The pharmacodynamic profiles of a wide range of antimicrobial agents can be assessed by a more flexible computational tool to support dosing selection.'),
(84888, 2011, 'plos', 'Ten simple rules for getting ahead as a computational biologist in Academia', 'Bourne, Philip E', 'Department of Clinical Sciences and Administration, College of Pharmacy, University of Houston, Houston, Texas, United States of America. vtam@uh.edu', 'United States', 0, 'Computational Biology|Education|Internet|Software', 'Editorial', '10.1371/journal.pcbi.1002001', '21253560', '-'),
(84889, 2011, 'plos', 'Neural development features: spatio-temporal development of the Caenorhabditis elegans neuronal network', 'Varier, Sreedevi|Kaiser, Marcus', 'School of Computing Science, Newcastle University, Newcastle upon Tyne, United Kingdom.|School of Computing Science, Newcastle University, Newcastle upon Tyne, United Kingdom.', 'United Kingdom|United Kingdom', 0, 'Animals|Caenorhabditis elegans|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.1001044', '21253561', 'The nematode Caenorhabditis elegans, with information on neural connectivity, three-dimensional position and cell linage, provides a unique system for understanding the development of neural networks. Although C. elegans has been widely studied in the past, we present the first statistical study from a developmental perspective, with findings that raise interesting suggestions on the establishment of long-distance connections and network hubs. Here, we analyze the neuro-development for temporal and spatial features, using birth times of neurons and their three-dimensional positions. Comparisons of growth in C. elegans with random spatial network growth highlight two findings relevant to neural network development. First, most neurons which are linked by long-distance connections are born around the same time and early on, suggesting the possibility of early contact or interaction between connected neurons during development. Second, early-born neurons are more highly connected (tendency to form hubs) than later-born neurons. This indicates that the longer time frame available to them might underlie high connectivity. Both outcomes are not observed for random connection formation. The study finds that around one-third of electrically coupled long-range connections are late forming, raising the question of what mechanisms are involved in ensuring their accuracy, particularly in light of the extremely invariant connectivity observed in C. elegans. In conclusion, the sequence of neural network development highlights the possibility of early contact or interaction in securing long-distance and high-degree connectivity.'),
(84890, 2011, 'plos', 'A comprehensive model of the spatio-temporal stem cell and tissue organisation in the intestinal crypt', 'Buske, Peter|Galle, Jörg|Barker, Nick|Aust, Gabriela|Clevers, Hans|Loeffler, Markus', 'Interdisciplinary Centre for Bioinformatics, University Leipzig, Leipzig, Germany. buske@izbi.uni-leipzig.de|Interdisciplinary Centre for Bioinformatics, University Leipzig, Leipzig, Germany. buske@izbi.uni-leipzig.de|Interdisciplinary Centre for Bioinformatics, University Leipzig, Leipzig, Germany. buske@izbi.uni-leipzig.de|Interdisciplinary Centre for Bioinformatics, University Leipzig, Leipzig, Germany. buske@izbi.uni-leipzig.de|Interdisciplinary Centre for Bioinformatics, University Leipzig, Leipzig, Germany. buske@izbi.uni-leipzig.de|Interdisciplinary Centre for Bioinformatics, University Leipzig, Leipzig, Germany. buske@izbi.uni-leipzig.de', 'Germany|Germany|Germany|Germany|Germany|Germany', 0, 'Apoptosis|Cell Proliferation|Intestinal Mucosa|Intestines|Models, Biological|Receptors, Notch|Signal Transduction|Stem Cells|Wnt Proteins', 'Journal Article', '10.1371/journal.pcbi.1001045', '21253562', 'We introduce a novel dynamic model of stem cell and tissue organisation in murine intestinal crypts. Integrating the molecular, cellular and tissue level of description, this model links a broad spectrum of experimental observations encompassing spatially confined cell proliferation, directed cell migration, multiple cell lineage decisions and clonal competition.Using computational simulations we demonstrate that the model is capable of quantitatively describing and predicting the dynamic behaviour of the intestinal tissue during steady state as well as after cell damage and following selective gain or loss of gene function manipulations affecting Wnt- and Notch-signalling. Our simulation results suggest that reversibility and flexibility of cellular decisions are key elements of robust tissue organisation of the intestine. We predict that the tissue should be able to fully recover after complete elimination of cellular subpopulations including subpopulations deemed to be functional stem cells. This challenges current views of tissue stem cell organisation.'),
(84891, 2011, 'plos', 'Decrypting the sequence of structural events during the gating transition of pentameric ligand-gated ion channels based on an interpolated elastic network model', 'Zheng, Wenjun|Auerbach, Anthony', 'Department of Physics, University at Buffalo, Buffalo, New York, United States of America.|Department of Physics, University at Buffalo, Buffalo, New York, United States of America.', 'United States|United States', 0, 'Ion Channel Gating|Ion Channels|Ligands|Models, Molecular', 'Journal Article', '10.1371/journal.pcbi.1001046', '21253563', 'Despite many experimental and computational studies of the gating transition of pentameric ligand-gated ion channels (pLGICs), the structural basis of how ligand binding couples to channel gating remains unknown. By using a newly developed interpolated elastic network model (iENM), we have attempted to compute a likely transition pathway from the closed- to the open-channel conformation of pLGICs as captured by the crystal structures of two prokaryotic pLGICs. The iENM pathway predicts a sequence of structural events that begins at the ligand-binding loops and is followed by the displacements of two key loops (loop 2 and loop 7) at the interface between the extracellular and transmembrane domain, the tilting/bending of the pore-lining M2 helix, and subsequent movements of M4, M3 and M1 helices in the transmembrane domain. The predicted order of structural events is in broad agreement with the xcexa6-value analysis of xcexb1 subunit of nicotinic acetylcholine receptor mutants, which supports a conserved core mechanism for ligand-gated channel opening in pLGICs. Further perturbation analysis has supported the critical role of certain intra-subunit and inter-subunit interactions in dictating the above sequence of events.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84892, 2011, 'plos', 'Risk, unexpected uncertainty, and estimation uncertainty: Bayesian learning in unstable settings', 'Payzan-LeNestour, Elise|Bossaerts, Peter', 'University of New South Wales, Sydney, Australia. elise@unsw.edu.au|University of New South Wales, Sydney, Australia. elise@unsw.edu.au', 'Australia|Australia', 109, 'Bayes Theorem|Probability|Risk|Uncertainty', 'Journal Article', '10.1371/journal.pcbi.1001048', '21283774', 'Recently, evidence has emerged that humans approach learning using Bayesian updating rather than (model-free) reinforcement algorithms in a six-arm restless bandit problem. Here, we investigate what this implies for human appreciation of uncertainty. In our task, a Bayesian learner distinguishes three equally salient levels of uncertainty. First, the Bayesian perceives irreducible uncertainty or risk: even knowing the payoff probabilities of a given arm, the outcome remains uncertain. Second, there is (parameter) estimation uncertainty or ambiguity: payoff probabilities are unknown and need to be estimated. Third, the outcome probabilities of the arms change: the sudden jumps are referred to as unexpected uncertainty. We document how the three levels of uncertainty evolved during the course of our experiment and how it affected the learning rate. We then zoom in on estimation uncertainty, which has been suggested to be a driving force in exploration, in spite of evidence of widespread aversion to ambiguity. Our data corroborate the latter. We discuss neural evidence that foreshadowed the ability of humans to distinguish between the three levels of uncertainty. Finally, we investigate the boundaries of human capacity to implement Bayesian learning. We repeat the experiment with different instructions, reflecting varying levels of structural uncertainty. Under this fourth notion of uncertainty, choices were no better explained by Bayesian updating than by (model-free) reinforcement learning. Exit questionnaires revealed that participants remained unaware of the presence of unexpected uncertainty and failed to acquire the right model with which to implement Bayesian updating.'),
(84893, 2011, 'plos', 'PhylOTU: a high-throughput procedure quantifies microbial community diversity and resolves novel taxa from metagenomic data', 'Sharpton, Thomas J|Riesenfeld, Samantha J|Kembel, Steven W|Ladau, Joshua|ODwyer, James P|Green, Jessica L|Eisen, Jonathan A|Pollard, Katherine S', 'The J. David Gladstone Institutes, University of California San Francisco, San Francisco, California, United States of America. thomas.sharpton@gladstone.ucsf.edu|The J. David Gladstone Institutes, University of California San Francisco, San Francisco, California, United States of America. thomas.sharpton@gladstone.ucsf.edu|The J. David Gladstone Institutes, University of California San Francisco, San Francisco, California, United States of America. thomas.sharpton@gladstone.ucsf.edu|The J. David Gladstone Institutes, University of California San Francisco, San Francisco, California, United States of America. thomas.sharpton@gladstone.ucsf.edu|The J. David Gladstone Institutes, University of California San Francisco, San Francisco, California, United States of America. thomas.sharpton@gladstone.ucsf.edu|The J. David Gladstone Institutes, University of California San Francisco, San Francisco, California, United States of America. thomas.sharpton@gladstone.ucsf.edu|The J. David Gladstone Institutes, University of California San Francisco, San Francisco, California, United States of America. thomas.sharpton@gladstone.ucsf.edu|The J. David Gladstone Institutes, University of California San Francisco, San Francisco, California, United States of America. thomas.sharpton@gladstone.ucsf.edu', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Cluster Analysis|Genomics|Phylogeny|Polymerase Chain Reaction|RNA, Ribosomal', 'Journal Article', '10.1371/journal.pcbi.1001061', '21283775', 'Microbial diversity is typically characterized by clustering ribosomal RNA (SSU-rRNA) sequences into operational taxonomic units (OTUs). Targeted sequencing of environmental SSU-rRNA markers via PCR may fail to detect OTUs due to biases in priming and amplification. Analysis of shotgun sequenced environmental DNA, known as metagenomics, avoids amplification bias but generates fragmentary, non-overlapping sequence reads that cannot be clustered by existing OTU-finding methods. To circumvent these limitations, we developed PhylOTU, a computational workflow that identifies OTUs from metagenomic SSU-rRNA sequence data through the use of phylogenetic principles and probabilistic sequence profiles. Using simulated metagenomic data, we quantified the accuracy with which PhylOTU clusters reads into OTUs. Comparisons of PCR and shotgun sequenced SSU-rRNA markers derived from the global open ocean revealed that while PCR libraries identify more OTUs per sequenced residue, metagenomic libraries recover a greater taxonomic diversity of OTUs. In addition, we discover novel species, genera and families in the metagenomic libraries, including OTUs from phyla missed by analysis of PCR sequences. Taken together, these results suggest that PhylOTU enables characterization of part of the biosphere currently hidden from PCR-based surveys of diversity?'),
(84894, 2011, 'plos', 'Is my network module preserved and reproducible?', 'Langfelder, Peter|Luo, Rui|Oldham, Michael C|Horvath, Steve', 'Department of Human Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.|Department of Human Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.|Department of Human Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.|Department of Human Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.', 'United States|United States|United States|United States', 0, 'Animals|Brain|Female|Gene Expression|Humans|Male|Mice|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1001057', '21283776', 'In many applications, one is interested in determining which of the properties of a network module change across conditions. For example, to validate the existence of a module, it is desirable to show that it is reproducible (or preserved) in an independent test network. Here we study several types of network preservation statistics that do not require a module assignment in the test network. We distinguish network preservation statistics by the type of the underlying network. Some preservation statistics are defined for a general network (defined by an adjacency matrix) while others are only defined for a correlation network (constructed on the basis of pairwise correlations between numeric variables). Our applications show that the correlation structure facilitates the definition of particularly powerful module preservation statistics. We illustrate that evaluating module preservation is in general different from evaluating cluster preservation. We find that it is advantageous to aggregate multiple preservation statistics into summary preservation statistics. We illustrate the use of these methods in six gene co-expression network applications including 1) preservation of cholesterol biosynthesis pathway in mouse tissues, 2) comparison of human and chimpanzee brain networks, 3) preservation of selected KEGG pathways between human and chimpanzee brain networks, 4) sex differences in human cortical networks, 5) sex differences in mouse liver networks. While we find no evidence for sex specific modules in human cortical networks, we find that several human cortical modules are less preserved in chimpanzees. In particular, apoptosis genes are differentially co-expressed between humans and chimpanzees. Our simulation studies and applications show that module preservation statistics are useful for studying differences between the modular structure of networks. Data, R software and accompanying tutorials can be downloaded from the following webpage: http://www.genetics.ucla.edu/labs/horvath/CoexpressionNetwork/ModulePreservation.'),
(84895, 2011, 'plos', 'From spiking neuron models to linear-nonlinear models', 'Ostojic, Srdjan|Brunel, Nicolas', 'Center for Theoretical Neuroscience, Columbia University, New York, New York, United States of America. so2310@columbia.edu|Center for Theoretical Neuroscience, Columbia University, New York, New York, United States of America. so2310@columbia.edu', 'United States|United States', 107, 'Action Potentials|Humans|Linear Models|Neurons|Nonlinear Dynamics', 'Journal Article', '10.1371/journal.pcbi.1001056', '21283777', 'Neurons transform time-varying inputs into action potentials emitted stochastically at a time dependent rate. The mapping from current input to output firing rate is often represented with the help of phenomenological models such as the linear-nonlinear (LN) cascade, in which the output firing rate is estimated by applying to the input successively a linear temporal filter and a static non-linear transformation. These simplified models leave out the biophysical details of action potential generation. It is not a priori clear to which extent the input-output mapping of biophysically more realistic, spiking neuron models can be reduced to a simple linear-nonlinear cascade. Here we investigate this question for the leaky integrate-and-fire (LIF), exponential integrate-and-fire (EIF) and conductance-based Wang-Buzsáki models in presence of background synaptic activity. We exploit available analytic results for these models to determine the corresponding linear filter and static non-linearity in a parameter-free form. We show that the obtained functions are identical to the linear filter and static non-linearity determined using standard reverse correlation analysis. We then quantitatively compare the output of the corresponding linear-nonlinear cascade with numerical simulations of spiking neurons, systematically varying the parameters of input signal and background noise. We find that the LN cascade provides accurate estimates of the firing rates of spiking neurons in most of parameter space. For the EIF and Wang-Buzsáki models, we show that the LN cascade can be reduced to a firing rate model, the timescale of which we determine analytically. Finally we introduce an adaptive timescale rate model in which the timescale of the linear filter depends on the instantaneous firing rate. This model leads to highly accurate estimates of instantaneous firing rates.'),
(84896, 2011, 'plos', 'Theoretical analysis of the stress induced B-Z transition in superhelical DNA', 'Zhabinskaya, Dina|Benham, Craig J', 'UC Davis Genome Center, University of California, Davis, Davis California, United States of America. dzhabinskaya@ucdavis.edu|UC Davis Genome Center, University of California, Davis, Davis California, United States of America. dzhabinskaya@ucdavis.edu', 'United States|United States', 20, 'Algorithms|Animals|DNA, Superhelical|Mice|Models, Theoretical|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1001051', '21283778', 'We present a method to calculate the propensities of regions within a DNA molecule to transition from B-form to Z-form under negative superhelical stresses. We use statistical mechanics to analyze the competition that occurs among all susceptible Z-forming regions at thermodynamic equilibrium in a superhelically stressed DNA of specified sequence. This method, which we call SIBZ, is similar to the SIDD algorithm that was previously developed to analyze superhelical duplex destabilization. A state of the system is determined by assigning to each base pair either the B- or the Z-conformation, accounting for the dinucleotide repeat unit of Z-DNA. The free energy of a state is comprised of the nucleation energy, the sequence-dependent B-Z transition energy, and the energy associated with the residual superhelicity remaining after the change of twist due to transition. Using this information, SIBZ calculates the equilibrium B-Z transition probability of each base pair in the sequence. This can be done at any physiologically reasonable level of negative superhelicity. We use SIBZ to analyze a variety of representative genomic DNA sequences. We show that the dominant Z-DNA forming regions in a sequence can compete in highly complex ways as the superhelicity level changes. Despite having no tunable parameters, the predictions of SIBZ agree precisely with experimental results, both for the onset of transition in plasmids containing introduced Z-forming sequences and for the locations of Z-forming regions in genomic sequences. We calculate the transition profiles of 5 kb regions taken from each of 12,841 mouse genes and centered on the transcription start site (TSS). We find a substantial increase in the frequency of Z-forming regions immediately upstream from the TSS. The approach developed here has the potential to illuminate the occurrence of Z-form regions in vivo, and the possible roles this transition may play in biological processes.'),
(84897, 2011, 'plos', 'Practical measures of integrated information for time-series data', 'Barrett, Adam B|Seth, Anil K', 'Sackler Centre for Consciousness Science and School of Informatics, University of Sussex, Brighton, United Kingdom. adam.barrett@sussex.ac.uk|Sackler Centre for Consciousness Science and School of Informatics, University of Sussex, Brighton, United Kingdom. adam.barrett@sussex.ac.uk', 'United Kingdom|United Kingdom', 0, 'Information Services|Markov Chains|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1001052', '21283779', 'A recent measure of integrated information, xcexa6(DM), quantifies the extent to which a system generates more information than the sum of its parts as it transitions between states, possibly reflecting levels of consciousness generated by neural systems. However, xcexa6(DM) is defined only for discrete Markov systems, which are unusual in biology, as a result, xcexa6(DM) can rarely be measured in practice. Here, we describe two new measures, xcexa6(E) and xcexa6(AR), that overcome these limitations and are easy to apply to time-series data. We use simulations to demonstrate the in-practice applicability of our measures, and to explore their properties. Our results provide new opportunities for examining information integration in real and model systems and carry implications for relations between integrated information, consciousness, and other neurocognitive processes. However, our findings pose challenges for theories that ascribe physical meaning to the measured quantities.'),
(84898, 2011, 'plos', 'A computational and experimental study of the regulatory mechanisms of the complement system', 'Liu, Bing|Zhang, Jing|Tan, Pei Yi|Hsu, David|Blom, Anna M|Leong, Benjamin|Sethi, Sunil|Ho, Bow|Ding, Jeak Ling|Thiagarajan, P S', 'School of Computing, National University of Singapore, Singapore.|School of Computing, National University of Singapore, Singapore.|School of Computing, National University of Singapore, Singapore.|School of Computing, National University of Singapore, Singapore.|School of Computing, National University of Singapore, Singapore.|School of Computing, National University of Singapore, Singapore.|School of Computing, National University of Singapore, Singapore.|School of Computing, National University of Singapore, Singapore.|School of Computing, National University of Singapore, Singapore.|School of Computing, National University of Singapore, Singapore.', 'Singapore|Singapore|Singapore|Singapore|Singapore|Singapore|Singapore|Singapore|Singapore|Singapore', 0, 'Bayes Theorem|Complement System Proteins|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1001059', '21283780', 'The complement system is key to innate immunity and its activation is necessary for the clearance of bacteria and apoptotic cells. However, insufficient or excessive complement activation will lead to immune-related diseases. It is so far unknown how the complement activity is up- or down- regulated and what the associated pathophysiological mechanisms are. To quantitatively understand the modulatory mechanisms of the complement system, we built a computational model involving the enhancement and suppression mechanisms that regulate complement activity. Our model consists of a large system of Ordinary Differential Equations (ODEs) accompanied by a dynamic Bayesian network as a probabilistic approximation of the ODE dynamics. Applying Bayesian inference techniques, this approximation was used to perform parameter estimation and sensitivity analysis. Our combined computational and experimental study showed that the antimicrobial response is sensitive to changes in pH and calcium levels, which determines the strength of the crosstalk between CRP and L-ficolin. Our study also revealed differential regulatory effects of C4BP. While C4BP delays but does not decrease the classical complement activation, it attenuates but does not significantly delay the lectin pathway activation. We also found that the major inhibitory role of C4BP is to facilitate the decay of C3 convertase. In summary, the present work elucidates the regulatory mechanisms of the complement system and demonstrates how the bio-pathway machinery maintains the balance between activation and inhibition. The insights we have gained could contribute to the development of therapies targeting the complement system.'),
(84899, 2011, 'plos', 'Impact of sarcoplasmic reticulum calcium release on calcium dynamics and action potential morphology in human atrial myocytes: a computational study', 'Koivumäki, Jussi T|Korhonen, Topi|Tavi, Pasi', 'Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.|Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.|Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.', 'Finland|Finland|Finland', 75, 'Action Potentials|Calcium|Diffusion|Heart Atria|Humans|Sarcoplasmic Reticulum', 'Journal Article', '10.1371/journal.pcbi.1001067', '21298076', 'Electrophysiological studies of the human heart face the fundamental challenge that experimental data can be acquired only from patients with underlying heart disease. Regarding human atria, there exist sizable gaps in the understanding of the functional role of cellular Ca²+ dynamics, which differ crucially from that of ventricular cells, in the modulation of excitation-contraction coupling. Accordingly, the objective of this study was to develop a mathematical model of the human atrial myocyte that, in addition to the sarcolemmal (SL) ion currents, accounts for the heterogeneity of intracellular Ca²+ dynamics emerging from a structurally detailed sarcoplasmic reticulum (SR). Based on the simulation results, our model convincingly reproduces the principal characteristics of Ca²+ dynamics: 1) the biphasic increment during the upstroke of the Ca²+ transient resulting from the delay between the peripheral and central SR Ca²+ release, and 2) the relative contribution of SL Ca²+ current and SR Ca²+ release to the Ca²+ transient. In line with experimental findings, the model also replicates the strong impact of intracellular Ca²+ dynamics on the shape of the action potential. The simulation results suggest that the peripheral SR Ca²+ release sites define the interface between Ca²+ and AP, whereas the central release sites are important for the fire-diffuse-fire propagation of Ca²+ diffusion. Furthermore, our analysis predicts that the modulation of the action potential duration due to increasing heart rate is largely mediated by changes in the intracellular Na+ concentration. Finally, the results indicate that the SR Ca²+ release is a strong modulator of AP duration and, consequently, myocyte refractoriness/excitability. We conclude that the developed model is robust and reproduces many fundamental aspects of the tight coupling between SL ion currents and intracellular Ca²+ signaling. Thus, the model provides a useful framework for future studies of excitation-contraction coupling in human atrial myocytes.'),
(84900, 2011, 'plos', 'A Review of 2010 for PLoS Computational Biology', 'Dickin, Rosemary|Marden, Cecy|Collings, Andrew M|Nussinov, Ruth|Bourne, Philip E', 'Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.|Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.|Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.|Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.|Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.', 'Finland|Finland|Finland|Finland|Finland', 0, 'Computational Biology|Publishing', 'Editorial', '10.1371/journal.pcbi.1002003', '21298077', '-'),
(84901, 2011, 'plos', 'Estimation of parent specific DNA copy number in tumors using high-density genotyping arrays', 'Chen, Hao|Xing, Haipeng|Zhang, Nancy R', 'Department of Statistics, Stanford University, Stanford, California, United States of America.|Department of Statistics, Stanford University, Stanford, California, United States of America.|Department of Statistics, Stanford University, Stanford, California, United States of America.', 'United States|United States|United States', 0, 'Alleles|DNA, Neoplasm|Gene Dosage|Genotype|Humans|Markov Chains|Parents|Polymorphism, Single Nucleotide', 'Journal Article', '10.1371/journal.pcbi.1001060', '21298078', 'Chromosomal gains and losses comprise an important type of genetic change in tumors, and can now be assayed using microarray hybridization-based experiments. Most current statistical models for DNA copy number estimate total copy number, which do not distinguish between the underlying quantities of the two inherited chromosomes. This latter information, sometimes called parent specific copy number, is important for identifying allele-specific amplifications and deletions, for quantifying normal cell contamination, and for giving a more complete molecular portrait of the tumor. We propose a stochastic segmentation model for parent-specific DNA copy number in tumor samples, and give an estimation procedure that is computationally efficient and can be applied to data from the current high density genotyping platforms. The proposed method does not require matched normal samples, and can estimate the unknown genotypes simultaneously with the parent specific copy number. The new method is used to analyze 223 glioblastoma samples from the Cancer Genome Atlas (TCGA) project, giving a more comprehensive summary of the copy number events in these samples. Detailed case studies on these samples reveal the additional insights that can be gained from an allele-specific copy number analysis, such as the quantification of fractional gains and losses, the identification of copy neutral loss of heterozygosity, and the characterization of regions of simultaneous changes of both inherited chromosomes.'),
(84902, 2011, 'plos', 'Protrusive push versus enveloping embrace: computational model of phagocytosis predicts key regulatory role of cytoskeletal membrane anchors', 'Herant, Marc|Lee, Cheng-Yuk|Dembo, Micah|Heinrich, Volkmar', 'Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America.|Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America.|Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America.|Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America.', 'United States|United States|United States|United States', 26, 'Computer Simulation|Cytoskeleton|Intracellular Membranes|Phagocytosis', 'Journal Article', '10.1371/journal.pcbi.1001068', '21298079', 'Encounters between human neutrophils and zymosan elicit an initially protrusive cell response that is distinct from the thin lamella embracing antibody-coated targets. Recent experiments have led us to hypothesize that this behavior has its mechanistic roots in the modulation of interactions between membrane and cytoskeleton. To test and refine this hypothesis, we confront our experimental results with predictions of a computer model of leukocyte mechanical behavior, and establish the minimum set of mechanistic variations of this computational framework that reproduces the differences between zymosan and antibody phagocytosis. We confirm that the structural linkages between the cytoskeleton and the membrane patch adherent to a target form the switchboard that controls the target specificity of a neutrophils mechanical response. These linkages are presumably actin-binding protein complexes associating with the cytoplasmic domains of cell-surface receptors that are engaged in adhesion to zymosan and Fc-domains.'),
(84903, 2011, 'plos', 'The role of additive neurogenesis and synaptic plasticity in a hippocampal memory model with grid-cell like input', 'Appleby, Peter A|Kempermann, Gerd|Wiskott, Laurenz', 'School of Computing, University of Leeds, Leeds, United Kingdom. p.a.appleby@leeds.ac.uk|School of Computing, University of Leeds, Leeds, United Kingdom. p.a.appleby@leeds.ac.uk|School of Computing, University of Leeds, Leeds, United Kingdom. p.a.appleby@leeds.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Animals|Hippocampus|Memory|Neurogenesis|Neuronal Plasticity|Rats', 'Journal Article', '10.1371/journal.pcbi.1001063', '21298080', 'Recently, we presented a study of adult neurogenesis in a simplified hippocampal memory model. The network was required to encode and decode memory patterns despite changing input statistics. We showed that additive neurogenesis was a more effective adaptation strategy compared to neuronal turnover and conventional synaptic plasticity as it allowed the network to respond to changes in the input statistics while preserving representations of earlier environments. Here we extend our model to include realistic, spatially driven input firing patterns in the form of grid cells in the entorhinal cortex. We compare network performance across a sequence of spatial environments using three distinct adaptation strategies: conventional synaptic plasticity, where the network is of fixed size but the connectivity is plastic, neuronal turnover, where the network is of fixed size but units in the network may die and be replaced, and additive neurogenesis, where the network starts out with fewer initial units but grows over time. We confirm that additive neurogenesis is a superior adaptation strategy when using realistic, spatially structured input patterns. We then show that a more biologically plausible neurogenesis rule that incorporates cell death and enhanced plasticity of new granule cells has an overall performance significantly better than any one of the three individual strategies operating alone. This adaptation rule can be tailored to maximise performance of the network when operating as either a short- or long-term memory store. We also examine the time course of adult neurogenesis over the lifetime of an animal raised under different hypothetical rearing conditions. These growth profiles have several distinct features that form a theoretical prediction that could be tested experimentally. Finally, we show that place cells can emerge and refine in a realistic manner in our model as a direct result of the sparsification performed by the dentate gyrus layer.'),
(84904, 2011, 'plos', 'Integrative features of the yeast phosphoproteome and protein-protein interaction map', 'Yachie, Nozomu|Saito, Rintaro|Sugiyama, Naoyuki|Tomita, Masaru|Ishihama, Yasushi', 'Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan.|Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan.|Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan.|Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan.|Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan.', 'Japan|Japan|Japan|Japan|Japan', 0, 'Fungal Proteins|Phosphoproteins|Phosphorylation|Protein Binding|Proteome', 'Journal Article', '10.1371/journal.pcbi.1001064', '21298081', 'Following recent advances in high-throughput mass spectrometry (MS)-based proteomics, the numbers of identified phosphoproteins and their phosphosites have greatly increased in a wide variety of organisms. Although a critical role of phosphorylation is control of protein signaling, our understanding of the phosphoproteome remains limited. Here, we report unexpected, large-scale connections revealed between the phosphoproteome and protein interactome by integrative data-mining of yeast multi-omics data. First, new phosphoproteome data on yeast cells were obtained by MS-based proteomics and unified with publicly available yeast phosphoproteome data. This revealed that nearly 60% of xe2x88xbc6,000 yeast genes encode phosphoproteins. We mapped these unified phosphoproteome data on a yeast protein-protein interaction (PPI) network with other yeast multi-omics datasets containing information about proteome abundance, proteome disorders, literature-derived signaling reactomes, and in vitro substratomes of kinases. In the phospho-PPI, phosphoproteins had more interacting partners than nonphosphoproteins, implying that a large fraction of intracellular protein interaction patterns (including those of protein complex formation) is affected by reversible and alternative phosphorylation reactions. Although highly abundant or unstructured proteins have a high chance of both interacting with other proteins and being phosphorylated within cells, the difference between the number counts of interacting partners of phosphoproteins and nonphosphoproteins was significant independently of protein abundance and disorder level. Moreover, analysis of the phospho-PPI and yeast signaling reactome data suggested that co-phosphorylation of interacting proteins by single kinases is common within cells. These multi-omics analyses illuminate how wide-ranging intracellular phosphorylation events and the diversity of physical protein interactions are largely affected by each other.'),
(84905, 2011, 'plos', 'Detecting remote evolutionary relationships among proteins by large-scale semantic embedding', 'Melvin, Iain|Weston, Jason|Noble, William Stafford|Leslie, Christina', 'NEC Laboratories America, Princeton, New Jersey, United States of America.|NEC Laboratories America, Princeton, New Jersey, United States of America.|NEC Laboratories America, Princeton, New Jersey, United States of America.|NEC Laboratories America, Princeton, New Jersey, United States of America.', 'Jersey|Jersey|Jersey|Jersey', 17, 'Algorithms|Biological Evolution|Proteins|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1001047', '21298082', 'Virtually every molecular biologist has searched a protein or DNA sequence database to find sequences that are evolutionarily related to a given query. Pairwise sequence comparison methods--i.e., measures of similarity between query and target sequences--provide the engine for sequence database search and have been the subject of 30 years of computational research. For the difficult problem of detecting remote evolutionary relationships between protein sequences, the most successful pairwise comparison methods involve building local models (e.g., profile hidden Markov models) of protein sequences. However, recent work in massive data domains like web search and natural language processing demonstrate the advantage of exploiting the global structure of the data space. Motivated by this work, we present a large-scale algorithm called ProtEmbed, which learns an embedding of protein sequences into a low-dimensional semantic space. Evolutionarily related proteins are embedded in close proximity, and additional pieces of evidence, such as 3D structural similarity or class labels, can be incorporated into the learning process. We find that ProtEmbed achieves superior accuracy to widely used pairwise sequence methods like PSI-BLAST and HHSearch for remote homology detection, it also outperforms our previous RankProp algorithm, which incorporates global structure in the form of a protein similarity network. Finally, the ProtEmbed embedding space can be visualized, both at the global level and local to a given query, yielding intuition about the structure of protein sequence space.'),
(84906, 2011, 'plos', 'Erratic flu vaccination emerges from short-sighted behavior in contact networks', 'Cornforth, Daniel M|Reluga, Timothy C|Shim, Eunha|Bauch, Chris T|Galvani, Alison P|Meyers, Lauren Ancel', 'Section of Integrative Biology, The University of Texas at Austin, Austin, Texas, United States of America.|Section of Integrative Biology, The University of Texas at Austin, Austin, Texas, United States of America.|Section of Integrative Biology, The University of Texas at Austin, Austin, Texas, United States of America.|Section of Integrative Biology, The University of Texas at Austin, Austin, Texas, United States of America.|Section of Integrative Biology, The University of Texas at Austin, Austin, Texas, United States of America.|Section of Integrative Biology, The University of Texas at Austin, Austin, Texas, United States of America.', 'United States|United States|United States|United States|United States|United States', 0, 'Game Theory|Humans|Influenza Vaccines|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1001062', '21298083', 'The effectiveness of seasonal influenza vaccination programs depends on individual-level compliance. Perceptions about risks associated with infection and vaccination can strongly influence vaccination decisions and thus the ultimate course of an epidemic. Here we investigate the interplay between contact patterns, influenza-related behavior, and disease dynamics by incorporating game theory into network models. When individuals make decisions based on past epidemics, we find that individuals with many contacts vaccinate, whereas individuals with few contacts do not. However, the threshold number of contacts above which to vaccinate is highly dependent on the overall network structure of the population and has the potential to oscillate more wildly than has been observed empirically. When we increase the number of prior seasons that individuals recall when making vaccination decisions, behavior and thus disease dynamics become less variable. For some networks, we also find that higher flu transmission rates may, counterintuitively, lead to lower (vaccine-mediated) disease prevalence. Our work demonstrates that rich and complex dynamics can result from the interaction between infectious diseases, human contact patterns, and behavior.'),
(84907, 2011, 'plos', 'Using transcription modules to identify expression clusters perturbed in Williams-Beuren syndrome', 'Henrichsen, Charlotte N|Csárdi, Gábor|Zabot, Marie-Thérèse|Fusco, Carmela|Bergmann, Sven|Merla, Giuseppe|Reymond, Alexandre', 'The Center for Integrative Genomics, Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.|The Center for Integrative Genomics, Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.|The Center for Integrative Genomics, Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.|The Center for Integrative Genomics, Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.|The Center for Integrative Genomics, Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.|The Center for Integrative Genomics, Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.|The Center for Integrative Genomics, Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 18, 'Case-Control Studies|Cell Line|Gene Expression Profiling|Humans|Multigene Family|Transcription, Genetic|Williams Syndrome', 'Journal Article', '10.1371/journal.pcbi.1001054', '21304579', 'The genetic dissection of the phenotypes associated with Williams-Beuren Syndrome (WBS) is advancing thanks to the study of individuals carrying typical or atypical structural rearrangements, as well as in vitro and animal studies. However, little is known about the global dysregulations caused by the WBS deletion. We profiled the transcriptomes of skin fibroblasts from WBS patients and compared them to matched controls. We identified 868 differentially expressed genes that were significantly enriched in extracellular matrix genes, major histocompatibility complex (MHC) genes, as well as genes in which the products localize to the postsynaptic membrane. We then used public expression datasets from human fibroblasts to establish transcription modules, sets of genes coexpressed in this cell type. We identified those sets in which the average gene expression was altered in WBS samples. Dysregulated modules are often interconnected and share multiple common genes, suggesting that intricate regulatory networks connected by a few central genes are disturbed in WBS. This modular approach increases the power to identify pathways dysregulated in WBS patients, thus providing a testable set of additional candidates for genes and their interactions that modulate the WBS phenotypes.'),
(84908, 2011, 'plos', 'A mathematical framework for protein structure comparison', 'Liu, Wei|Srivastava, Anuj|Zhang, Jinfeng', 'Department of Statistics, Florida State University, Tallahassee, Florida, United States of America.|Department of Statistics, Florida State University, Tallahassee, Florida, United States of America.|Department of Statistics, Florida State University, Tallahassee, Florida, United States of America.', 'United States|United States|United States', 0, 'Computational Biology|Computer Simulation|Elasticity|Evolution, Molecular|Mathematical Concepts|Models, Molecular|Protein Conformation|Proteins|Structural Homology, Protein', 'Comparative Study', '10.1371/journal.pcbi.1001075', '21304929', 'Comparison of protein structures is important for revealing the evolutionary relationship among proteins, predicting protein functions and predicting protein structures. Many methods have been developed in the past to align two or multiple protein structures. Despite the importance of this problem, rigorous mathematical or statistical frameworks have seldom been pursued for general protein structure comparison. One notable issue in this field is that with many different distances used to measure the similarity between protein structures, none of them are proper distances when protein structures of different sequences are compared. Statistical approaches based on those non-proper distances or similarity scores as random variables are thus not mathematically rigorous. In this work, we develop a mathematical framework for protein structure comparison by treating protein structures as three-dimensional curves. Using an elastic Riemannian metric on spaces of curves, geodesic distance, a proper distance on spaces of curves, can be computed for any two protein structures. In this framework, protein structures can be treated as random variables on the shape manifold, and means and covariance can be computed for populations of protein structures. Furthermore, these moments can be used to build Gaussian-type probability distributions of protein structures for use in hypothesis testing. The covariance of a population of protein structures can reveal the population-specific variations and be helpful in improving structure classification. With curves representing protein structures, the matching is performed using elastic shape analysis of curves, which can effectively model conformational changes and insertions/deletions. We show that our method performs comparably with commonly used methods in protein structure classification on a large manually annotated data set.'),
(84909, 2011, 'plos', 'Structural properties of the Caenorhabditis elegans neuronal network', 'Varshney, Lav R|Chen, Beth L|Paniagua, Eric|Hall, David H|Chklovskii, Dmitri B', 'Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States', 413, 'Animals|Caenorhabditis elegans|Computational Biology|Gap Junctions|Interneurons|Mathematical Concepts|Models, Anatomic|Models, Neurological|Motor Neurons|Nerve Net|Sensory Receptor Cells|Synapses|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1001066', '21304930', 'Despite recent interest in reconstructing neuronal networks, complete wiring diagrams on the level of individual synapses remain scarce and the insights into function they can provide remain unclear. Even for Caenorhabditis elegans, whose neuronal network is relatively small and stereotypical from animal to animal, published wiring diagrams are neither accurate nor complete and self-consistent. Using materials from White et al. and new electron micrographs we assemble whole, self-consistent gap junction and chemical synapse networks of hermaphrodite C. elegans. We propose a method to visualize the wiring diagram, which reflects network signal flow. We calculate statistical and topological properties of the network, such as degree distributions, synaptic multiplicities, and small-world properties, that help in understanding network signal propagation. We identify neurons that may play central roles in information processing, and network motifs that could serve as functional modules of the network. We explore propagation of neuronal activity in response to sensory or artificial stimulation using linear systems theory and find several activity patterns that could serve as substrates of previously described behaviors. Finally, we analyze the interaction between the gap junction and the chemical synapse networks. Since several statistical properties of the C. elegans network, such as multiplicity and motif distributions are similar to those found in mammalian neocortex, they likely point to general principles of neuronal networks. The wiring diagram reported here can help in understanding the mechanistic basis of behavior by generating predictions about future experiments involving genetic perturbations, laser ablations, or monitoring propagation of neuronal activity in response to stimulation.'),
(84910, 2011, 'plos', 'Gene expression noise in spatial patterning: hunchback promoter structure affects noise amplitude and distribution in Drosophila segmentation', 'Holloway, David M|Lopes, Francisco J P|da Fontoura Costa, Luciano|Travençolo, Bruno A N|Golyandina, Nina|Usevich, Konstantin|Spirov, Alexander V', 'Mathematics Department, British Columbia Institute of Technology, Burnaby, British Columbia, Canada. David_Holloway@bcit.ca|Mathematics Department, British Columbia Institute of Technology, Burnaby, British Columbia, Canada. David_Holloway@bcit.ca|Mathematics Department, British Columbia Institute of Technology, Burnaby, British Columbia, Canada. David_Holloway@bcit.ca|Mathematics Department, British Columbia Institute of Technology, Burnaby, British Columbia, Canada. David_Holloway@bcit.ca|Mathematics Department, British Columbia Institute of Technology, Burnaby, British Columbia, Canada. David_Holloway@bcit.ca|Mathematics Department, British Columbia Institute of Technology, Burnaby, British Columbia, Canada. David_Holloway@bcit.ca|Mathematics Department, British Columbia Institute of Technology, Burnaby, British Columbia, Canada. David_Holloway@bcit.ca', 'Canada|Canada|Canada|Canada|Canada|Canada|Canada', 0, 'Animals|Animals, Genetically Modified|Binding Sites|Body Patterning|Computational Biology|DNA-Binding Proteins|Drosophila Proteins|Drosophila melanogaster|Gene Expression Profiling|Gene Expression Regulation, Developmental|Genes, Insect|Homeodomain Proteins|Models, Genetic|Mutation|Promoter Regions, Genetic|Protein Binding|RNA, Messenger|Stochastic Processes|Trans-Activators|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1001069', '21304932', 'Positional information in developing embryos is specified by spatial gradients of transcriptional regulators. One of the classic systems for studying this is the activation of the hunchback (hb) gene in early fruit fly (Drosophila) segmentation by the maternally-derived gradient of the Bicoid (Bcd) protein. Gene regulation is subject to intrinsic noise which can produce variable expression. This variability must be constrained in the highly reproducible and coordinated events of development. We identify means by which noise is controlled during gene expression by characterizing the dependence of hb mRNA and protein output noise on hb promoter structure and transcriptional dynamics. We use a stochastic model of the hb promoter in which the number and strength of Bcd and Hb (self-regulatory) binding sites can be varied. Model parameters are fit to data from WT embryos, the self-regulation mutant hb(14F), and lacZ reporter constructs using different portions of the hb promoter. We have corroborated model noise predictions experimentally. The results indicate that WT (self-regulatory) Hb output noise is predominantly dependent on the transcription and translation dynamics of its own expression, rather than on Bcd fluctuations. The constructs and mutant, which lack self-regulation, indicate that the multiple Bcd binding sites in the hb promoter (and their strengths) also play a role in buffering noise. The model is robust to the variation in Bcd binding site number across a number of fly species. This study identifies particular ways in which promoter structure and regulatory dynamics reduce hb output noise. Insofar as many of these are common features of genes (e.g. multiple regulatory sites, cooperativity, self-feedback), the current results contribute to the general understanding of the reproducibility and determinacy of spatial patterning in early development.'),
(84911, 2011, 'plos', 'Stochastic theory of early viral infection: continuous versus burst production of virions', 'Pearson, John E|Krapivsky, Paul|Perelson, Alan S', 'Theoretical Biology & Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology & Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology & Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.', 'Mexico|Mexico|Mexico', 0, 'Animals|Computational Biology|HIV|HIV Infections|Humans|Mathematical Concepts|Models, Biological|Simian Acquired Immunodeficiency Syndrome|Simian Immunodeficiency Virus|Stochastic Processes|Time Factors|Viral Load|Virion|Virus Diseases|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.1001058', '21304934', 'Viral production from infected cells can occur continuously or in a burst that generally kills the cell. For HIV infection, both modes of production have been suggested. Standard viral dynamic models formulated as sets of ordinary differential equations can not distinguish between these two modes of viral production, as the predicted dynamics is identical as long as infected cells produce the same total number of virions over their lifespan. Here we show that in stochastic models of viral infection the two modes of viral production yield different early term dynamics. Further, we analytically determine the probability that infections initiated with any number of virions and infected cells reach extinction, the state when both the population of virions and infected cells vanish, and show this too has different solutions for continuous and burst production. We also compute the distributions of times to establish infection as well as the distribution of times to extinction starting from both a single virion as well as from a single infected cell for both modes of virion production.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84912, 2011, 'plos', 'Pharmacodynamic modeling of anti-cancer activity of tetraiodothyroacetic acid in a perfused cell culture system', 'Lin, Hung-Yun|Landersdorfer, Cornelia B|London, David|Meng, Ran|Lim, Chang-Uk|Lin, Cassie|Lin, Sharon|Tang, Heng-Yuan|Brown, David|Van Scoy, Brian|Kulawy, Robert|Queimado, Lurdes|Drusano, George L|Louie, Arnold|Davis, Faith B|Mousa, Shaker A|Davis, Paul J', 'Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.|Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.|Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.|Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.|Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.|Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.|Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.|Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.|Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.|Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.|Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.|Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.|Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.|Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.|Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.|Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.|Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 42, 'Antibodies, Monoclonal|Antibodies, Monoclonal, Humanized|Antineoplastic Agents|Apoptosis|Breast Neoplasms|Cell Culture Techniques|Cell Line, Tumor|Cell Proliferation|Cetuximab|Colonic Neoplasms|Computational Biology|Drug Therapy, Combination|Female|Humans|Models, Biological|Monte Carlo Method|Nanoparticles|Resveratrol|Stilbenes|Thyroxine', 'Journal Article', '10.1371/journal.pcbi.1001073', '21304935', 'Unmodified or as a poly[lactide-co-glycolide] nanoparticle, tetraiodothyroacetic acid (tetrac) acts at the integrin xcexb1vxcexb23 receptor on human cancer cells to inhibit tumor cell proliferation and xenograft growth. To study in vitro the pharmacodynamics of tetrac formulations in the absence of and in conjunction with other chemotherapeutic agents, we developed a perfusion bellows cell culture system. Cells were grown on polymer flakes and exposed to various concentrations of tetrac, nano-tetrac, resveratrol, cetuximab, or a combination for up to 18 days. Cells were harvested and counted every one or two days. Both NONMEM VI and the exact Monte Carlo parametric expectation maximization algorithm in S-ADAPT were utilized for mathematical modeling. Unmodified tetrac inhibited the proliferation of cancer cells and did so with differing potency in different cell lines. The developed mechanism-based model included two effects of tetrac on different parts of the cell cycle which could be distinguished. For human breast cancer cells, modeling suggested a higher sensitivity (lower IC50) to the effect on success rate of replication than the effect on rate of growth, whereas the capacity (Imax) was larger for the effect on growth rate. Nanoparticulate tetrac (nano-tetrac), which does not enter into cells, had a higher potency and a larger anti-proliferative effect than unmodified tetrac. Fluorescence-activated cell sorting analysis of harvested cells revealed tetrac and nano-tetrac induced concentration-dependent apoptosis that was correlated with expression of pro-apoptotic proteins, such as p53, p21, PIG3 and BAD for nano-tetrac, while unmodified tetrac showed a different profile. Approximately additive anti-proliferative effects were found for the combinations of tetrac and resveratrol, tetrac and cetuximab (Erbitux), and nano-tetrac and cetuximab. Our in vitro perfusion cancer cell system together with mathematical modeling successfully described the anti-proliferative effects over time of tetrac and nano-tetrac and may be useful for dose-finding and studying the pharmacodynamics of other chemotherapeutic agents or their combinations.'),
(84913, 2011, 'plos', 'Accurate quantification of functional analogy among close homologs', 'Chikina, Maria D|Troyanskaya, Olga G', 'Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America.|Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America.', 'Jersey|Jersey', 20, 'Animals|Bayes Theorem|Computational Biology|Evolution, Molecular|Gene Expression Profiling|Gene Regulatory Networks|Humans|Lamins|Oligonucleotide Array Sequence Analysis|Proteins|Saccharomyces cerevisiae Proteins|Sequence Homology, Amino Acid|Species Specificity|Structural Homology, Protein|Superoxide Dismutase|Synaptosomal-Associated Protein 25', 'Evaluation Studies', '10.1371/journal.pcbi.1001074', '21304936', 'Correctly evaluating functional similarities among homologous proteins is necessary for accurate transfer of experimental knowledge from one organism to another, and is of particular importance for the development of animal models of human disease. While the fact that sequence similarity implies functional similarity is a fundamental paradigm of molecular biology, sequence comparison does not directly assess the extent to which two proteins participate in the same biological processes, and has limited utility for analyzing families with several parologous members. Nevertheless, we show that it is possible to provide a cross-organism functional similarity measure in an unbiased way through the exclusive use of high-throughput gene-expression data. Our methodology is based on probabilistic cross-species mapping of functionally analogous proteins based on Bayesian integrative analysis of gene expression compendia. We demonstrate that even among closely related genes, our method is able to predict functionally analogous homolog pairs better than relying on sequence comparison alone. We also demonstrate that the landscape of functional similarity is often complex and that definitive functional orthologs do not always exist. Even in these cases, our method and the online interface we provide are designed to allow detailed exploration of sources of inferred functional similarity that can be evaluated by the user.'),
(84914, 2011, 'plos', 'Ribavirin-induced anemia in hepatitis C virus patients undergoing combination therapy', 'Krishnan, Sheeja M|Dixit, Narendra M', 'Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.|Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.', 'India|India', 27, 'Anemia, Hemolytic|Antiviral Agents|Computational Biology|Drug Therapy, Combination|Erythrocyte Aging|Hepatitis C|Humans|Interferon alpha-2|Interferon-alpha|Mathematical Concepts|Models, Biological|Polyethylene Glycols|Recombinant Proteins|Ribavirin', 'Journal Article', '10.1371/journal.pcbi.1001072', '21304937', 'The current standard of care for hepatitis C virus (HCV) infection - combination therapy with pegylated interferon and ribavirin - elicits sustained responses in only xe2x88xbc50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin substantially improves response rates to interferon and lowers relapse rates following the cessation of therapy, suggesting that increasing ribavirin exposure may further improve treatment response. A key limitation, however, is the toxic side-effect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced erythrocyte lifespan during therapy, and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones, such as erythropoietin, that stimulate erythrocyte production and avert the reduction of ribavirin dosage, thereby improving treatment response. Our model thus facilitates, in conjunction with models of viral kinetics, the rational identification of treatment protocols that maximize treatment response while curtailing side effects.'),
(84915, 2011, 'plos', 'Digital atlasing and standardization in the mouse brain', 'Hawrylycz, Michael|Baldock, Richard A|Burger, Albert|Hashikawa, Tsutomu|Johnson, G Allan|Martone, Maryann|Ng, Lydia|Lau, Chris|Larson, Stephen D|Larsen, Stephen D|Nissanov, Jonathan|Puelles, Luis|Ruffins, Seth|Verbeek, Fons|Zaslavsky, Ilya|Boline, Jyl', 'Allen Institute for Brain Science, Seattle, Washington, United States of America. mikeh@alleninstitute.org|Allen Institute for Brain Science, Seattle, Washington, United States of America. mikeh@alleninstitute.org|Allen Institute for Brain Science, Seattle, Washington, United States of America. mikeh@alleninstitute.org|Allen Institute for Brain Science, Seattle, Washington, United States of America. mikeh@alleninstitute.org|Allen Institute for Brain Science, Seattle, Washington, United States of America. mikeh@alleninstitute.org|Allen Institute for Brain Science, Seattle, Washington, United States of America. mikeh@alleninstitute.org|Allen Institute for Brain Science, Seattle, Washington, United States of America. mikeh@alleninstitute.org|Allen Institute for Brain Science, Seattle, Washington, United States of America. mikeh@alleninstitute.org|Allen Institute for Brain Science, Seattle, Washington, United States of America. mikeh@alleninstitute.org|Allen Institute for Brain Science, Seattle, Washington, United States of America. mikeh@alleninstitute.org|Allen Institute for Brain Science, Seattle, Washington, United States of America. mikeh@alleninstitute.org|Allen Institute for Brain Science, Seattle, Washington, United States of America. mikeh@alleninstitute.org|Allen Institute for Brain Science, Seattle, Washington, United States of America. mikeh@alleninstitute.org|Allen Institute for Brain Science, Seattle, Washington, United States of America. mikeh@alleninstitute.org|Allen Institute for Brain Science, Seattle, Washington, United States of America. mikeh@alleninstitute.org|Allen Institute for Brain Science, Seattle, Washington, United States of America. mikeh@alleninstitute.org', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Anatomy, Artistic|Animals|Atlases as Topic|Brain|Computational Biology|Male|Mice|Mice, Inbred C57BL|Models, Anatomic|Models, Neurological', 'Journal Article', '10.1371/journal.pcbi.1001065', '21304938', '-'),
(84916, 2011, 'plos', 'De-novo discovery of differentially abundant transcription factor binding sites including their positional preference', 'Keilwagen, Jens|Grau, Jan|Paponov, Ivan A|Posch, Stefan|Strickert, Marc|Grosse, Ivo', 'Molecular Genetics, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany. Jens.Keilwagen@ipk-gatersleben.de|Molecular Genetics, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany. Jens.Keilwagen@ipk-gatersleben.de|Molecular Genetics, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany. Jens.Keilwagen@ipk-gatersleben.de|Molecular Genetics, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany. Jens.Keilwagen@ipk-gatersleben.de|Molecular Genetics, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany. Jens.Keilwagen@ipk-gatersleben.de|Molecular Genetics, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany. Jens.Keilwagen@ipk-gatersleben.de', 'Germany|Germany|Germany|Germany|Germany|Germany', 42, 'Animals|Arabidopsis|Arabidopsis Proteins|Binding Sites|Computational Biology|DNA, Plant|Databases, Genetic|Genes, Plant|Humans|Indoleacetic Acids|Models, Genetic|Models, Statistical|Promoter Regions, Genetic|Transcription Factors', 'Evaluation Studies', '10.1371/journal.pcbi.1001070', '21347314', 'Transcription factors are a main component of gene regulation as they activate or repress gene expression by binding to specific binding sites in promoters. The de-novo discovery of transcription factor binding sites in target regions obtained by wet-lab experiments is a challenging problem in computational biology, which has not been fully solved yet. Here, we present a de-novo motif discovery tool called Dispom for finding differentially abundant transcription factor binding sites that models existing positional preferences of binding sites and adjusts the length of the motif in the learning process. Evaluating Dispom, we find that its prediction performance is superior to existing tools for de-novo motif discovery for 18 benchmark data sets with planted binding sites, and for a metazoan compendium based on experimental data from micro-array, ChIP-chip, ChIP-DSL, and DamID as well as Gene Ontology data. Finally, we apply Dispom to find binding sites differentially abundant in promoters of auxin-responsive genes extracted from Arabidopsis thaliana microarray data, and we find a motif that can be interpreted as a refined auxin responsive element predominately positioned in the 250-bp region upstream of the transcription start site. Using an independent data set of auxin-responsive genes, we find in genome-wide predictions that the refined motif is more specific for auxin-responsive genes than the canonical auxin-responsive element. In general, Dispom can be used to find differentially abundant motifs in sequences of any origin. However, the positional distribution learned by Dispom is especially beneficial if all sequences are aligned to some anchor point like the transcription start site in case of promoter sequences. We demonstrate that the combination of searching for differentially abundant motifs and inferring a position distribution from the data is beneficial for de-novo motif discovery. Hence, we make the tool freely available as a component of the open-source Java framework Jstacs and as a stand-alone application at http://www.jstacs.de/index.php/Dispom.'),
(84917, 2011, 'plos', 'A computational clonal analysis of the developing mouse limb bud', 'Marcon, Luciano|Arqués, Carlos G|Torres, Miguel S|Sharpe, James', 'EMBL-CRG Systems Biology Research Unit, Center for Genomic Regulation (CRG), Universitat Pompeu Fabra, Barcelona, Spain. luciano.marcon@crg.es|EMBL-CRG Systems Biology Research Unit, Center for Genomic Regulation (CRG), Universitat Pompeu Fabra, Barcelona, Spain. luciano.marcon@crg.es|EMBL-CRG Systems Biology Research Unit, Center for Genomic Regulation (CRG), Universitat Pompeu Fabra, Barcelona, Spain. luciano.marcon@crg.es|EMBL-CRG Systems Biology Research Unit, Center for Genomic Regulation (CRG), Universitat Pompeu Fabra, Barcelona, Spain. luciano.marcon@crg.es', 'Spain|Spain|Spain|Spain', 22, 'Animals|Body Patterning|Cell Movement|Clone Cells|Computational Biology|Computer Simulation|Gene Expression Regulation, Developmental|Homeodomain Proteins|Limb Buds|Mice|Mice, Inbred C57BL|Models, Anatomic|Models, Biological|Morphogenesis|Organogenesis|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1001071', '21347315', 'A comprehensive spatio-temporal description of the tissue movements underlying organogenesis would be an extremely useful resource to developmental biology. Clonal analysis and fate mappings are popular experiments to study tissue movement during morphogenesis. Such experiments allow cell populations to be labeled at an early stage of development and to follow their spatial evolution over time. However, disentangling the cumulative effects of the multiple events responsible for the expansion of the labeled cell population is not always straightforward. To overcome this problem, we develop a novel computational method that combines accurate quantification of 2D limb bud morphologies and growth modeling to analyze mouse clonal data of early limb development. Firstly, we explore various tissue movements that match experimental limb bud shape changes. Secondly, by comparing computational clones with newly generated mouse clonal data we are able to choose and characterize the tissue movement map that better matches experimental data. Our computational analysis produces for the first time a two dimensional model of limb growth based on experimental data that can be used to better characterize limb tissue movement in space and time. The model shows that the distribution and shapes of clones can be described as a combination of anisotropic growth with isotropic cell mixing, without the need for lineage compartmentalization along the AP and PD axis. Lastly, we show that this comprehensive description can be used to reassess spatio-temporal gene regulations taking tissue movement into account and to investigate PD patterning hypothesis.'),
(84918, 2011, 'plos', 'Mitigation strategies for pandemic influenza A: balancing conflicting policy objectives', 'Hollingsworth, T Déirdre|Klinkenberg, Don|Heesterbeek, Hans|Anderson, Roy M', 'MRC Centre for Outbreak Control and Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom. d.hollingsworth@imperial.ac.uk|MRC Centre for Outbreak Control and Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom. d.hollingsworth@imperial.ac.uk|MRC Centre for Outbreak Control and Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom. d.hollingsworth@imperial.ac.uk|MRC Centre for Outbreak Control and Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom. d.hollingsworth@imperial.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Antiviral Agents|Computational Biology|Health Policy|Humans|Influenza A virus|Influenza Vaccines|Influenza, Human|Mathematical Concepts|Models, Biological|Pandemics|Social Distance|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1001076', '21347316', 'Mitigation of a severe influenza pandemic can be achieved using a range of interventions to reduce transmission. Interventions can reduce the impact of an outbreak and buy time until vaccines are developed, but they may have high social and economic costs. The non-linear effect on the epidemic dynamics means that suitable strategies crucially depend on the precise aim of the intervention. National pandemic influenza plans rarely contain clear statements of policy objectives or prioritization of potentially conflicting aims, such as minimizing mortality (depending on the severity of a pandemic) or peak prevalence or limiting the socio-economic burden of contact-reducing interventions. We use epidemiological models of influenza A to investigate how contact-reducing interventions and availability of antiviral drugs or pre-pandemic vaccines contribute to achieving particular policy objectives. Our analyses show that the ideal strategy depends on the aim of an intervention and that the achievement of one policy objective may preclude success with others, e.g., constraining peak demand for public health resources may lengthen the duration of the epidemic and hence its economic and social impact. Constraining total case numbers can be achieved by a range of strategies, whereas strategies which additionally constrain peak demand for services require a more sophisticated intervention. If, for example, there are multiple objectives which must be achieved prior to the availability of a pandemic vaccine (i.e., a time-limited intervention), our analysis shows that interventions should be implemented several weeks into the epidemic, not at the very start. This observation is shown to be robust across a range of constraints and for uncertainty in estimates of both R(0) and the timing of vaccine availability. These analyses highlight the need for more precise statements of policy objectives and their assumed consequences when planning and implementing strategies to mitigate the impact of an influenza pandemic.'),
(84919, 2011, 'plos', 'A hybrid model of mammalian cell cycle regulation', 'Singhania, Rajat|Sramkoski, R Michael|Jacobberger, James W|Tyson, John J', 'Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.|Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.|Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.|Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.', 'United States|United States|United States|United States', 58, 'Cell Cycle|Cell Line|Cell Line, Tumor|Computational Biology|Contact Inhibition|Cyclin-Dependent Kinases|Cyclins|DNA|Endothelial Cells|Flow Cytometry|Humans|Mathematical Concepts|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1001077', '21347318', 'The timing of DNA synthesis, mitosis and cell division is regulated by a complex network of biochemical reactions that control the activities of a family of cyclin-dependent kinases. The temporal dynamics of this reaction network is typically modeled by nonlinear differential equations describing the rates of the component reactions. This approach provides exquisite details about molecular regulatory processes but is hampered by the need to estimate realistic values for the many kinetic constants that determine the reaction rates. It is difficult to estimate these kinetic constants from available experimental data. To avoid this problem, modelers often resort to qualitative modeling strategies, such as Boolean switching networks, but these models describe only the coarsest features of cell cycle regulation. In this paper we describe a hybrid approach that combines the best features of continuous differential equations and discrete Boolean networks. Cyclin abundances are tracked by piecewise linear differential equations for cyclin synthesis and degradation. Cyclin synthesis is regulated by transcription factors whose activities are represented by discrete variables (0 or 1) and likewise for the activities of the ubiquitin-ligating enzyme complexes that govern cyclin degradation. The discrete variables change according to a predetermined sequence, with the times between transitions determined in part by cyclin accumulation and degradation and as well by exponentially distributed random variables. The model is evaluated in terms of flow cytometry measurements of cyclin proteins in asynchronous populations of human cell lines. The few kinetic constants in the model are easily estimated from the experimental data. Using this hybrid approach, modelers can quickly create quantitatively accurate, computational models of protein regulatory networks in cells.'),
(84920, 2011, 'plos', 'Spike-based population coding and working memory', 'Boerlin, Martin|Denève, Sophie', 'Group for Neural Theory, Département dÉtudes Cognitives, École Normale Supérieure, Paris, France.|Group for Neural Theory, Département dÉtudes Cognitives, École Normale Supérieure, Paris, France.', 'France|France', 0, 'Action Potentials|Animals|Cats|Computational Biology|Computer Simulation|Feedback, Sensory|Humans|Memory|Models, Neurological|Neurons|Poisson Distribution', 'Journal Article', '10.1371/journal.pcbi.1001080', '21379319', 'Compelling behavioral evidence suggests that humans can make optimal decisions despite the uncertainty inherent in perceptual or motor tasks. A key question in neuroscience is how populations of spiking neurons can implement such probabilistic computations. In this article, we develop a comprehensive framework for optimal, spike-based sensory integration and working memory in a dynamic environment. We propose that probability distributions are inferred spike-per-spike in recurrently connected networks of integrate-and-fire neurons. As a result, these networks can combine sensory cues optimally, track the state of a time-varying stimulus and memorize accumulated evidence over periods much longer than the time constant of single neurons. Importantly, we propose that population responses and persistent working memory states represent entire probability distributions and not only single stimulus values. These memories are reflected by sustained, asynchronous patterns of activity which make relevant information available to downstream neurons within their short time window of integration. Model neurons act as predictive encoders, only firing spikes which account for new information that has not yet been signaled. Thus, spike times signal deterministically a prediction error, contrary to rate codes in which spike times are considered to be random samples of an underlying firing rate. As a consequence of this coding scheme, a multitude of spike patterns can reliably encode the same information. This results in weakly correlated, Poisson-like spike trains that are sensitive to initial conditions but robust to even high levels of external neural noise. This spike train variability reproduces the one observed in cortical sensory spike trains, but cannot be equated to noise. On the contrary, it is a consequence of optimal spike-based inference. In contrast, we show that rate-based models perform poorly when implemented with stochastically spiking neurons.'),
(84921, 2011, 'plos', 'First principles modeling of nonlinear incidence rates in seasonal epidemics', 'Ponciano, José M|Capistrán, Marcos A', 'Department of Biology, University of Florida, Gainesville, Florida, United States of America. josemi@ufl.edu|Department of Biology, University of Florida, Gainesville, Florida, United States of America. josemi@ufl.edu', 'United States|United States', 20, 'Algorithms|Child|Cohort Studies|Computational Biology|Databases, Factual|Epidemics|Epidemiologic Methods|Finland|Gambia|Humans|Measles|Models, Statistical|Nonlinear Dynamics|Research Design|Respiratory Syncytial Virus Infections|Seasons|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1001079', '21379320', 'In this paper we used a general stochastic processes framework to derive from first principles the incidence rate function that characterizes epidemic models. We investigate a particular case, the Liu-Hethcote-van den Driessches (LHD) incidence rate function, which results from modeling the number of successful transmission encounters as a pure birth process. This derivation also takes into account heterogeneity in the population with regard to the per individual transmission probability. We adjusted a deterministic SIRS model with both the classical and the LHD incidence rate functions to time series of the number of children infected with syncytial respiratory virus in Banjul, Gambia and Turku, Finland. We also adjusted a deterministic SEIR model with both incidence rate functions to the famous measles data sets from the UK cities of London and Birmingham. Two lines of evidence supported our conclusion that the model with the LHD incidence rate may very well be a better description of the seasonal epidemic processes studied here. First, our model was repeatedly selected as best according to two different information criteria and two different likelihood formulations. The second line of evidence is qualitative in nature: contrary to what the SIRS model with classical incidence rate predicts, the solution of the deterministic SIRS model with LHD incidence rate will reach either the disease free equilibrium or the endemic equilibrium depending on the initial conditions. These findings along with computer intensive simulations of the models Poincaré map with environmental stochasticity contributed to attain a clear separation of the roles of the environmental forcing and the mechanics of the disease transmission in shaping seasonal epidemics dynamics.'),
(84922, 2011, 'plos', 'Loss of genetic redundancy in reductive genome evolution', 'Mendonça, André G|Alves, Renato J|Pereira-Leal, José B', 'Instituto Gulbenkian de Ciência, Oeiras, Portugal.|Instituto Gulbenkian de Ciência, Oeiras, Portugal.|Instituto Gulbenkian de Ciência, Oeiras, Portugal.', 'Portugal|Portugal|Portugal', 40, 'Bacterial Proteins|Evolution, Molecular|Genome, Bacterial|Genomics|Models, Genetic|Sequence Deletion|Symbiosis', 'Journal Article', '10.1371/journal.pcbi.1001082', '21379323', 'Biological systems evolved to be functionally robust in uncertain environments, but also highly adaptable. Such robustness is partly achieved by genetic redundancy, where the failure of a specific component through mutation or environmental challenge can be compensated by duplicate components capable of performing, to a limited extent, the same function. Highly variable environments require very robust systems. Conversely, predictable environments should not place a high selective value on robustness. Here we test this hypothesis by investigating the evolutionary dynamics of genetic redundancy in extremely reduced genomes, found mostly in intracellular parasites and endosymbionts. By combining data analysis with simulations of genome evolution we show that in the extensive gene loss suffered by reduced genomes there is a selective drive to keep the diversity of protein families while sacrificing paralogy. We show that this is not a by-product of the known drivers of genome reduction and that there is very limited convergence to a common core of families, indicating that the repertoire of protein families in reduced genomes is the result of historical contingency and niche-specific adaptations. We propose that our observations reflect a loss of genetic redundancy due to a decreased selection for robustness in a predictable environment.'),
(84923, 2011, 'plos', 'Effect of 1918 PB1-F2 expression on influenza A virus infection kinetics', 'Smith, Amber M|Adler, Frederick R|McAuley, Julie L|Gutenkunst, Ryan N|Ribeiro, Ruy M|McCullers, Jonathan A|Perelson, Alan S', 'Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.', 'Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico', 45, 'Animals|Cluster Analysis|Disease Models, Animal|Host-Pathogen Interactions|Influenza A Virus, H1N1 Subtype|Kinetics|Linear Models|Lung|Mice|Models, Biological|Orthomyxoviridae Infections|Pandemics|Viral Load|Viral Proteins|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.1001081', '21379324', 'Relatively little is known about the viral factors contributing to the lethality of the 1918 pandemic, although its unparalleled virulence was likely due in part to the newly discovered PB1-F2 protein. This protein, while unnecessary for replication, increases apoptosis in monocytes, alters viral polymerase activity in vitro, enhances inflammation and increases secondary pneumonia in vivo. However, the effects the PB1-F2 protein have in vivo remain unclear. To address the mechanisms involved, we intranasally infected groups of mice with either influenza A virus PR8 or a genetically engineered virus that expresses the 1918 PB1-F2 protein on a PR8 background, PR8-PB1-F2(1918). Mice inoculated with PR8 had viral concentrations peaking at 72 hours, while those infected with PR8-PB1-F2(1918) reached peak concentrations earlier, 48 hours. Mice given PR8-PB1-F2(1918) also showed a faster decline in viral loads. We fit a mathematical model to these data to estimate parameter values. The model supports a higher viral production rate per cell and a higher infected cell death rate with the PR8-PB1-F2(1918) virus. We discuss the implications these mechanisms have during an infection with a virus expressing a virulent PB1-F2 on the possibility of a pandemic and on the importance of antiviral treatments.'),
(84924, 2011, 'plos', 'Molecular dynamics simulations of forced unbending of integrin xcexb1(v)xcexb2xe2x82x83', 'Chen, Wei|Lou, Jizhong|Hsin, Jen|Schulten, Klaus|Harvey, Stephen C|Zhu, Cheng', 'Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.|Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.|Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.|Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.|Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.|Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.', 'Georgia|Georgia|Georgia|Georgia|Georgia|Georgia', 36, 'Humans|Integrin alphaVbeta3|Molecular Dynamics Simulation|Oligopeptides|Protein Binding|Protein Conformation|Protein Stability|Protein Structure, Tertiary', 'Journal Article', '10.1371/journal.pcbi.1001086', '21379327', 'Integrins may undergo large conformational changes during activation, but the dynamic processes and pathways remain poorly understood. We used molecular dynamics to simulate forced unbending of a complete integrin xcexb1(v)xcexb2xe2x82x83 ectodomain in both unliganded and liganded forms. Pulling the head of the integrin readily induced changes in the integrin from a bent to an extended conformation. Pulling at a cyclic RGD ligand bound to the integrin head also extended the integrin, suggesting that force can activate integrins. Interactions at the interfaces between the hybrid and xcexb2 tail domains and between the hybrid and epidermal growth factor 4 domains formed the major energy barrier along the unbending pathway, which could be overcome spontaneously in ~1 xc2xb5s to yield a partially-extended conformation that tended to rebend. By comparison, a fully-extended conformation was stable. A newly-formed coordination between the xcexb1(v) Asp457 and the xcexb1-genu metal ion might contribute to the stability of the fully-extended conformation. These results reveal the dynamic processes and pathways of integrin conformational changes with atomic details and provide new insights into the structural mechanisms of integrin activation.'),
(84925, 2011, 'plos', 'A dynamical systems model for combinatorial cancer therapy enhances oncolytic adenovirus efficacy by MEK-inhibition', 'Bagheri, Neda|Shiina, Marisa|Lauffenburger, Douglas A|Korn, W Michael', 'Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States', 0, 'Adenoviridae|Antineoplastic Combined Chemotherapy Protocols|Cell Cycle|Cell Survival|Combined Modality Therapy|Computer Simulation|Coxsackie and Adenovirus Receptor-Like Membrane Protein|HCT116 Cells|Humans|MAP Kinase Signaling System|Mitogen-Activated Protein Kinase Kinases|Models, Biological|Neoplasms|Nonlinear Dynamics|Oncolytic Virotherapy|Receptors, Virus|Reproducibility of Results|Viral Vaccines|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.1001085', '21379332', 'Oncolytic adenoviruses, such as ONYX-015, have been tested in clinical trials for currently untreatable tumors, but have yet to demonstrate adequate therapeutic efficacy. The extent to which viruses infect targeted cells determines the efficacy of this approach but many tumors down-regulate the Coxsackievirus and Adenovirus Receptor (CAR), rendering them less susceptible to infection. Disrupting MAPK pathway signaling by pharmacological inhibition of MEK up-regulates CAR expression, offering possible enhanced adenovirus infection. MEK inhibition, however, interferes with adenovirus replication due to resulting G1-phase cell cycle arrest. Therefore, enhanced efficacy will depend on treatment protocols that productively balance these competing effects. Predictive understanding of how to attain and enhance therapeutic efficacy of combinatorial treatment is difficult since the effects of MEK inhibitors, in conjunction with adenovirus/cell interactions, are complex nonlinear dynamic processes. We investigated combinatorial treatment strategies using a mathematical model that predicts the impact of MEK inhibition on tumor cell proliferation, ONYX-015 infection, and oncolysis. Specifically, we fit a nonlinear differential equation system to dedicated experimental data and analyzed the resulting simulations for favorable treatment strategies. Simulations predicted enhanced combinatorial therapy when both treatments were applied simultaneously, we successfully validated these predictions in an ensuing explicit test study. Further analysis revealed that a CAR-independent mechanism may be responsible for amplified virus production and cell death. We conclude that integrated computational and experimental analysis of combinatorial therapy provides a useful means to identify treatment/infection protocols that yield clinically significant oncolysis. Enhanced oncolytic therapy has the potential to dramatically improve non-surgical cancer treatment, especially in locally advanced or metastatic cases where treatment options remain limited.'),
(84926, 2011, 'plos', 'The free energy landscape of small molecule unbinding', 'Huang, Danzhi|Caflisch, Amedeo', 'Department of Biochemistry, University of Zürich, Zürich, Switzerland.|Department of Biochemistry, University of Zürich, Zürich, Switzerland.', 'Switzerland|Switzerland', 65, 'Crystallography, X-Ray|Dimethyl Sulfoxide|Molecular Dynamics Simulation|Pentanones|Protein Binding|Protein Folding|Tacrolimus Binding Proteins|Thermodynamics|Water', 'Journal Article', '10.1371/journal.pcbi.1002002', '21390201', 'The spontaneous dissociation of six small ligands from the active site of FKBP (the FK506 binding protein) is investigated by explicit water molecular dynamics simulations and network analysis. The ligands have between four (dimethylsulphoxide) and eleven (5-diethylamino-2-pentanone) non-hydrogen atoms, and an affinity for FKBP ranging from 20 to 0.2 mM. The conformations of the FKBP/ligand complex saved along multiple trajectories (50 runs at 310 K for each ligand) are grouped according to a set of intermolecular distances into nodes of a network, and the direct transitions between them are the links. The network analysis reveals that the bound state consists of several subbasins, i.e., binding modes characterized by distinct intermolecular hydrogen bonds and hydrophobic contacts. The dissociation kinetics show a simple (i.e., single-exponential) time dependence because the unbinding barrier is much higher than the barriers between subbasins in the bound state. The unbinding transition state is made up of heterogeneous positions and orientations of the ligand in the FKBP active site, which correspond to multiple pathways of dissociation. For the six small ligands of FKBP, the weaker the binding affinity the closer to the bound state (along the intermolecular distance) are the transition state structures, which is a new manifestation of Hammond behavior. Experimental approaches to the study of fragment binding to proteins have limitations in temporal and spatial resolution. Our network analysis of the unbinding simulations of small inhibitors from an enzyme paints a clear picture of the free energy landscape (both thermodynamics and kinetics) of ligand unbinding.'),
(84927, 2011, 'plos', 'Informed switching strongly decreases the prevalence of antibiotic resistance in hospital wards', 'Kouyos, Roger D|Abel Zur Wiesch, Pia|Bonhoeffer, Sebastian', 'Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. roger.kouyos@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. roger.kouyos@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. roger.kouyos@env.ethz.ch', 'Switzerland|Switzerland|Switzerland', 0, 'Anti-Bacterial Agents|Bacteria|Bacterial Infections|Cross Infection|Drug Resistance, Bacterial|Hospitals|Humans|Models, Biological|Prevalence|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1001094', '21390265', 'Antibiotic resistant nosocomial infections are an important cause of mortality and morbidity in hospitals. Antibiotic cycling has been proposed to contain this spread by a coordinated use of different antibiotics. Theoretical work, however, suggests that often the random deployment of drugs (mixing) might be the better strategy. We use an epidemiological model for a single hospital ward in order to assess the performance of cycling strategies which take into account the frequency of antibiotic resistance in the hospital ward. We assume that information on resistance frequencies stems from microbiological tests, which are performed in order to optimize individual therapy. Thus the strategy proposed here represents an optimization at population-level, which comes as a free byproduct of optimizing treatment at the individual level. We find that in most cases such an informed switching strategy outperforms both periodic cycling and mixing, despite the fact that information on the frequency of resistance is derived only from a small sub-population of patients. Furthermore we show that the success of this strategy is essentially a stochastic phenomenon taking advantage of the small population sizes in hospital wards. We find that the performance of an informed switching strategy can be improved substantially if information on resistance tests is integrated over a period of one to two weeks. Finally we argue that our findings are robust against a (moderate) preexistence of doubly resistant strains and against transmission via environmental reservoirs. Overall, our results suggest that switching between different antibiotics might be a valuable strategy in small patient populations, if the switching strategies take the frequencies of resistance alleles into account.'),
(84928, 2011, 'plos', 'Flexible cognitive strategies during motor learning', 'Taylor, Jordan A|Ivry, Richard B', 'Department of Psychology, University of California, Berkeley, Berkeley, California, USA. jordan.a.taylor@berkeley.edu|Department of Psychology, University of California, Berkeley, Berkeley, California, USA. jordan.a.taylor@berkeley.edu', 'United States|United States', 120, 'Algorithms|Cognition|Computational Biology|Feedback, Physiological|Female|Humans|Learning|Models, Neurological|Motor Skills|Psychomotor Performance|Task Performance and Analysis', 'Journal Article', '10.1371/journal.pcbi.1001096', '21390266', 'Visuomotor rotation tasks have proven to be a powerful tool to study adaptation of the motor system. While adaptation in such tasks is seemingly automatic and incremental, participants may gain knowledge of the perturbation and invoke a compensatory strategy. When provided with an explicit strategy to counteract a rotation, participants are initially very accurate, even without on-line feedback. Surprisingly, with further testing, the angle of their reaching movements drifts in the direction of the strategy, producing an increase in endpoint errors. This drift is attributed to the gradual adaptation of an internal model that operates independently from the strategy, even at the cost of task accuracy. Here we identify constraints that influence this process, allowing us to explore models of the interaction between strategic and implicit changes during visuomotor adaptation. When the adaptation phase was extended, participants eventually modified their strategy to offset the rise in endpoint errors. Moreover, when we removed visual markers that provided external landmarks to support a strategy, the degree of drift was sharply attenuated. These effects are accounted for by a setpoint state-space model in which a strategy is flexibly adjusted to offset performance errors arising from the implicit adaptation of an internal model. More generally, these results suggest that strategic processes may operate in many studies of visuomotor adaptation, with participants arriving at a synergy between a strategic plan and the effects of sensorimotor adaptation.'),
(84929, 2011, 'plos', 'Natural selection on functional modules, a genome-wide analysis', 'Serra, François|Arbiza, Leonardo|Dopazo, Joaquín|Dopazo, Hernán', 'Evolutionary Genomics Lab, Bioinformatics & Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain.|Evolutionary Genomics Lab, Bioinformatics & Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain.|Evolutionary Genomics Lab, Bioinformatics & Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain.|Evolutionary Genomics Lab, Bioinformatics & Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain.', 'Spain|Spain|Spain|Spain', 9, 'Animals|Databases, Genetic|Drosophila|Genome, Insect|Genome-Wide Association Study|Genomics|Mammals|Phylogeny|Selection, Genetic|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1001093', '21390268', 'Classically, the functional consequences of natural selection over genomes have been analyzed as the compound effects of individual genes. The current paradigm for large-scale analysis of adaptation is based on the observed significant deviations of rates of individual genes from neutral evolutionary expectation. This approach, which assumed independence among genes, has not been able to identify biological functions significantly enriched in positively selected genes in individual species. Alternatively, pooling related species has enhanced the search for signatures of selection. However, grouping signatures does not allow testing for adaptive differences between species. Here we introduce the Gene-Set Selection Analysis (GSSA), a new genome-wide approach to test for evidences of natural selection on functional modules. GSSA is able to detect lineage specific evolutionary rate changes in a notable number of functional modules. For example, in nine mammal and Drosophilae genomes GSSA identifies hundreds of functional modules with significant associations to high and low rates of evolution. Many of the detected functional modules with high evolutionary rates have been previously identified as biological functions under positive selection. Notably, GSSA identifies conserved functional modules with many positively selected genes, which questions whether they are exclusively selected for fitting genomes to environmental changes. Our results agree with previous studies suggesting that adaptation requires positive selection, but not every mutation under positive selection contributes to the adaptive dynamical process of the evolution of species.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84930, 2011, 'plos', 'Effect of promoter architecture on the cell-to-cell variability in gene expression', 'Sanchez, Alvaro|Garcia, Hernan G|Jones, Daniel|Phillips, Rob|Kondev, Jané', 'Graduate Program in Biophysics and Structural Biology, Brandeis University, Waltham, Massachusetts,USA.|Graduate Program in Biophysics and Structural Biology, Brandeis University, Waltham, Massachusetts,USA.|Graduate Program in Biophysics and Structural Biology, Brandeis University, Waltham, Massachusetts,USA.|Graduate Program in Biophysics and Structural Biology, Brandeis University, Waltham, Massachusetts,USA.|Graduate Program in Biophysics and Structural Biology, Brandeis University, Waltham, Massachusetts,USA.', 'United States|United States|United States|United States|United States', 87, 'Algorithms|Binding Sites|Computational Biology|Escherichia coli|Gene Expression Regulation, Bacterial|Kinetics|Models, Genetic|Molecular Dynamics Simulation|Poisson Distribution|Promoter Regions, Genetic|Repressor Proteins|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1001100', '21390269', 'According to recent experimental evidence, promoter architecture, defined by the number, strength and regulatory role of the operators that control transcription, plays a major role in determining the level of cell-to-cell variability in gene expression. These quantitative experiments call for a corresponding modeling effort that addresses the question of how changes in promoter architecture affect variability in gene expression in a systematic rather than case-by-case fashion. In this article we make such a systematic investigation, based on a microscopic model of gene regulation that incorporates stochastic effects. In particular, we show how operator strength and operator multiplicity affect this variability. We examine different modes of transcription factor binding to complex promoters (cooperative, independent, simultaneous) and how each of these affects the level of variability in transcriptional output from cell-to-cell. We propose that direct comparison between in vivo single-cell experiments and theoretical predictions for the moments of the probability distribution of mRNA number per cell can be used to test kinetic models of gene regulation. The emphasis of the discussion is on prokaryotic gene regulation, but our analysis can be extended to eukaryotic cells as well.'),
(84931, 2011, 'plos', 'Nucleotide binding switches the information flow in ras GTPases', 'Raimondi, Francesco|Portella, Guillem|Orozco, Modesto|Fanelli, Francesca', 'Department of Chemistry, University of Modena and Reggio Emilia, Modena, Italy.|Department of Chemistry, University of Modena and Reggio Emilia, Modena, Italy.|Department of Chemistry, University of Modena and Reggio Emilia, Modena, Italy.|Department of Chemistry, University of Modena and Reggio Emilia, Modena, Italy.', 'Italy|Italy|Italy|Italy', 0, 'Amino Acid Sequence|Binding Sites|Computational Biology|Guanosine Diphosphate|Guanosine Triphosphate|Molecular Dynamics Simulation|Molecular Sequence Data|Pliability|Principal Component Analysis|Protein Structure, Tertiary|Sequence Alignment|ras Proteins', 'Journal Article', '10.1371/journal.pcbi.1001098', '21390270', 'The Ras superfamily comprises many guanine nucleotide-binding proteins (G proteins) that are essential to intracellular signal transduction. The guanine nucleotide-dependent intrinsic flexibility patterns of five G proteins were investigated in atomic detail through Molecular Dynamics simulations of the GDP- and GTP-bound states (S(GDP) and S(GTP), respectively). For all the considered systems, the intrinsic flexibility of S(GDP) was higher than that of S(GTP), suggesting that Guanine Exchange Factor (GEF) recognition and nucleotide switch require higher amplitude motions than effector recognition or GTP hydrolysis. Functional mode, dynamic domain, and interaction energy correlation analyses highlighted significant differences in the dynamics of small G proteins and Gxcexb1 proteins, especially in the inactive state. Indeed, S(GDP) of Gxcexb1(t), is characterized by a more extensive energy coupling between nucleotide binding site and distal regions involved in GEF recognition compared to small G proteins, which attenuates in the active state. Moreover, mechanically distinct domains implicated in nucleotide switch could be detected in the presence of GDP but not in the presence of GTP. Finally, in small G proteins, functional modes are more detectable in the inactive state than in the active one and involve changes in solvent exposure of two highly conserved amino acids in switches I and II involved in GEF recognition. The average solvent exposure of these amino acids correlates in turn with the rate of GDP release, suggesting for them either direct or indirect roles in the process of nucleotide switch. Collectively, nucleotide binding changes the information flow through the conserved Ras-like domain, where GDP enhances the flexibility of mechanically distinct portions involved in nucleotide switch, and favors long distance allosteric communication (in Gxcexb1 proteins), compared to GTP.'),
(84932, 2011, 'plos', 'Identifying causal genes and dysregulated pathways in complex diseases', 'Kim, Yoo-Ah|Wuchty, Stefan|Przytycka, Teresa M', 'National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.|National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.|National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.', 'United States|United States|United States', 120, 'Chromosomes|Cluster Analysis|DNA Copy Number Variations|Gene Dosage|Gene Expression Profiling|Gene Expression Regulation, Neoplastic|Gene Regulatory Networks|Genomics|Glioblastoma|Humans|Quantitative Trait Loci|Reproducibility of Results|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1001095', '21390271', 'In complex diseases, various combinations of genomic perturbations often lead to the same phenotype. On a molecular level, combinations of genomic perturbations are assumed to dys-regulate the same cellular pathways. Such a pathway-centric perspective is fundamental to understanding the mechanisms of complex diseases and the identification of potential drug targets. In order to provide an integrated perspective on complex disease mechanisms, we developed a novel computational method to simultaneously identify causal genes and dys-regulated pathways. First, we identified a representative set of genes that are differentially expressed in cancer compared to non-tumor control cases. Assuming that disease-associated gene expression changes are caused by genomic alterations, we determined potential paths from such genomic causes to target genes through a network of molecular interactions. Applying our method to sets of genomic alterations and gene expression profiles of 158 Glioblastoma multiforme (GBM) patients we uncovered candidate causal genes and causal paths that are potentially responsible for the altered expression of disease genes. We discovered a set of putative causal genes that potentially play a role in the disease. Combining an expression Quantitative Trait Loci (eQTL) analysis with pathway information, our approach allowed us not only to identify potential causal genes but also to find intermediate nodes and pathways mediating the information flow between causal and target genes. Our results indicate that different genomic perturbations indeed dys-regulate the same functional pathways, supporting a pathway-centric perspective of cancer. While copy number alterations and gene expression data of glioblastoma patients provided opportunities to test our approach, our method can be applied to any disease system where genetic variations play a fundamental causal role.'),
(84933, 2011, 'plos', 'Blockade of neuronal xcexb17-nAChR by xcexb1-conotoxin ImI explained by computational scanning and energy calculations', 'Yu, Rilei|Craik, David J|Kaas, Quentin', 'Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.|Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.|Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.', 'Australia|Australia|Australia', 58, 'Amino Acid Sequence|Animals|Aplysia|Apoproteins|Conotoxins|Humans|Mice|Models, Molecular|Molecular Sequence Data|Point Mutation|Protein Binding|Protein Stability|Receptors, Nicotinic|Sequence Alignment|Systems Biology|Thermodynamics|alpha7 Nicotinic Acetylcholine Receptor', 'Journal Article', '10.1371/journal.pcbi.1002011', '21390272', 'xcexb1-Conotoxins potently inhibit isoforms of nicotinic acetylcholine receptors (nAChRs), which are essential for neuronal and neuromuscular transmission. They are also used as neurochemical tools to study nAChR physiology and are being evaluated as drug leads to treat various neuronal disorders. A number of experimental studies have been performed to investigate the structure-activity relationships of conotoxin/nAChR complexes. However, the structural determinants of their binding interactions are still ambiguous in the absence of experimental structures of conotoxin-receptor complexes. In this study, the binding modes of xcexb1-conotoxin ImI to the xcexb17-nAChR, currently the best-studied system experimentally, were investigated using comparative modeling and molecular dynamics simulations. The structures of more than 30 single point mutants of either the conotoxin or the receptor were modeled and analyzed. The models were used to explain qualitatively the change of affinities measured experimentally, including some nAChR positions located outside the binding site. Mutational energies were calculated using different methods that combine a conformational refinement procedure (minimization with a distance dependent dielectric constant or explicit water, or molecular dynamics using five restraint strategies) and a binding energy function (MM-GB/SA or MM-PB/SA). The protocol using explicit water energy minimization and MM-GB/SA gave the best correlations with experimental binding affinities, with an R2 value of 0.74. The van der Waals and non-polar desolvation components were found to be the main driving force for binding of the conotoxin to the nAChR. The electrostatic component was responsible for the selectivity of the various ImI mutants. Overall, this study provides novel insights into the binding mechanism of xcexb1-conotoxins to nAChRs and the methodological developments reported here open avenues for computational scanning studies of a rapidly expanding range of wild-type and chemically modified xcexb1-conotoxins.'),
(84934, 2011, 'plos', 'Dynamic conformational changes in munc18 prevent syntaxin binding', 'Bar-On, Dana|Nachliel, Esther|Gutman, Menachem|Ashery, Uri', 'Department of Neurobiology, Tel Aviv University, Tel Aviv, Israel.|Department of Neurobiology, Tel Aviv University, Tel Aviv, Israel.|Department of Neurobiology, Tel Aviv University, Tel Aviv, Israel.|Department of Neurobiology, Tel Aviv University, Tel Aviv, Israel.', 'Israel|Israel|Israel|Israel', 0, 'Animals|Binding Sites|Cluster Analysis|Computational Biology|Decapodiformes|Fungal Proteins|Molecular Dynamics Simulation|Munc18 Proteins|Mutation|Porcupines|Protein Binding|Protein Conformation|Protein Stability|Protein Structure, Tertiary|Qa-SNARE Proteins|Rats|Static Electricity', 'Journal Article', '10.1371/journal.pcbi.1001097', '21390273', 'The Sec1/munc18 protein family is essential for vesicle fusion in eukaryotic cells via binding to SNARE proteins. Protein kinase C modulates these interactions by phosphorylating munc18a thereby reducing its affinity to one of the central SNARE members, syntaxin-1a. The established hypothesis is that the reduced affinity of the phosphorylated munc18a to syntaxin-1a is a result of local electrostatic repulsion between the two proteins, which interferes with their compatibility. The current study challenges this paradigm and offers a novel mechanistic explanation by revealing a syntaxin-non-binding conformation of munc18a that is induced by the phosphomimetic mutations. In the present study, using molecular dynamics simulations, we explored the dynamics of the wild-type munc18a versus phosphomimetic mutant munc18a. We focused on the structural changes that occur in the cavity between domains 3a and 1, which serves as the main syntaxin-binding site. The results of the simulations suggest that the free wild-type munc18a exhibits a dynamic equilibrium between several conformations differing in the size of its cavity (the main syntaxin-binding site). The flexibility of the cavitys size might facilitate the binding or unbinding of syntaxin. In silico insertion of phosphomimetic mutations into the munc18a structure induces the formation of a conformation where the syntaxin-binding area is rigid and blocked as a result of interactions between residues located on both sides of the cavity. Therefore, we suggest that the reduced affinity of the phosphomimetic mutant/phosphorylated munc18a is a result of the closed-cavity conformation, which makes syntaxin binding energetically and sterically unfavorable. The current study demonstrates the potential of phosphorylation, an essential biological process, to serve as a driving force for dramatic conformational changes of proteins modulating their affinity to target proteins.'),
(84935, 2011, 'plos', 'Synaptic plasticity and connectivity requirements to produce stimulus-pair specific responses in recurrent networks of spiking neurons', 'Bourjaily, Mark A|Miller, Paul', 'Department of Biology and Neuroscience Program, Volen Center for Complex Systems, Brandeis University, Waltham, Massachusetts, United States of America.|Department of Biology and Neuroscience Program, Volen Center for Complex Systems, Brandeis University, Waltham, Massachusetts, United States of America.', 'United States|United States', 20, 'Action Potentials|Algorithms|Computer Simulation|Decision Making|Models, Neurological|Neuronal Plasticity|Neurons|Synapses', 'Journal Article', '10.1371/journal.pcbi.1001091', '21390275', 'Animals must respond selectively to specific combinations of salient environmental stimuli in order to survive in complex environments. A task with these features, biconditional discrimination, requires responses to select pairs of stimuli that are opposite to responses to those stimuli in another combination. We investigate the characteristics of synaptic plasticity and network connectivity needed to produce stimulus-pair neural responses within randomly connected model networks of spiking neurons trained in biconditional discrimination. Using reward-based plasticity for synapses from the random associative network onto a winner-takes-all decision-making network representing perceptual decision-making, we find that reliably correct decision making requires upstream neurons with strong stimulus-pair selectivity. By chance, selective neurons were present in initial networks, appropriate plasticity mechanisms improved task performance by enhancing the initial diversity of responses. We find long-term potentiation of inhibition to be the most beneficial plasticity rule by suppressing weak responses to produce reliably correct decisions across an extensive range of networks.'),
(84936, 2011, 'plos', 'Self-organization of muscle cell structure and function', 'Grosberg, Anna|Kuo, Po-Ling|Guo, Chin-Lin|Geisse, Nicholas A|Bray, Mark-Anthony|Adams, William J|Sheehy, Sean P|Parker, Kevin Kit', 'Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.|Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.|Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.|Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.|Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.|Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.|Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.|Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 69, 'Actins|Animals|Cells, Cultured|Computer Simulation|Cytoskeleton|Focal Adhesions|Immunohistochemistry|Models, Biological|Muscle Contraction|Myocytes, Cardiac|Myofibrils|Rats|Rats, Sprague-Dawley|Sarcomeres', 'Journal Article', '10.1371/journal.pcbi.1001088', '21390276', 'The organization of muscle is the product of functional adaptation over several length scales spanning from the sarcomere to the muscle bundle. One possible strategy for solving this multiscale coupling problem is to physically constrain the muscle cells in microenvironments that potentiate the organization of their intracellular space. We hypothesized that boundary conditions in the extracellular space potentiate the organization of cytoskeletal scaffolds for directed sarcomeregenesis. We developed a quantitative model of how the cytoskeleton of neonatal rat ventricular myocytes organizes with respect to geometric cues in the extracellular matrix. Numerical results and in vitro assays to control myocyte shape indicated that distinct cytoskeletal architectures arise from two temporally-ordered, organizational processes: the interaction between actin fibers, premyofibrils and focal adhesions, as well as cooperative alignment and parallel bundling of nascent myofibrils. Our results suggest that a hierarchy of mechanisms regulate the self-organization of the contractile cytoskeleton and that a positive feedback loop is responsible for initiating the break in symmetry, potentiated by extracellular boundary conditions, is required to polarize the contractile cytoskeleton.'),
(84937, 2011, 'plos', 'ISCB Public Policy Statement on Open Access to Scientific and Technical Research Literature', 'Lathrop, Richard H|Rost, Burkhard|ISCB Membership|ISCB Executive Committee|ISCB Board of Directors|ISCB Public Affairs Committee', 'admin@iscb.org|admin@iscb.org|admin@iscb.org|admin@iscb.org|admin@iscb.org|admin@iscb.org', '-|-|-|-|-|-', 0, 'Access to Information|Biomedical Research|Databases, Factual|Publishing', 'Journal Article', '10.1371/journal.pcbi.1002014', '21390278', '-'),
(84938, 2011, 'plos', 'Application of biomarkers in cancer risk management: evaluation from stochastic clonal evolutionary and dynamic system optimization points of view', 'Li, Xiaohong|Blount, Patricia L|Vaughan, Thomas L|Reid, Brian J', 'Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, United States of America. xili@fhcrc.org|Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, United States of America. xili@fhcrc.org|Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, United States of America. xili@fhcrc.org|Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, United States of America. xili@fhcrc.org', 'United States|United States|United States|United States', 17, 'Biomarkers, Tumor|Disease Management|Humans|Neoplasms|Predictive Value of Tests|Risk Factors|Stochastic Processes|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1001087', '21390279', 'Aside from primary prevention, early detection remains the most effective way to decrease mortality associated with the majority of solid cancers. Previous cancer screening models are largely based on classification of at-risk populations into three conceptually defined groups (normal, cancer without symptoms, and cancer with symptoms). Unfortunately, this approach has achieved limited successes in reducing cancer mortality. With advances in molecular biology and genomic technologies, many candidate somatic genetic and epigenetic biomarkers have been identified as potential predictors of cancer risk. However, none have yet been validated as robust predictors of progression to cancer or shown to reduce cancer mortality. In this Perspective, we first define the necessary and sufficient conditions for precise prediction of future cancer development and early cancer detection within a simple physical model framework. We then evaluate cancer risk prediction and early detection from a dynamic clonal evolution point of view, examining the implications of dynamic clonal evolution of biomarkers and the application of clonal evolution for cancer risk management in clinical practice. Finally, we propose a framework to guide future collaborative research between mathematical modelers and biomarker researchers to design studies to investigate and model dynamic clonal evolution. This approach will allow optimization of available resources for cancer control and intervention timing based on molecular biomarkers in predicting cancer among various risk subsets that dynamically evolve over time.'),
(84939, 2011, 'plos', 'Power-law input-output transfer functions explain the contrast-response and tuning properties of neurons in visual cortex', 'Persi, Erez|Hansel, David|Nowak, Lionel|Barone, Pascal|van Vreeswijk, Carl', 'Laboratoire de Neurophysique et Physiologie, Université Paris Descartes, Paris, France.|Laboratoire de Neurophysique et Physiologie, Université Paris Descartes, Paris, France.|Laboratoire de Neurophysique et Physiologie, Université Paris Descartes, Paris, France.|Laboratoire de Neurophysique et Physiologie, Université Paris Descartes, Paris, France.|Laboratoire de Neurophysique et Physiologie, Université Paris Descartes, Paris, France.', 'France|France|France|France|France', 0, 'Algorithms|Animals|Callithrix|Computational Biology|Membrane Potentials|Models, Neurological|Neurons|Reproducibility of Results|Synapses|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1001078', '21390280', 'We develop a unified model accounting simultaneously for the contrast invariance of the width of the orientation tuning curves (OT) and for the sigmoidal shape of the contrast response function (CRF) of neurons in the primary visual cortex (V1). We determine analytically the conditions for the structure of the afferent LGN and recurrent V1 inputs that lead to these properties for a hypercolumn composed of rate based neurons with a power-law transfer function. We investigate what are the relative contributions of single neuron and network properties in shaping the OT and the CRF. We test these results with numerical simulations of a network of conductance-based model (CBM) neurons and we demonstrate that they are valid and more robust here than in the rate model. The results indicate that because of the acceleration in the transfer function, described here by a power-law, the orientation tuning curves of V1 neurons are more tuned, and their CRF is steeper than those of their inputs. Last, we show that it is possible to account for the diversity in the measured CRFs by introducing heterogeneities either in single neuron properties or in the input to the neurons. We show how correlations among the parameters that characterize the CRF depend on these sources of heterogeneities. Comparison with experimental data suggests that both sources contribute nearly equally to the diversity of CRF shapes observed in V1 neurons.'),
(84940, 2011, 'plos', 'Dynamically-driven inactivation of the catalytic machinery of the SARS 3C-like protease by the N214A mutation on the extra domain', 'Shi, Jiahai|Han, Nanyu|Lim, Liangzhong|Lua, Shixiong|Sivaraman, J|Wang, Lushan|Mu, Yuguang|Song, Jianxing', 'Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore.|Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore.|Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore.|Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore.|Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore.|Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore.|Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore.|Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore.', 'Singapore|Singapore|Singapore|Singapore|Singapore|Singapore|Singapore|Singapore', 17, 'Crystallography|Cysteine Endopeptidases|Molecular Dynamics Simulation|Mutation|Protein Multimerization|Protein Structure, Tertiary|Recombinant Proteins|Viral Proteins', 'Journal Article', '10.1371/journal.pcbi.1001084', '21390281', 'Despite utilizing the same chymotrypsin fold to host the catalytic machinery, coronavirus 3C-like proteases (3CLpro) noticeably differ from picornavirus 3C proteases in acquiring an extra helical domain in evolution. Previously, the extra domain was demonstrated to regulate the catalysis of the SARS-CoV 3CLpro by controlling its dimerization. Here, we studied N214A, another mutant with only a doubled dissociation constant but significantly abolished activity. Unexpectedly, N214A still adopts the dimeric structure almost identical to that of the wild-type (WT) enzyme. Thus, we conducted 30-ns molecular dynamics (MD) simulations for N214A, WT, and R298A which we previously characterized to be a monomer with the collapsed catalytic machinery. Remarkably, three proteases display distinctive dynamical behaviors. While in WT, the catalytic machinery stably retains in the activated state, in R298A it remains largely collapsed in the inactivated state, thus implying that two states are not only structurally very distinguishable but also dynamically well separated. Surprisingly, in N214A the catalytic dyad becomes dynamically unstable and many residues constituting the catalytic machinery jump to sample the conformations highly resembling those of R298A. Therefore, the N214A mutation appears to trigger the dramatic change of the enzyme dynamics in the context of the dimeric form which ultimately inactivates the catalytic machinery. The present MD simulations represent the longest reported so far for the SARS-CoV 3CLpro, unveiling that its catalysis is critically dependent on the dynamics, which can be amazingly modulated by the extra domain. Consequently, mediating the dynamics may offer a potential avenue to inhibit the SARS-CoV 3CLpro.'),
(84941, 2011, 'plos', 'Quantitative prediction of miRNA-mRNA interaction based on equilibrium concentrations', 'Ragan, Chikako|Zuker, Michael|Ragan, Mark A', 'ARC Centre of Excellence in Bioinformatics, and Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.|ARC Centre of Excellence in Bioinformatics, and Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.|ARC Centre of Excellence in Bioinformatics, and Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.', 'Australia|Australia|Australia', 54, 'Animals|Computational Biology|Drosophila melanogaster|Gene Expression Regulation|Humans|MicroRNAs|Models, Genetic|RNA, Messenger|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1001090', '21390282', 'MicroRNAs (miRNAs) suppress gene expression by forming a duplex with a target messenger RNA (mRNA), blocking translation or initiating cleavage. Computational approaches have proven valuable for predicting which mRNAs can be targeted by a given miRNA, but currently available prediction methods do not address the extent of duplex formation under physiological conditions. Some miRNAs can at low concentrations bind to target mRNAs, whereas others are unlikely to bind within a physiologically relevant concentration range. Here we present a novel approach in which we find potential target sites on mRNA that minimize the calculated free energy of duplex formation, compute the free energy change involved in unfolding these sites, and use these energies to estimate the extent of duplex formation at specified initial concentrations of both species. We compare our predictions to experimentally confirmed miRNA-mRNA interactions (and non-interactions) in Drosophila melanogaster and in human. Although our method does not predict whether the targeted mRNA is degraded and/or its translation to protein inhibited, our quantitative estimates generally track experimentally supported results, indicating that this approach can be used to predict whether an interaction occurs at specified concentrations. Our approach offers a more-quantitative understanding of post-translational regulation in different cell types, tissues, and developmental conditions.'),
(84942, 2011, 'plos', 'Protein complexes are central in the yeast genetic landscape', 'Michaut, Magali|Baryshnikova, Anastasia|Costanzo, Michael|Myers, Chad L|Andrews, Brenda J|Boone, Charles|Bader, Gary D', 'The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.', 'Canada|Canada|Canada|Canada|Canada|Canada|Canada', 37, 'Computational Biology|Gene Regulatory Networks|Genes, Fungal|Models, Biological|Phenotype|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1001092', '21390331', 'If perturbing two genes together has a stronger or weaker effect than expected, they are said to genetically interact. Genetic interactions are important because they help map gene function, and functionally related genes have similar genetic interaction patterns. Mapping quantitative (positive and negative) genetic interactions on a global scale has recently become possible. This data clearly shows groups of genes connected by predominantly positive or negative interactions, termed monochromatic groups. These groups often correspond to functional modules, like biological processes or complexes, or connections between modules. However it is not yet known how these patterns globally relate to known functional modules. Here we systematically study the monochromatic nature of known biological processes using the largest quantitative genetic interaction data set available, which includes fitness measurements for xe2x88xbc5.4 million gene pairs in the yeast Saccharomyces cerevisiae. We find that only 10% of biological processes, as defined by Gene Ontology annotations, and less than 1% of inter-process connections are monochromatic. Further, we show that protein complexes are responsible for a surprisingly large fraction of these patterns. This suggests that complexes play a central role in shaping the monochromatic landscape of biological processes. Altogether this work shows that both positive and negative monochromatic patterns are found in known biological processes and in their connections and that protein complexes play an important role in these patterns. The monochromatic processes, complexes and connections we find chart a hierarchical and modular map of sensitive and redundant biological systems in the yeast cell that will be useful for gene function prediction and comparison across phenotypes and organisms. Furthermore the analysis methods we develop are applicable to other species for which genetic interactions will progressively become more available.'),
(84943, 2011, 'plos', 'Transition from persistent to anti-persistent correlations in postural sway indicates velocity-based control', 'Delignières, Didier|Torre, Kjerstin|Bernard, Pierre-Louis', 'EA 2991 Movement To Health, Montpellier-1 University, Euromov, Montpellier, France. didier.delignieres@univ-montp1.fr|EA 2991 Movement To Health, Montpellier-1 University, Euromov, Montpellier, France. didier.delignieres@univ-montp1.fr|EA 2991 Movement To Health, Montpellier-1 University, Euromov, Montpellier, France. didier.delignieres@univ-montp1.fr', 'France|France|France', 70, 'Age Factors|Fractals|Humans|Male|Normal Distribution|Postural Balance|Posture|Vision, Ocular|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1001089', '21390333', 'The displacement of the center-of-pressure (COP) during quiet stance has often been accounted for by the control of COP position dynamics. In this paper, we discuss the conclusions drawn from previous analyses of COP dynamics using fractal-related methods. On the basis of some methodological clarification and the analysis of experimental data using stabilogram diffusion analysis, detrended fluctuation analysis, and an improved version of spectral analysis, we show that COP velocity is typically bounded between upper and lower limits. We argue that the hypothesis of an intermittent velocity-based control of posture is more relevant than position-based control. A simple model for COP velocity dynamics, based on a bounded correlated random walk, reproduces the main statistical signatures evidenced in the experimental series. The implications of these results are discussed.'),
(84944, 2011, 'plos', 'Automatic design of digital synthetic gene circuits', 'Marchisio, Mario A|Stelling, Jörg', 'Department of Biosystems Science and Engineering and Swiss Institute of Bioinformatics, ETH Zurich, Basel, Switzerland.|Department of Biosystems Science and Engineering and Swiss Institute of Bioinformatics, ETH Zurich, Basel, Switzerland.', 'Switzerland|Switzerland', 63, 'Algorithms|Computational Biology|Computer Simulation|Gene Regulatory Networks|Genes, Synthetic|Models, Genetic|RNA, Messenger|RNA, Small Interfering|Stochastic Processes|Synthetic Biology', 'Journal Article', '10.1371/journal.pcbi.1001083', '21399700', 'De novo computational design of synthetic gene circuits that achieve well-defined target functions is a hard task. Existing, brute-force approaches run optimization algorithms on the structure and on the kinetic parameter values of the network. However, more direct rational methods for automatic circuit design are lacking. Focusing on digital synthetic gene circuits, we developed a methodology and a corresponding tool for in silico automatic design. For a given truth table that specifies a circuits input-output relations, our algorithm generates and ranks several possible circuit schemes without the need for any optimization. Logic behavior is reproduced by the action of regulatory factors and chemicals on the promoters and on the ribosome binding sites of biological Boolean gates. Simulations of circuits with up to four inputs show a faithful and unequivocal truth table representation, even under parametric perturbations and stochastic noise. A comparison with already implemented circuits, in addition, reveals the potential for simpler designs with the same function. Therefore, we expect the method to help both in devising new circuits and in simplifying existing solutions.'),
(84945, 2011, 'plos', 'Training signaling pathway maps to biochemical data with constrained fuzzy logic: quantitative analysis of liver cell responses to inflammatory stimuli', 'Morris, Melody K|Saez-Rodriguez, Julio|Clarke, David C|Sorger, Peter K|Lauffenburger, Douglas A', 'Center for Cell Decision Processes, Massachusetts Institute of Technology and Harvard Medical School, Boston, MA, USA.|Center for Cell Decision Processes, Massachusetts Institute of Technology and Harvard Medical School, Boston, MA, USA.|Center for Cell Decision Processes, Massachusetts Institute of Technology and Harvard Medical School, Boston, MA, USA.|Center for Cell Decision Processes, Massachusetts Institute of Technology and Harvard Medical School, Boston, MA, USA.|Center for Cell Decision Processes, Massachusetts Institute of Technology and Harvard Medical School, Boston, MA, USA.', 'United States|United States|United States|United States|United States', 97, 'Algorithms|Animals|Computational Biology|Computer Simulation|Cytokines|Fuzzy Logic|Hep G2 Cells|Humans|Inflammation Mediators|Liver|Models, Biological|Phosphorylation|Proteins|Rats|Reproducibility of Results|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1001099', '21408212', 'Predictive understanding of cell signaling network operation based on general prior knowledge but consistent with empirical data in a specific environmental context is a current challenge in computational biology. Recent work has demonstrated that Boolean logic can be used to create context-specific network models by training proteomic pathway maps to dedicated biochemical data, however, the Boolean formalism is restricted to characterizing protein species as either fully active or inactive. To advance beyond this limitation, we propose a novel form of fuzzy logic sufficiently flexible to model quantitative data but also sufficiently simple to efficiently construct models by training pathway maps on dedicated experimental measurements. Our new approach, termed constrained fuzzy logic (cFL), converts a prior knowledge network (obtained from literature or interactome databases) into a computable model that describes graded values of protein activation across multiple pathways. We train a cFL-converted network to experimental data describing hepatocytic protein activation by inflammatory cytokines and demonstrate the application of the resultant trained models for three important purposes: (a) generating experimentally testable biological hypotheses concerning pathway crosstalk, (b) establishing capability for quantitative prediction of protein activity, and (c) prediction and understanding of the cytokine release phenotypic response. Our methodology systematically and quantitatively trains a protein pathway map summarizing curated literature to context-specific biochemical data. This process generates a computable model yielding successful prediction of new test data and offering biological insight into complex datasets that are difficult to fully analyze by intuition alone.'),
(84946, 2011, 'plos', 'Quantification of the relative importance of CTL, B cell, NK cell, and target cell limitation in the control of primary SIV-infection', 'Elemans, Marjet|Thiébaut, Rodolphe|Kaur, Amitinder|Asquith, Becca', 'Department of Immunology, Imperial College London, London, United Kingdom. m.elemans@imperial.ac.uk|Department of Immunology, Imperial College London, London, United Kingdom. m.elemans@imperial.ac.uk|Department of Immunology, Imperial College London, London, United Kingdom. m.elemans@imperial.ac.uk|Department of Immunology, Imperial College London, London, United Kingdom. m.elemans@imperial.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Analysis of Variance|Animals|B-Lymphocytes|Bayes Theorem|Cell Death|Computational Biology|Host-Pathogen Interactions|Killer Cells, Natural|Macaca mulatta|Markov Chains|Models, Immunological|Monte Carlo Method|Regression Analysis|Simian Acquired Immunodeficiency Syndrome|Simian Immunodeficiency Virus|T-Lymphocytes, Cytotoxic|Viral Load', 'Journal Article', '10.1371/journal.pcbi.1001103', '21408213', 'CD8+ cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, B cells and target cell limitation have all been suggested to play a role in the control of SIV and HIV-1 infection. However, previous research typically studied each population in isolation leaving the magnitude, relative importance and in vivo relevance of each effect unclear. Here we quantify the relative importance of CTLs, NK cells, B cells and target cell limitation in controlling acute SIV infection in rhesus macaques. Using three different methods, we find that the availability of target cells and CD8+ T cells are important predictors of viral load dynamics. If CTL are assumed to mediate this anti-viral effect via a lytic mechanism then we estimate that CTL killing is responsible for approximately 40% of productively infected cell death, the remaining cell death being attributable to intrinsic, immune (CD8+ T cell, NK cell, B cell) -independent mechanisms. Furthermore, we find that NK cells have little impact on the death rate of infected CD4+ cells and that their net impact is to increase viral load. We hypothesize that NK cells play a detrimental role in SIV infection, possibly by increasing T cell activation.'),
(84947, 2011, 'plos', 'Animal interactions and the emergence of territoriality', 'Giuggioli, Luca|Potts, Jonathan R|Harris, Stephen', 'Bristol Centre for Complexity Sciences, University of Bristol, Bristol, United Kingdom. Luca.Giuggioli@bristol.ac.uk|Bristol Centre for Complexity Sciences, University of Bristol, Bristol, United Kingdom. Luca.Giuggioli@bristol.ac.uk|Bristol Centre for Complexity Sciences, University of Bristol, Bristol, United Kingdom. Luca.Giuggioli@bristol.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Animals|Behavior, Animal|Odorants|Pheromones|Population Density|Territoriality', 'Journal Article', '10.1371/journal.pcbi.1002008', '21423708', 'Inferring the role of interactions in territorial animals relies upon accurate recordings of the behaviour of neighbouring individuals. Such accurate recordings are rarely available from field studies. As a result, quantification of the interaction mechanisms has often relied upon theoretical approaches, which hitherto have been limited to comparisons of macroscopic population-level predictions from un-tested interaction models. Here we present a quantitative framework that possesses a microscopic testable hypothesis on the mechanism of conspecific avoidance mediated by olfactory signals in the form of scent marks. We find that the key parameters controlling territoriality are two: the average territory size, i.e. the inverse of the population density, and the time span during which animal scent marks remain active. Since permanent monitoring of a territorial border is not possible, scent marks need to function in the temporary absence of the resident. As chemical signals carried by the scent only last a finite amount of time, each animal needs to revisit territorial boundaries frequently and refresh its own scent marks in order to deter possible intruders. The size of the territory an animal can maintain is thus proportional to the time necessary for an animal to move between its own territorial boundaries. By using an agent-based model to take into account the possible spatio-temporal movement trajectories of individual animals, we show that the emerging territories are the result of a form of collective animal movement where, different to shoaling, flocking or herding, interactions are highly heterogeneous in space and time. The applicability of our hypothesis has been tested with a prototypical territorial animal, the red fox (Vulpes vulpes).'),
(84948, 2011, 'plos', 'Conformational sampling and nucleotide-dependent transitions of the GroEL subunit probed by unbiased molecular dynamics simulations', 'Skjaerven, Lars|Grant, Barry|Muga, Arturo|Teigen, Knut|McCammon, J Andrew|Reuter, Nathalie|Martinez, Aurora', 'Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Biomedicine, University of Bergen, Bergen, Norway.', 'Norway|Norway|Norway|Norway|Norway|Norway|Norway', 0, 'Binding Sites|Chaperonin 60|Ligands|Models, Molecular|Molecular Dynamics Simulation|Nucleotides|Protein Conformation|Protein Subunits', 'Journal Article', '10.1371/journal.pcbi.1002004', '21423709', 'GroEL is an ATP dependent molecular chaperone that promotes the folding of a large number of substrate proteins in E. coli. Large-scale conformational transitions occurring during the reaction cycle have been characterized from extensive crystallographic studies. However, the link between the observed conformations and the mechanisms involved in the allosteric response to ATP and the nucleotide-driven reaction cycle are not completely established. Here we describe extensive (in total long) unbiased molecular dynamics (MD) simulations that probe the response of GroEL subunits to ATP binding. We observe nucleotide dependent conformational transitions, and show with multiple 100 ns long simulations that the ligand-induced shift in the conformational populations are intrinsically coded in the structure-dynamics relationship of the protein subunit. Thus, these simulations reveal a stabilization of the equatorial domain upon nucleotide binding and a concomitant opening of the subunit, which reaches a conformation close to that observed in the crystal structure of the subunits within the ADP-bound oligomer. Moreover, we identify changes in a set of unique intrasubunit interactions potentially important for the conformational transition.'),
(84949, 2011, 'plos', 'Crawling cells can close wounds without purse strings or signaling', 'Lee, Pilhwa|Wolgemuth, Charles W', 'Department of Cell Biology and Center for Cell Analysis and Modeling, University of Connecticut Health Center, Farmington, Connecticut, United States of America.|Department of Cell Biology and Center for Cell Analysis and Modeling, University of Connecticut Health Center, Farmington, Connecticut, United States of America.', 'United States|United States', 70, 'Cell Line|Cell Movement|Computer Simulation|Cytoskeleton|Epithelial Cells|Signal Transduction|Wound Healing', 'Journal Article', '10.1371/journal.pcbi.1002007', '21423710', 'When a gash or gouge is made in a confluent layer of epithelial cells, the cells move to fill in the wound. In some cases, such as in wounded embryonic chick wing buds, the movement of the cells is driven by cortical actin contraction (i.e., a purse string mechanism). In adult tissue, though, cells apparently crawl to close wounds. At the single cell level, this crawling is driven by the dynamics of the cells actin cytoskeleton, which is regulated by a complex biochemical network, and cell signaling has been proposed to play a significant role in directing cells to move into the denuded area. However, wounds made in monolayers of Madin-Darby canine kidney (MDCK) cells still close even when a row of cells is deactivated at the periphery of the wound, and recent experiments show complex, highly-correlated cellular motions that extend tens of cell lengths away from the boundary. These experiments suggest a dominant role for mechanics in wound healing. Here we present a biophysical description of the collective migration of epithelial cells during wound healing based on the basic motility of single cells and cell-cell interactions. This model quantitatively captures the dynamics of wound closure and reproduces the complex cellular flows that are observed. These results suggest that wound healing is predominantly a mechanical process that is modified, but not produced, by cell-cell signaling.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84950, 2011, 'plos', 'Learning from sensory and reward prediction errors during motor adaptation', 'Izawa, Jun|Shadmehr, Reza', 'Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America. jizawa@jhu.edu|Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America. jizawa@jhu.edu', 'United States|United States', 0, 'Adaptation, Physiological|Adult|Analysis of Variance|Feedback|Feedback, Sensory|Humans|Motor Activity|Psychomotor Performance|Reward|Task Performance and Analysis', 'Journal Article', '10.1371/journal.pcbi.1002012', '21423711', 'Voluntary motor commands produce two kinds of consequences. Initially, a sensory consequence is observed in terms of activity in our primary sensory organs (e.g., vision, proprioception). Subsequently, the brain evaluates the sensory feedback and produces a subjective measure of utility or usefulness of the motor commands (e.g., reward). As a result, comparisons between predicted and observed consequences of motor commands produce two forms of prediction error. How do these errors contribute to changes in motor commands? Here, we considered a reach adaptation protocol and found that when high quality sensory feedback was available, adaptation of motor commands was driven almost exclusively by sensory prediction errors. This form of learning had a distinct signature: as motor commands adapted, the subjects altered their predictions regarding sensory consequences of motor commands, and generalized this learning broadly to neighboring motor commands. In contrast, as the quality of the sensory feedback degraded, adaptation of motor commands became more dependent on reward prediction errors. Reward prediction errors produced comparable changes in the motor commands, but produced no change in the predicted sensory consequences of motor commands, and generalized only locally. Because we found that there was a within subject correlation between generalization patterns and sensory remapping, it is plausible that during adaptation an individuals relative reliance on sensory vs. reward prediction errors could be inferred. We suggest that while motor commands change because of sensory and reward prediction errors, only sensory prediction errors produce a change in the neural system that predicts sensory consequences of motor commands.'),
(84951, 2011, 'plos', 'Accurate and fast simulation of channel noise in conductance-based model neurons by diffusion approximation', 'Linaro, Daniele|Storace, Marco|Giugliano, Michele', 'Biophysical and Electronic Engineering Department, University of Genoa, Genoa, Italy.|Biophysical and Electronic Engineering Department, University of Genoa, Genoa, Italy.|Biophysical and Electronic Engineering Department, University of Genoa, Genoa, Italy.', 'Italy|Italy|Italy', 55, 'Computer Simulation|Ion Channel Gating|Ion Channels|Markov Chains|Membrane Potentials|Models, Neurological|Neurons', 'Journal Article', '10.1371/journal.pcbi.1001102', '21423712', 'Stochastic channel gating is the major source of intrinsic neuronal noise whose functional consequences at the microcircuit- and network-levels have been only partly explored. A systematic study of this channel noise in large ensembles of biophysically detailed model neurons calls for the availability of fast numerical methods. In fact, exact techniques employ the microscopic simulation of the random opening and closing of individual ion channels, usually based on Markov models, whose computational loads are prohibitive for next generation massive computer models of the brain. In this work, we operatively define a procedure for translating any Markov model describing voltage- or ligand-gated membrane ion-conductances into an effective stochastic version, whose computer simulation is efficient, without compromising accuracy. Our approximation is based on an improved Langevin-like approach, which employs stochastic differential equations and no Montecarlo methods. As opposed to an earlier proposal recently debated in the literature, our approximation reproduces accurately the statistical properties of the exact microscopic simulations, under a variety of conditions, from spontaneous to evoked response features. In addition, our method is not restricted to the Hodgkin-Huxley sodium and potassium currents and is general for a variety of voltage- and ligand-gated ion currents. As a by-product, the analysis of the properties emerging in exact Markov schemes by standard probability calculus enables us for the first time to analytically identify the sources of inaccuracy of the previous proposal, while providing solid ground for its modification and improvement we present here.'),
(84952, 2011, 'plos', 'Causal modeling using network ensemble simulations of genetic and gene expression data predicts genes involved in rheumatoid arthritis', 'Xing, Heming|McDonagh, Paul D|Bienkowska, Jadwiga|Cashorali, Tanya|Runge, Karl|Miller, Robert E|Decaprio, Dave|Church, Bruce|Roubenoff, Ronenn|Khalil, Iya G|Carulli, John', 'Gene Network Sciences, Cambridge, Massachusetts, United States of America.|Gene Network Sciences, Cambridge, Massachusetts, United States of America.|Gene Network Sciences, Cambridge, Massachusetts, United States of America.|Gene Network Sciences, Cambridge, Massachusetts, United States of America.|Gene Network Sciences, Cambridge, Massachusetts, United States of America.|Gene Network Sciences, Cambridge, Massachusetts, United States of America.|Gene Network Sciences, Cambridge, Massachusetts, United States of America.|Gene Network Sciences, Cambridge, Massachusetts, United States of America.|Gene Network Sciences, Cambridge, Massachusetts, United States of America.|Gene Network Sciences, Cambridge, Massachusetts, United States of America.|Gene Network Sciences, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Abatacept|Antirheumatic Agents|Arthritis, Rheumatoid|Computer Simulation|Gene Expression|Gene Expression Profiling|Humans|Immunoconjugates|Interleukins|Sphingosine N-Acyltransferase|Tumor Necrosis Factor-alpha', 'Journal Article', '10.1371/journal.pcbi.1001105', '21423713', 'Tumor necrosis factor xcexb1 (TNF-xcexb1) is a key regulator of inflammation and rheumatoid arthritis (RA). TNF-xcexb1 blocker therapies can be very effective for a substantial number of patients, but fail to work in one third of patients who show no or minimal response. It is therefore necessary to discover new molecular intervention points involved in TNF-xcexb1 blocker treatment of rheumatoid arthritis patients. We describe a data analysis strategy for predicting gene expression measures that are critical for rheumatoid arthritis using a combination of comprehensive genotyping, whole blood gene expression profiles and the component clinical measures of the arthritis Disease Activity Score 28 (DAS28) score. Two separate network ensembles, each comprised of 1024 networks, were built from molecular measures from subjects before and 14 weeks after treatment with TNF-xcexb1 blocker. The network ensemble built from pre-treated data captures TNF-xcexb1 dependent mechanistic information, while the ensemble built from data collected under TNF-xcexb1 blocker treatment captures TNF-xcexb1 independent mechanisms. In silico simulations of targeted, personalized perturbations of gene expression measures from both network ensembles identify transcripts in three broad categories. Firstly, 22 transcripts are identified to have new roles in modulating the DAS28 score, secondly, there are 6 transcripts that could be alternative targets to TNF-xcexb1 blocker therapies, including CD86--a component of the signaling axis targeted by Abatacept (CTLA4-Ig), and finally, 59 transcripts that are predicted to modulate the count of tender or swollen joints but not sufficiently enough to have a significant impact on DAS28.'),
(84953, 2011, 'plos', 'Noise driven evolutionary waves', 'Hallatschek, Oskar', 'Biophysics and Evolutionary Dynamics Group, Max-Planck Institute for Dynamics and Self-Organization, Göttingen, Germany. oskar.hallatschek@ds.mpg.de', 'Germany', 0, 'Computer Simulation|Evolution, Molecular|Genetic Drift|Genetics, Population|Mutation|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002005', '21423714', 'Adaptation in spatially extended populations entails the propagation of evolutionary novelties across habitat ranges. Driven by natural selection, beneficial mutations sweep through the population in a wave of advance. The standard model for these traveling waves, due to R. Fisher and A. Kolmogorov, plays an important role in many scientific areas besides evolution, such as ecology, epidemiology, chemical kinetics, and recently even in particle physics. Here, we extend the Fisher-Kolmogorov model to account for mutations that confer an increase in the density of the population, for instance as a result of an improved metabolic efficiency. We show that these mutations invade by the action of random genetic drift, even if the mutations are slightly deleterious. The ensuing class of noise-driven waves are characterized by a wave speed that decreases with increasing population sizes, contrary to conventional Fisher-Kolmogorov waves. When a trade-off exists between density and growth rate, an evolutionary optimal population density can be predicted. Our simulations and analytical results show that genetic drift in conjunction with spatial structure promotes the economical use of limited resources. The simplicity of our model, which lacks any complex interactions between individuals, suggests that noise-induced pattern formation may arise in many complex biological systems including evolution.'),
(84954, 2011, 'plos', 'To lyse or not to lyse: transient-mediated stochastic fate determination in cells infected by bacteriophages', 'Joh, Richard I|Weitz, Joshua S', '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', 0, 'Bacteriophage lambda|Computer Simulation|Gene Expression Regulation, Viral|Gene Regulatory Networks|Lysogeny', 'Journal Article', '10.1371/journal.pcbi.1002006', '21423715', 'Cell fate determination is usually described as the result of the stochastic dynamics of gene regulatory networks (GRNs) reaching one of multiple steady-states each of which corresponds to a specific decision. However, the fate of a cell is determined in finite time suggesting the importance of transient dynamics in cellular decision making. Here we consider cellular decision making as resulting from first passage processes of regulatory proteins and examine the effect of transient dynamics within the initial lysis-lysogeny switch of phage xcexbb. Importantly, the fate of an infected cell depends, in part, on the number of coinfecting phages. Using a quantitative model of the phage xcexbb GRN, we find that changes in the likelihood of lysis and lysogeny can be driven by changes in phage co-infection number regardless of whether or not there exists steady-state bistability within the GRN. Furthermore, two GRNs which yield qualitatively distinct steady state behaviors as a function of phage infection number can show similar transient responses, sufficient for alternative cell fate determination. We compare our model results to a recent experimental study of cell fate determination in single cell assays of multiply infected bacteria. Whereas the experimental study proposed a quasi-independent hypothesis for cell fate determination consistent with an observed data collapse, we demonstrate that observed cell fate results are compatible with an alternative form of data collapse consistent with a partial gene dosage compensation mechanism. We show that including partial gene dosage compensation at the mRNA level in our stochastic model of fate determination leads to the same data collapse observed in the single cell study. Our findings elucidate the importance of transient gene regulatory dynamics in fate determination, and present a novel alternative hypothesis to explain single-cell level heterogeneity within the phage xcexbb lysis-lysogeny decision switch.'),
(84955, 2011, 'plos', 'Noise contributions in an inducible genetic switch: a whole-cell simulation study', 'Roberts, Elijah|Magis, Andrew|Ortiz, Julio O|Baumeister, Wolfgang|Luthey-Schulten, Zaida', 'Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Computer Simulation|Escherichia coli|Lac Operon|Models, Genetic|Phenotype|Regulatory Elements, Transcriptional', 'Journal Article', '10.1371/journal.pcbi.1002010', '21423716', 'Stochastic expression of genes produces heterogeneity in clonal populations of bacteria under identical conditions. We analyze and compare the behavior of the inducible lac genetic switch using well-stirred and spatially resolved simulations for Escherichia coli cells modeled under fast and slow-growth conditions. Our new kinetic model describing the switching of the lac operon from one phenotype to the other incorporates parameters obtained from recently published in vivo single-molecule fluorescence experiments along with in vitro rate constants. For the well-stirred system, investigation of the intrinsic noise in the circuit as a function of the inducer concentration and in the presence/absence of the feedback mechanism reveals that the noise peaks near the switching threshold. Applying maximum likelihood estimation, we show that the analytic two-state model of gene expression can be used to extract stochastic rates from the simulation data. The simulations also provide mRNA-protein probability landscapes, which demonstrate that switching is the result of crossing both mRNA and protein thresholds. Using cryoelectron tomography of an E. coli cell and data from proteomics studies, we construct spatial in vivo models of cells and quantify the noise contributions and effects on repressor rebinding due to cell structure and crowding in the cytoplasm. Compared to systems without spatial heterogeneity, the model for the fast-growth cells predicts a slight decrease in the overall noise and an increase in the repressors rebinding rate due to anomalous subdiffusion. The tomograms for E. coli grown under slow-growth conditions identify the positions of the ribosomes and the condensed nucleoid. The smaller slow-growth cells have increased mRNA localization and a larger internal inducer concentration, leading to a significant decrease in the lifetime of the repressor-operator complex and an increase in the frequency of transcriptional bursts.'),
(84956, 2011, 'plos', 'Genome-scale metabolic modeling elucidates the role of proliferative adaptation in causing the Warburg effect', 'Shlomi, Tomer|Benyamini, Tomer|Gottlieb, Eyal|Sharan, Roded|Ruppin, Eytan', 'Computer Science Department, Technion-Israel Institute of Technology, Haifa, Israel. tomersh@cs.technion.ac.il|Computer Science Department, Technion-Israel Institute of Technology, Haifa, Israel. tomersh@cs.technion.ac.il|Computer Science Department, Technion-Israel Institute of Technology, Haifa, Israel. tomersh@cs.technion.ac.il|Computer Science Department, Technion-Israel Institute of Technology, Haifa, Israel. tomersh@cs.technion.ac.il|Computer Science Department, Technion-Israel Institute of Technology, Haifa, Israel. tomersh@cs.technion.ac.il', 'Israel|Israel|Israel|Israel|Israel', 0, 'Biomass|Cell Proliferation|Energy Metabolism|Gene Expression|Genome, Human|Glutamine|Glycolysis|Humans|Metabolic Networks and Pathways|Neoplasms', 'Journal Article', '10.1371/journal.pcbi.1002018', '21423717', 'The Warburg effect--a classical hallmark of cancer metabolism--is a counter-intuitive phenomenon in which rapidly proliferating cancer cells resort to inefficient ATP production via glycolysis leading to lactate secretion, instead of relying primarily on more efficient energy production through mitochondrial oxidative phosphorylation, as most normal cells do. The causes for the Warburg effect have remained a subject of considerable controversy since its discovery over 80 years ago, with several competing hypotheses. Here, utilizing a genome-scale human metabolic network model accounting for stoichiometric and enzyme solvent capacity considerations, we show that the Warburg effect is a direct consequence of the metabolic adaptation of cancer cells to increase biomass production rate. The analysis is shown to accurately capture a three phase metabolic behavior that is observed experimentally during oncogenic progression, as well as a prominent characteristic of cancer cells involving their preference for glutamine uptake over other amino acids.'),
(84957, 2011, 'plos', 'The role of incoherent microRNA-mediated feedforward loops in noise buffering', 'Osella, Matteo|Bosia, Carla|Corá, Davide|Caselle, Michele', 'Dipartimento di Fisica Teorica and INFN University of Torino, Torino, Italy. mosella@to.infn.it|Dipartimento di Fisica Teorica and INFN University of Torino, Torino, Italy. mosella@to.infn.it|Dipartimento di Fisica Teorica and INFN University of Torino, Torino, Italy. mosella@to.infn.it|Dipartimento di Fisica Teorica and INFN University of Torino, Torino, Italy. mosella@to.infn.it', 'Italy|Italy|Italy|Italy', 164, 'Computational Biology|Gene Expression|Gene Regulatory Networks|MicroRNAs|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1001101', '21423718', 'MicroRNAs are endogenous non-coding RNAs which negatively regulate the expression of protein-coding genes in plants and animals. They are known to play an important role in several biological processes and, together with transcription factors, form a complex and highly interconnected regulatory network. Looking at the structure of this network, it is possible to recognize a few overrepresented motifs which are expected to perform important elementary regulatory functions. Among them, a special role is played by the microRNA-mediated feedforward loop in which a master transcription factor regulates a microRNA and, together with it, a set of target genes. In this paper we show analytically and through simulations that the incoherent version of this motif can couple the fine-tuning of a target protein level with an efficient noise control, thus conferring precision and stability to the overall gene expression program, especially in the presence of fluctuations in upstream regulators. Among the other results, a nontrivial prediction of our model is that the optimal attenuation of fluctuations coincides with a modest repression of the target expression. This feature is coherent with the expected fine-tuning function and in agreement with experimental observations of the actual impact of a wide class of microRNAs on the protein output of their targets. Finally, we describe the impact on noise-buffering efficiency of the cross-talk between microRNA targets that can naturally arise if the microRNA-mediated circuit is not considered as isolated, but embedded in a larger network of regulations.'),
(84958, 2011, 'plos', 'Context-dependent encoding of fear and extinction memories in a large-scale network model of the basal amygdala', 'Vlachos, Ioannis|Herry, Cyril|Lüthi, Andreas|Aertsen, Ad|Kumar, Arvind', 'Bernstein Center for Computational Neuroscience Frieburg, Freiburg, Germany.|Bernstein Center for Computational Neuroscience Frieburg, Freiburg, Germany.|Bernstein Center for Computational Neuroscience Frieburg, Freiburg, Germany.|Bernstein Center for Computational Neuroscience Frieburg, Freiburg, Germany.|Bernstein Center for Computational Neuroscience Frieburg, Freiburg, Germany.', 'Germany|Germany|Germany|Germany|Germany', 0, 'Action Potentials|Amygdala|Animals|Computational Biology|Extinction, Psychological|Fear|Memory|Models, Neurological|Neuronal Plasticity|Neurons|Rodentia|Synapses', 'Journal Article', '10.1371/journal.pcbi.1001104', '21437238', 'The basal nucleus of the amygdala (BA) is involved in the formation of context-dependent conditioned fear and extinction memories. To understand the underlying neural mechanisms we developed a large-scale neuron network model of the BA, composed of excitatory and inhibitory leaky-integrate-and-fire neurons. Excitatory BA neurons received conditioned stimulus (CS)-related input from the adjacent lateral nucleus (LA) and contextual input from the hippocampus or medial prefrontal cortex (mPFC). We implemented a plasticity mechanism according to which CS and contextual synapses were potentiated if CS and contextual inputs temporally coincided on the afferents of the excitatory neurons. Our simulations revealed a differential recruitment of two distinct subpopulations of BA neurons during conditioning and extinction, mimicking the activation of experimentally observed cell populations. We propose that these two subgroups encode contextual specificity of fear and extinction memories, respectively. Mutual competition between them, mediated by feedback inhibition and driven by contextual inputs, regulates the activity in the central amygdala (CEA) thereby controlling amygdala output and fear behavior. The model makes multiple testable predictions that may advance our understanding of fear and extinction memories.'),
(84959, 2011, 'plos', 'Frequency-invariant representation of interaural time differences in mammals', 'Lxc3xbcling, Hannes|Siveke, Ida|Grothe, Benedikt|Leibold, Christian', 'Department of Biology II, Ludwig-Maximilians Universitxc3xa4t Mxc3xbcnchen, Planegg-Martinsried, Germany.|Department of Biology II, Ludwig-Maximilians Universitxc3xa4t Mxc3xbcnchen, Planegg-Martinsried, Germany.|Department of Biology II, Ludwig-Maximilians Universitxc3xa4t Mxc3xbcnchen, Planegg-Martinsried, Germany.|Department of Biology II, Ludwig-Maximilians Universitxc3xa4t Mxc3xbcnchen, Planegg-Martinsried, Germany.', 'Germany|Germany|Germany|Germany', 16, 'Algorithms|Animals|Brain Stem|Evoked Potentials, Auditory, Brain Stem|Female|Gerbillinae|Linear Models|Male|Models, Neurological|Models, Statistical|Neurons|Normal Distribution|Poisson Distribution|Sound Localization|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1002013', '21445227', 'Interaural time differences (ITDs) are the major cue for localizing low-frequency sounds. The activity of neuronal populations in the brainstem encodes ITDs with an exquisite temporal acuity of about 10 xcexbcs. The response of single neurons, however, also changes with other stimulus properties like the spectral composition of sound. The influence of stimulus frequency is very different across neurons and thus it is unclear how ITDs are encoded independently of stimulus frequency by populations of neurons. Here we fitted a statistical model to single-cell rate responses of the dorsal nucleus of the lateral lemniscus. The model was used to evaluate the impact of single-cell response characteristics on the frequency-invariant mutual information between rate response and ITD. We found a rough correspondence between the measured cell characteristics and those predicted by computing mutual information. Furthermore, we studied two readout mechanisms, a linear classifier and a two-channel rate difference decoder. The latter turned out to be better suited to decode the population patterns obtained from the fitted model.'),
(84960, 2011, 'plos', 'Simulated epidemics in an empirical spatiotemporal network of 50,185 sexual contacts', 'Rocha, Luis E C|Liljeros, Fredrik|Holme, Petter', 'IceLab, Department of Physics, Umeå University, Umeå, Sweden. luis.rocha@tp.umu.se|IceLab, Department of Physics, Umeå University, Umeå, Sweden. luis.rocha@tp.umu.se|IceLab, Department of Physics, Umeå University, Umeå, Sweden. luis.rocha@tp.umu.se', 'Sweden|Sweden|Sweden', 172, 'Brazil|Computer Simulation|Disease Outbreaks|Female|Humans|Internet|Male|Models, Biological|Models, Statistical|Sex Work|Sexual Partners|Sexually Transmitted Diseases', 'Journal Article', '10.1371/journal.pcbi.1001109', '21445228', 'Sexual contact patterns, both in their temporal and network structure, can influence the spread of sexually transmitted infections (STI). Most previous literature has focused on effects of network topology, few studies have addressed the role of temporal structure. We simulate disease spread using SI and SIR models on an empirical temporal network of sexual contacts in high-end prostitution. We compare these results with several other approaches, including randomization of the data, classic mean-field approaches, and static network simulations. We observe that epidemic dynamics in this contact structure have well-defined, rather high epidemic thresholds. Temporal effects create a broad distribution of outbreak sizes, even if the per-contact transmission probability is taken to its hypothetical maximum of 100%. In general, we conclude that the temporal correlations of our network accelerate outbreaks, especially in the early phase of the epidemics, while the network topology (apart from the contact-rate distribution) slows them down. We find that the temporal correlations of sexual contacts can significantly change simulated outbreaks in a large empirical sexual network. Thus, temporal structures are needed alongside network topology to fully understand the spread of STIs. On a side note, our simulations further suggest that the specific type of commercial sex we investigate is not a reservoir of major importance for HIV.'),
(84961, 2011, 'plos', 'Dynamic phenotypic clustering in noisy ecosystems', 'Ernebjerg, Morten|Kishony, Roy', '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', 0, 'Algorithms|Cluster Analysis|Computational Biology|Ecosystem|Microbial Interactions|Models, Biological|Phenotype|Soil Microbiology', 'Journal Article', '10.1371/journal.pcbi.1002017', '21445229', 'In natural ecosystems, hundreds of species typically share the same environment and are connected by a dense network of interactions such as predation or competition for resources. Much is known about how fixed ecological niches can determine species abundances in such systems, but far less attention has been paid to patterns of abundances in randomly varying environments. Here, we study this question in a simple model of competition between many species in a patchy ecosystem with randomly fluctuating environmental conditions. Paradoxically, we find that introducing noise can actually induce ordered patterns of abundance-fluctuations, leading to a distinct periodic variation in the correlations between species as a function of the phenotypic distance between them, here, difference in growth rate. This is further accompanied by the formation of discrete, dynamic clusters of abundant species along this otherwise continuous phenotypic axis. These ordered patterns depend on the collective behavior of many species, they disappear when only individual or pairs of species are considered in isolation. We show that they arise from a balance between the tendency of shared environmental noise to synchronize species abundances and the tendency for competition among species to make them fluctuate out of step. Our results demonstrate that in highly interconnected ecosystems, noise can act as an ordering force, dynamically generating ecological patterns even in environments lacking explicit niches.'),
(84962, 2011, 'plos', 'A compact statistical model of the song syntax in Bengalese finch', 'Jin, Dezhe Z|Kozhevnikov, Alexay A', 'Department of Physics, The Pennsylvania State University, University Park, Pennsylvania, United States of America. djin@phys.psu.edu|Department of Physics, The Pennsylvania State University, University Park, Pennsylvania, United States of America. djin@phys.psu.edu', 'United States|United States', 36, 'Animals|Finches|Markov Chains|Models, Biological|Models, Statistical|Music|Sound Spectrography|Vocalization, Animal', 'Journal Article', '10.1371/journal.pcbi.1001108', '21445230', 'Songs of many songbird species consist of variable sequences of a finite number of syllables. A common approach for characterizing the syntax of these complex syllable sequences is to use transition probabilities between the syllables. This is equivalent to the Markov model, in which each syllable is associated with one state, and the transition probabilities between the states do not depend on the state transition history. Here we analyze the song syntax in Bengalese finch. We show that the Markov model fails to capture the statistical properties of the syllable sequences. Instead, a state transition model that accurately describes the statistics of the syllable sequences includes adaptation of the self-transition probabilities when states are revisited consecutively, and allows associations of more than one state to a given syllable. Such a model does not increase the model complexity significantly. Mathematically, the model is a partially observable Markov model with adaptation (POMMA). The success of the POMMA supports the branching chain network model of how syntax is controlled within the premotor song nucleus HVC, but also suggests that adaptation and many-to-one mapping from the syllable-encoding chain networks in HVC to syllables should be included in the network model.'),
(84963, 2011, 'plos', 'Human leg model predicts ankle muscle-tendon morphology, state, roles and energetics in walking', 'Krishnaswamy, Pavitra|Brown, Emery N|Herr, Hugh M', 'Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States', 39, 'Algorithms|Ankle|Bayes Theorem|Biomechanical Phenomena|Computational Biology|Electromyography|Gait|Humans|Leg|Male|Models, Anatomic|Models, Biological|Musculoskeletal Physiological Phenomena|Walking', 'Journal Article', '10.1371/journal.pcbi.1001107', '21445231', 'A common feature in biological neuromuscular systems is the redundancy in joint actuation. Understanding how these redundancies are resolved in typical joint movements has been a long-standing problem in biomechanics, neuroscience and prosthetics. Many empirical studies have uncovered neural, mechanical and energetic aspects of how humans resolve these degrees of freedom to actuate leg joints for common tasks like walking. However, a unifying theoretical framework that explains the many independent empirical observations and predicts individual muscle and tendon contributions to joint actuation is yet to be established. Here we develop a computational framework to address how the ankle joint actuation problem is resolved by the neuromuscular system in walking. Our framework is founded upon the proposal that a consideration of both neural control and leg muscle-tendon morphology is critical to obtain predictive, mechanistic insight into individual muscle and tendon contributions to joint actuation. We examine kinetic, kinematic and electromyographic data from healthy walking subjects to find that human leg muscle-tendon morphology and neural activations enable a metabolically optimal realization of biological ankle mechanics in walking. This optimal realization (a) corresponds to independent empirical observations of operation and performance of the soleus and gastrocnemius muscles, (b) gives rise to an efficient load-sharing amongst ankle muscle-tendon units and (c) causes soleus and gastrocnemius muscle fibers to take on distinct mechanical roles of force generation and power production at the end of stance phase in walking. The framework outlined here suggests that the dynamical interplay between leg structure and neural control may be key to the high walking economy of humans, and has implications as a means to obtain insight into empirically inaccessible features of individual muscle and tendons in biomechanical tasks.'),
(84964, 2011, 'plos', 'No need for a cognitive map: decentralized memory for insect navigation', 'Cruse, Holk|Wehner, Rüdiger', 'Biological Cybernetics, and Center for Excellence CITEC, University of Bielefeld, Bielefeld, Germany. Holk.Cruse@Uni-Bielefeld.de|Biological Cybernetics, and Center for Excellence CITEC, University of Bielefeld, Bielefeld, Germany. Holk.Cruse@Uni-Bielefeld.de', 'Germany|Germany', 0, 'Animals|Ants|Appetitive Behavior|Bees|Computational Biology|Homing Behavior|Memory|Models, Biological|Space Perception', 'Journal Article', '10.1371/journal.pcbi.1002009', '21445233', 'In many animals the ability to navigate over long distances is an important prerequisite for foraging. For example, it is widely accepted that desert ants and honey bees, but also mammals, use path integration for finding the way back to their home site. It is however a matter of a long standing debate whether animals in addition are able to acquire and use so called cognitive maps. Such a map, a global spatial representation of the foraging area, is generally assumed to allow the animal to find shortcuts between two sites although the direct connection has never been travelled before. Using the artificial neural network approach, here we develop an artificial memory system which is based on path integration and various landmark guidance mechanisms (a bank of individual and independent landmark-defined memory elements). Activation of the individual memory elements depends on a separate motivation network and an, in part, asymmetrical lateral inhibition network. The information concerning the absolute position of the agent is present, but resides in a separate memory that can only be used by the path integration subsystem to control the behaviour, but cannot be used for computational purposes with other memory elements of the system. Thus, in this simulation there is no neural basis of a cognitive map. Nevertheless, an agent controlled by this network is able to accomplish various navigational tasks known from ants and bees and often discussed as being dependent on a cognitive map. For example, map-like behaviour as observed in honey bees arises as an emergent property from a decentralized system. This behaviour thus can be explained without referring to the assumption that a cognitive map, a coherent representation of foraging space, must exist. We hypothesize that the proposed network essentially resides in the mushroom bodies of the insect brain.'),
(84965, 2011, 'plos', 'A Granger causality measure for point process models of ensemble neural spiking activity', 'Kim, Sanggyun|Putrino, David|Ghosh, Soumya|Brown, Emery N', 'Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. sgkim@neurostat.mit.edu|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. sgkim@neurostat.mit.edu|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. sgkim@neurostat.mit.edu|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. sgkim@neurostat.mit.edu', 'United States|United States|United States|United States', 124, 'Action Potentials|Animals|Brain|Cats|Likelihood Functions|Models, Neurological|Nerve Net|Neurons', 'Journal Article', '10.1371/journal.pcbi.1001110', '21455283', 'The ability to identify directional interactions that occur among multiple neurons in the brain is crucial to an understanding of how groups of neurons cooperate in order to generate specific brain functions. However, an optimal method of assessing these interactions has not been established. Granger causality has proven to be an effective method for the analysis of the directional interactions between multiple sets of continuous-valued data, but cannot be applied to neural spike train recordings due to their discrete nature. This paper proposes a point process framework that enables Granger causality to be applied to point process data such as neural spike trains. The proposed framework uses the point process likelihood function to relate a neurons spiking probability to possible covariates, such as its own spiking history and the concurrent activity of simultaneously recorded neurons. Granger causality is assessed based on the relative reduction of the point process likelihood of one neuron obtained excluding one of its covariates compared to the likelihood obtained using all of its covariates. The method was tested on simulated data, and then applied to neural activity recorded from the primary motor cortex (MI) of a Felis catus subject. The interactions present in the simulated data were predicted with a high degree of accuracy, and when applied to the real neural data, the proposed method identified causal relationships between many of the recorded neurons. This paper proposes a novel method that successfully applies Granger causality to point process data, and has the potential to provide unique physiological insights when applied to neural spike trains.'),
(84966, 2011, 'plos', 'Minimal models of multidimensional computations', 'Fitzgerald, Jeffrey D|Sincich, Lawrence C|Sharpee, Tatyana O', 'Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America.|Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America.|Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America.', 'United States|United States|United States', 24, 'Action Potentials|Artificial Intelligence|Computer Simulation|Entropy|Models, Neurological|Neurons', 'Journal Article', '10.1371/journal.pcbi.1001111', '21455284', 'The multidimensional computations performed by many biological systems are often characterized with limited information about the correlations between inputs and outputs. Given this limitation, our approach is to construct the maximum noise entropy response function of the system, leading to a closed-form and minimally biased model consistent with a given set of constraints on the input/output moments, the result is equivalent to conditional random field models from machine learning. For systems with binary outputs, such as neurons encoding sensory stimuli, the maximum noise entropy models are logistic functions whose arguments depend on the constraints. A constraint on the average output turns the binary maximum noise entropy models into minimum mutual information models, allowing for the calculation of the information content of the constraints and an information theoretic characterization of the systems computations. We use this approach to analyze the nonlinear input/output functions in macaque retina and thalamus, although these systems have been previously shown to be responsive to two input dimensions, the functional form of the response function in this reduced space had not been unambiguously identified. A second order model based on the logistic function is found to be both necessary and sufficient to accurately describe the neural responses to naturalistic stimuli, accounting for an average of 93% of the mutual information with a small number of parameters. Thus, despite the fact that the stimulus is highly non-Gaussian, the vast majority of the information in the neural responses is related to first and second order correlations. Our results suggest a principled and unbiased way to model multidimensional computations and determine the statistics of the inputs that are being encoded in the outputs.'),
(84967, 2011, 'plos', 'Molecular mechanism of cyclodextrin mediated cholesterol extraction', 'Lxc3xb3pez, Cesar A|de Vries, Alex H|Marrink, Siewert J', 'Groningen Biomolecular Sciences and Biotechnology Institute & Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands.|Groningen Biomolecular Sciences and Biotechnology Institute & Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands.|Groningen Biomolecular Sciences and Biotechnology Institute & Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands.', 'Netherlands|Netherlands|Netherlands', 105, 'Cholesterol|Cyclodextrins|Kinetics|Models, Molecular|Molecular Dynamics Simulation|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002020', '21455285', 'The depletion of cholesterol from membranes, mediated by xcexb2-cyclodextrin (xcexb2-CD) is well known and documented, but the molecular details of this process are largely unknown. Using molecular dynamics simulations, we have been able to study the CD mediated extraction of cholesterol from model membranes, in particular from a pure cholesterol monolayer, at atomic resolution. Our results show that efficient cholesterol extraction depends on the structural distribution of the CDs on the surface of the monolayer. With a suitably oriented dimer, cholesterol is extracted spontaneously on a nanosecond time scale. Additional free energy calculations reveal that the CDs have a strong affinity to bind to the membrane surface, and, by doing so, destabilize the local packing of cholesterol molecules making their extraction favorable. Our results have implications for the interpretation of experimental measurements, and may help in the rational design of efficient CD based nano-carriers.'),
(84968, 2011, 'plos', 'Fluctuograms reveal the intermittent intra-protein communication in subtilisin Carlsberg and correlate mechanical coupling with co-evolution', 'Silvestre-Ryan, Jordi|Lin, Yuchun|Chu, Jhih-Wei', 'Department of Bioengineering, University of California, Berkeley, Berkeley, California, United States of America.|Department of Bioengineering, University of California, Berkeley, Berkeley, California, United States of America.|Department of Bioengineering, University of California, Berkeley, Berkeley, California, United States of America.', 'United States|United States|United States', 17, 'Binding Sites|Calcium|Models, Molecular|Molecular Dynamics Simulation|Molecular Sequence Data|Mutation|Protein Conformation|Sequence Alignment|Subtilisins', 'Journal Article', '10.1371/journal.pcbi.1002023', '21455286', 'The mechanism of intra-protein communication and allosteric coupling is key to understanding the structure-property relationship of protein function. For subtilisin Carlsberg, the Ca²+-binding loop is distal to substrate-binding and active sites, yet the serine protease function depends on Ca²+ binding. The atomic molecular dynamics (MD) simulations of apo and Ca²+-bound subtilisin show similar structures and there is no direct evidence that subtilisin has alternative conformations. To model the intra-protein communication due to Ca²+ binding, we transform the sequential segments of an atomic MD trajectory into separate elastic network models to represent anharmonicity and nonlinearity effectively as the temporal and spatial variation of the mechanical coupling network. In analogy to the spectrogram of sound waves, this transformation is termed the fluctuogram of protein dynamics. We illustrate that the Ca²+-bound and apo states of subtilisin have different fluctuograms and that intra-protein communication proceeds intermittently both in space and in time. We found that residues with large mechanical coupling variation due to Ca²+ binding correlate with the reported mutation sites selected by directed evolution for improving the stability of subtilisin and its activity in a non-aqueous environment. Furthermore, we utilize the fluctuograms calculated from MD to capture the highly correlated residues in a multiple sequence alignment. We show that in addition to the magnitude, the variance of coupling strength is also an indicative property for the sequence correlation observed in a statistical coupling analysis. The results of this work illustrate that the mechanical coupling networks calculated from atomic details can be used to correlate with functionally important mutation sites and co-evolution.'),
(84969, 2011, 'plos', 'On the origin of DNA genomes: evolution of the division of labor between template and catalyst in model replicator systems', 'Takeuchi, Nobuto|Hogeweg, Paulien|Koonin, Eugene V', 'National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America. takeuchi@ncbi.nlm.nih.gov|National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America. takeuchi@ncbi.nlm.nih.gov|National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America. takeuchi@ncbi.nlm.nih.gov', 'United States|United States|United States', 38, 'DNA|DNA Replication|Evolution, Molecular|Genome|Models, Genetic|RNA|Templates, Genetic|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002024', '21455287', 'The division of labor between template and catalyst is a fundamental property of all living systems: DNA stores genetic information whereas proteins function as catalysts. The RNA world hypothesis, however, posits that, at the earlier stages of evolution, RNA acted as both template and catalyst. Why would such division of labor evolve in the RNA world? We investigated the evolution of DNA-like molecules, i.e. molecules that can function only as template, in minimal computational models of RNA replicator systems. In the models, RNA can function as both template-directed polymerase and template, whereas DNA can function only as template. Two classes of models were explored. In the surface models, replicators are attached to surfaces with finite diffusion. In the compartment models, replicators are compartmentalized by vesicle-like boundaries. Both models displayed the evolution of DNA and the ensuing division of labor between templates and catalysts. In the surface model, DNA provides the advantage of greater resistance against parasitic templates. However, this advantage is at least partially offset by the disadvantage of slower multiplication due to the increased complexity of the replication cycle. In the compartment model, DNA can significantly delay the intra-compartment evolution of RNA towards catalytic deterioration. These results are explained in terms of the trade-off between template and catalyst that is inherent in RNA-only replication cycles: DNA releases RNA from this trade-off by making it unnecessary for RNA to serve as template and so rendering the system more resistant against evolving parasitism. Our analysis of these simple models suggests that the lack of catalytic activity in DNA by itself can generate a sufficient selective advantage for RNA replicator systems to produce DNA. Given the widespread notion that DNA evolved owing to its superior chemical properties as a template, this study offers a novel insight into the evolutionary origin of DNA.');
