INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86005, 2013, 'plos', 'Phosphorylation of the retinoic acid receptor alpha induces a mechanical allosteric regulation and changes in internal dynamics', 'Chebaro, Yassmine|Amal, Ismail|Rochel, Natacha|Rochette-Egly, Cxc3xa9cile|Stote, Roland H|Dejaegere, Annick', 'Institute of Genetics and Molecular and Cellular Biology, Integrated Structural Biology Department, Illkirch, France.|Institute of Genetics and Molecular and Cellular Biology, Integrated Structural Biology Department, Illkirch, France.|Institute of Genetics and Molecular and Cellular Biology, Integrated Structural Biology Department, Illkirch, France.|Institute of Genetics and Molecular and Cellular Biology, Integrated Structural Biology Department, Illkirch, France.|Institute of Genetics and Molecular and Cellular Biology, Integrated Structural Biology Department, Illkirch, France.|Institute of Genetics and Molecular and Cellular Biology, Integrated Structural Biology Department, Illkirch, France.', 'France|France|France|France|France|France', 0, 'Allosteric Regulation|Allosteric Site|Animals|Binding Sites|Cell Nucleus|Computer Simulation|Crystallography, X-Ray|Cyclin H|Gene Expression Regulation|Ligands|Mice|Phosphorylation|Protein Binding|Protein Structure, Secondary|Receptors, Retinoic Acid|Retinoic Acid Receptor alpha|Salts|Serine|Signal Transduction|Solvents|Transcriptional Activation|Tretinoin', 'Journal Article', '10.1371/journal.pcbi.1003012', '23637584', 'Nuclear receptor proteins constitute a superfamily of proteins that function as ligand dependent transcription factors. They are implicated in the transcriptional cascades underlying many physiological phenomena, such as embryogenesis, cell growth and differentiation, and apoptosis, making them one of the major signal transduction paradigms in metazoans. Regulation of these receptors occurs through the binding of hormones, and in the case of the retinoic acid receptor (RAR), through the binding of retinoic acid (RA). In addition to this canonical scenario of RAR activity, recent discoveries have shown that RAR regulation also occurs as a result of phosphorylation. In fact, RA induces non-genomic effects, such as the activation of kinase signaling pathways, resulting in the phosphorylation of several targets including RARs themselves. In the case of RARxcexb1, phosphorylation of Ser369 located in loop L9-10 of the ligand-binding domain leads to an increase in the affinity for the protein cyclin H, which is part of the Cdk-activating kinase complex of the general transcription factor TFIIH. The cyclin H binding site in RARxcexb1 is situated more than 40 xc3x85 from the phosphorylated serine. Using molecular dynamics simulations of the unphosphorylated and phosphorylated forms of the receptor RARxcexb1, we analyzed the structural implications of receptor phosphorylation, which led to the identification of a structural mechanism for the allosteric coupling between the two remote sites of interest. The results show that phosphorylation leads to a reorganization of a local salt bridge network, which induces changes in helix extension and orientation that affects the cyclin H binding site. This results in changes in conformation and flexibility of the latter. The high conservation of the residues implicated in this signal transduction suggests a mechanism that could be applied to other nuclear receptor proteins.'),
(86006, 2013, 'plos', 'Biomarker discovery by sparse canonical correlation analysis of complex clinical phenotypes of tuberculosis and malaria', 'Rousu, Juho|Agranoff, Daniel D|Sodeinde, Olugbemiro|Shawe-Taylor, John|Fernandez-Reyes, Delmiro', 'Helsinki Institute for Information Technology, Department of Information and Computer Science, Aalto University, Espoo, Finland.|Helsinki Institute for Information Technology, Department of Information and Computer Science, Aalto University, Espoo, Finland.|Helsinki Institute for Information Technology, Department of Information and Computer Science, Aalto University, Espoo, Finland.|Helsinki Institute for Information Technology, Department of Information and Computer Science, Aalto University, Espoo, Finland.|Helsinki Institute for Information Technology, Department of Information and Computer Science, Aalto University, Espoo, Finland.', 'Finland|Finland|Finland|Finland|Finland', 0, 'Algorithms|Biomarkers|Computational Biology|Genomics|Humans|Malaria|Phenotype|Proteomics|Reproducibility of Results|Tuberculosis', 'Journal Article', '10.1371/journal.pcbi.1003018', '23637585', 'Biomarker discovery aims to find small subsets of relevant variables in omics data that correlate with the clinical syndromes of interest. Despite the fact that clinical phenotypes are usually characterized by a complex set of clinical parameters, current computational approaches assume univariate targets, e.g. diagnostic classes, against which associations are sought for. We propose an approach based on asymmetrical sparse canonical correlation analysis (SCCA) that finds multivariate correlations between the omics measurements and the complex clinical phenotypes. We correlated plasma proteomics data to multivariate overlapping complex clinical phenotypes from tuberculosis and malaria datasets. We discovered relevant omic biomarkers that have a high correlation to profiles of clinical measurements and are remarkably sparse, containing 1.5-3% of all omic variables. We show that using clinical view projections we obtain remarkable improvements in diagnostic class prediction, up to 11% in tuberculosis and up to 5% in malaria. Our approach finds proteomic-biomarkers that correlate with complex combinations of clinical-biomarkers. Using the clinical-biomarkers improves the accuracy of diagnostic class prediction while not requiring the measurement plasma proteomic profiles of each subject. Our approach makes it feasible to use omics data to build accurate diagnostic algorithms that can be deployed to community health centres lacking the expensive omics measurement capabilities.'),
(86007, 2013, 'plos', 'Malarias missing number: calculating the human component of R0 by a within-host mechanistic model of Plasmodium falciparum infection and transmission', 'Johnston, Geoffrey L|Smith, David L|Fidock, David A', 'Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York, USA.|Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York, USA.|Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York, USA.', 'United States|United States|United States', 35, 'Algorithms|Animals|Anopheles|Antimalarials|Computational Biology|Computer Simulation|Erythrocytes|Humans|Malaria, Falciparum|Models, Theoretical|Plasmodium falciparum|Software|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1003025', '23637586', 'Human infection by malarial parasites of the genus Plasmodium begins with the bite of an infected Anopheles mosquito. Current estimates place malaria mortality at over 650,000 individuals each year, mostly in African children. Efforts to reduce disease burden can benefit from the development of mathematical models of disease transmission. To date, however, comprehensive modeling of the parameters defining human infectivity to mosquitoes has remained elusive. Here, we describe a mechanistic within-host model of Plasmodium falciparum infection in humans and pathogen transmission to the mosquito vector. Our model incorporates the entire parasite lifecycle, including the intra-erythrocytic asexual forms responsible for disease, the onset of symptoms, the development and maturation of intra-erythrocytic gametocytes that are transmissible to Anopheles mosquitoes, and human-to-mosquito infectivity. These model components were parameterized from malaria therapy data and other studies to simulate individual infections, and the ensemble of outputs was found to reproduce the full range of patient responses to infection. Using this model, we assessed human infectivity over the course of untreated infections and examined the effects in relation to transmission intensity, expressed by the basic reproduction number R0 (defined as the number of secondary cases produced by a single typical infection in a completely susceptible population). Our studies predict that net human-to-mosquito infectivity from a single non-immune individual is on average equal to 32 fully infectious days. This estimate of mean infectivity is equivalent to calculating the human component of malarial R0 . We also predict that mean daily infectivity exceeds five percent for approximately 138 days. The mechanistic framework described herein, made available as stand-alone software, will enable investigators to conduct detailed studies into theories of malaria control, including the effects of drug treatment and drug resistance on transmission.'),
(86008, 2013, 'plos', 'Semi-automated 3D leaf reconstruction and analysis of trichome patterning from light microscopic images', 'Failmezger, Henrik|Jaegle, Benjamin|Schrader, Andrea|Hülskamp, Martin|Tresch, Achim', 'Max Planck Institute for Plant Breeding Research, Cologne, Germany.|Max Planck Institute for Plant Breeding Research, Cologne, Germany.|Max Planck Institute for Plant Breeding Research, Cologne, Germany.|Max Planck Institute for Plant Breeding Research, Cologne, Germany.|Max Planck Institute for Plant Breeding Research, Cologne, Germany.', 'Germany|Germany|Germany|Germany|Germany', 0, 'Arabidopsis|Arabidopsis Proteins|Automation|Cell Differentiation|Computational Biology|Computer Graphics|Genes, Plant|Image Processing, Computer-Assisted|Imaging, Three-Dimensional|Mutation|Phenotype|Plant Epidermis|Plant Leaves|Software|Trichomes', 'Journal Article', '10.1371/journal.pcbi.1003029', '23637587', 'Trichomes are leaf hairs that are formed by single cells on the leaf surface. They are known to be involved in pathogen resistance. Their patterning is considered to emerge from a field of initially equivalent cells through the action of a gene regulatory network involving trichome fate promoting and inhibiting factors. For a quantitative analysis of single and double mutants or the phenotypic variation of patterns in different ecotypes, it is imperative to statistically evaluate the pattern reliably on a large number of leaves. Here we present a method that enables the analysis of trichome patterns at early developmental leaf stages and the automatic analysis of various spatial parameters. We focus on the most challenging young leaf stages that require the analysis in three dimensions, as the leaves are typically not flat. Our software TrichEratops reconstructs 3D surface models from 2D stacks of conventional light-microscope pictures. It allows the GUI-based annotation of different stages of trichome development, which can be analyzed with respect to their spatial distribution to capture trichome patterning events. We show that 3D modeling removes biases of simpler 2D models and that novel trichome patterning features increase the sensitivity for inter-accession comparisons.'),
(86009, 2013, 'plos', 'Learning multisensory integration and coordinate transformation via density estimation', 'Makin, Joseph G|Fellows, Matthew R|Sabes, Philip N', 'Department of Physiology and the Center for Integrative Neuroscience, University of California San Francisco, San Francisco, California, USA. makin@phy.ucsf.edu|Department of Physiology and the Center for Integrative Neuroscience, University of California San Francisco, San Francisco, California, USA. makin@phy.ucsf.edu|Department of Physiology and the Center for Integrative Neuroscience, University of California San Francisco, San Francisco, California, USA. makin@phy.ucsf.edu', 'United States|United States|United States', 0, 'Algorithms|Animals|Brain|Cues|Humans|Learning|Models, Neurological|Normal Distribution|Photic Stimulation|Poisson Distribution|Probability|Sensation|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1003035', '23637588', 'Sensory processing in the brain includes three key operations: multisensory integration-the task of combining cues into a single estimate of a common underlying stimulus, coordinate transformations-the change of reference frame for a stimulus (e.g., retinotopic to body-centered) effected through knowledge about an intervening variable (e.g., gaze position), and the incorporation of prior information. Statistically optimal sensory processing requires that each of these operations maintains the correct posterior distribution over the stimulus. Elements of this optimality have been demonstrated in many behavioral contexts in humans and other animals, suggesting that the neural computations are indeed optimal. That the relationships between sensory modalities are complex and plastic further suggests that these computations are learned-but how? We provide a principled answer, by treating the acquisition of these mappings as a case of density estimation, a well-studied problem in machine learning and statistics, in which the distribution of observed data is modeled in terms of a set of fixed parameters and a set of latent variables. In our case, the observed data are unisensory-population activities, the fixed parameters are synaptic connections, and the latent variables are multisensory-population activities. In particular, we train a restricted Boltzmann machine with the biologically plausible contrastive-divergence rule to learn a range of neural computations not previously demonstrated under a single approach: optimal integration, encoding of priors, hierarchical integration of cues, learning when not to integrate, and coordinate transformation. The model makes testable predictions about the nature of multisensory representations.'),
(86010, 2013, 'plos', 'The evolution of collective restraint: policing and obedience among non-conjugative plasmids', 'Kentzoglanakis, Kyriakos|García López, Diana|Brown, Sam P|Goldstein, Richard A', 'Division of Mathematical Biology, MRC National Institute of Medical Research, London, United Kingdom.|Division of Mathematical Biology, MRC National Institute of Medical Research, London, United Kingdom.|Division of Mathematical Biology, MRC National Institute of Medical Research, London, United Kingdom.|Division of Mathematical Biology, MRC National Institute of Medical Research, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 2, 'Algorithms|Biological Evolution|Biomass|Computational Biology|Computer Simulation|DNA Replication|Gene Dosage|Models, Genetic|Plasmids|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1003036', '23637589', 'The repression of competition by mechanisms of policing is now recognized as a major force in the maintenance of cooperation. General models on the evolution of policing have focused on the interplay between individual competitiveness and mutual policing, demonstrating a positive relationship between within-group diversity and levels of policing. We expand this perspective by investigating what is possibly the simplest example of reproductive policing: copy number control (CNC) among non-conjugative plasmids, a class of extra-chromosomal vertically transmitted molecular symbionts of bacteria. Through the formulation and analysis of a multi-scale dynamical model, we show that the establishment of stable reproductive restraint among plasmids requires the co-evolution of two fundamental plasmid traits: policing, through the production of plasmid-coded trans-acting replication inhibitors, and obedience, expressed as the binding affinity of plasmid-specific targets to those inhibitors. We explain the intrinsic replication instabilities that arise in the absence of policing and we show how these instabilities are resolved by the evolution of copy number control. Increasing levels of policing and obedience lead to improvements in group performance due to tighter control of local population size (plasmid copy number), delivering benefits both to plasmids, by reducing the risk of segregational loss and to the plasmid-host partnership, by increasing the rate of cell reproduction, and therefore plasmid vertical transmission.'),
(86011, 2013, 'plos', 'Human germline antibody gene segments encode polyspecific antibodies', 'Willis, Jordan R|Briney, Bryan S|DeLuca, Samuel L|Crowe, James E|Meiler, Jens', 'Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA.|Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA.|Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA.|Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA.|Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA.', 'United States|United States|United States|United States|United States', 0, 'Algorithms|Amino Acids|Antibodies|Antigen-Antibody Complex|Antigens|Computational Biology|Computer Simulation|Epitopes|Genes, Immunoglobulin|Humans|Mutation|Programming Languages|Protein Binding|Protein Conformation|Software', 'Journal Article', '10.1371/journal.pcbi.1003045', '23637590', 'Structural flexibility in germline gene-encoded antibodies allows promiscuous binding to diverse antigens. The binding affinity and specificity for a particular epitope typically increase as antibody genes acquire somatic mutations in antigen-stimulated B cells. In this work, we investigated whether germline gene-encoded antibodies are optimal for polyspecificity by determining the basis for recognition of diverse antigens by antibodies encoded by three VH gene segments. Panels of somatically mutated antibodies encoded by a common VH gene, but each binding to a different antigen, were computationally redesigned to predict antibodies that could engage multiple antigens at once. The Rosetta multi-state design process predicted antibody sequences for the entire heavy chain variable region, including framework, CDR1, and CDR2 mutations. The predicted sequences matched the germline gene sequences to a remarkable degree, revealing by computational design the residues that are predicted to enable polyspecificity, i.e., binding of many unrelated antigens with a common sequence. The process thereby reverses antibody maturation in silico. In contrast, when designing antibodies to bind a single antigen, a sequence similar to that of the mature antibody sequence was returned, mimicking natural antibody maturation in silico. We demonstrated that the Rosetta computational design algorithm captures important aspects of antibody/antigen recognition. While the hypervariable region CDR3 often mediates much of the specificity of mature antibodies, we identified key positions in the VH gene encoding CDR1, CDR2, and the immunoglobulin framework that are critical contributors for polyspecificity in germline antibodies. Computational design of antibodies capable of binding multiple antigens may allow the rational design of antibodies that retain polyspecificity for diverse epitope binding.'),
(86012, 2013, 'plos', 'Inference of R(0) and transmission heterogeneity from the size distribution of stuttering chains', 'Blumberg, Seth|Lloyd-Smith, James O', 'Fogarty International Center, National Institute of Health, Bethesda, Maryland, USA. seth.blumberg@ucsf.edu|Fogarty International Center, National Institute of Health, Bethesda, Maryland, USA. seth.blumberg@ucsf.edu', 'United States|United States', 66, 'Animals|Cluster Analysis|Computer Simulation|Contact Tracing|Democratic Republic of the Congo|Disease Transmission, Infectious|Humans|Models, Biological|Models, Statistical|Monkeypox|Zoonoses', 'Journal Article', '10.1371/journal.pcbi.1002993', '23658504', 'For many infectious disease processes such as emerging zoonoses and vaccine-preventable diseases, [Formula: see text] and infections occur as self-limited stuttering transmission chains. A mechanistic understanding of transmission is essential for characterizing the risk of emerging diseases and monitoring spatio-temporal dynamics. Thus methods for inferring [Formula: see text] and the degree of heterogeneity in transmission from stuttering chain data have important applications in disease surveillance and management. Previous researchers have used chain size distributions to infer [Formula: see text], but estimation of the degree of individual-level variation in infectiousness (as quantified by the dispersion parameter, [Formula: see text]) has typically required contact tracing data. Utilizing branching process theory along with a negative binomial offspring distribution, we demonstrate how maximum likelihood estimation can be applied to chain size data to infer both [Formula: see text] and the dispersion parameter that characterizes heterogeneity. While the maximum likelihood value for [Formula: see text] is a simple function of the average chain size, the associated confidence intervals are dependent on the inferred degree of transmission heterogeneity. As demonstrated for monkeypox data from the Democratic Republic of Congo, this impacts when a statistically significant change in [Formula: see text] is detectable. In addition, by allowing for superspreading events, inference of [Formula: see text] shifts the threshold above which a transmission chain should be considered anomalously large for a given value of [Formula: see text] (thus reducing the probability of false alarms about pathogen adaptation). Our analysis of monkeypox also clarifies the various ways that imperfect observation can impact inference of transmission parameters, and highlights the need to quantitatively evaluate whether observation is likely to significantly bias results.'),
(86013, 2013, 'plos', 'Cell patterns emerge from coupled chemical and physical fields with cell proliferation dynamics: the Arabidopsis thaliana root as a study system', 'Barrio, Rafael A|Romero-Arias, José Roberto|Noguez, Marco A|Azpeitia, Eugenio|Ortiz-Gutiérrez, Elizabeth|Hernández-Hernández, Valeria|Cortes-Poza, Yuriria|Álvarez-Buylla, Elena R', 'Instituto de Física, Universidad Nacional Autónoma de México (UNAM), México, Distrito Federal, México.|Instituto de Física, Universidad Nacional Autónoma de México (UNAM), México, Distrito Federal, México.|Instituto de Física, Universidad Nacional Autónoma de México (UNAM), México, Distrito Federal, México.|Instituto de Física, Universidad Nacional Autónoma de México (UNAM), México, Distrito Federal, México.|Instituto de Física, Universidad Nacional Autónoma de México (UNAM), México, Distrito Federal, México.|Instituto de Física, Universidad Nacional Autónoma de México (UNAM), México, Distrito Federal, México.|Instituto de Física, Universidad Nacional Autónoma de México (UNAM), México, Distrito Federal, México.|Instituto de Física, Universidad Nacional Autónoma de México (UNAM), México, Distrito Federal, México.', '-|-|-|-|-|-|-|-', 0, 'Arabidopsis|Cell Cycle|Cell Growth Processes|Computer Simulation|Indoleacetic Acids|Meristem|Microscopy, Confocal|Models, Biological|Plant Growth Regulators|Plant Roots', 'Journal Article', '10.1371/journal.pcbi.1003026', '23658505', 'A central issue in developmental biology is to uncover the mechanisms by which stem cells maintain their capacity to regenerate, yet at the same time produce daughter cells that differentiate and attain their ultimate fate as a functional part of a tissue or an organ. In this paper we propose that, during development, cells within growing organs obtain positional information from a macroscopic physical field that is produced in space while cells are proliferating. This dynamical interaction triggers and responds to chemical and genetic processes that are specific to each biological system. We chose the root apical meristem of Arabidopsis thaliana to develop our dynamical model because this system is well studied at the molecular, genetic and cellular levels and has the key traits of multicellular stem-cell niches. We built a dynamical model that couples fundamental molecular mechanisms of the cell cycle to a tension physical field and to auxin dynamics, both of which are known to play a role in root development. We perform extensive numerical calculations that allow for quantitative comparison with experimental measurements that consider the cellular patterns at the root tip. Our model recovers, as an emergent pattern, the transition from proliferative to transition and elongation domains, characteristic of stem-cell niches in multicellular organisms. In addition, we successfully predict altered cellular patterns that are expected under various applied auxin treatments or modified physical growth conditions. Our modeling platform may be extended to explicitly consider gene regulatory networks or to treat other developmental systems.'),
(86014, 2013, 'plos', 'Modeling and measuring signal relay in noisy directed migration of cell groups', 'Guven, Can|Rericha, Erin|Ott, Edward|Losert, Wolfgang', 'Department of Physics, University of Maryland, College Park, Maryland, USA.|Department of Physics, University of Maryland, College Park, Maryland, USA.|Department of Physics, University of Maryland, College Park, Maryland, USA.|Department of Physics, University of Maryland, College Park, Maryland, USA.', 'United States|United States|United States|United States', 0, 'Algorithms|Cell Movement|Cell Tracking|Computational Biology|Computer Simulation|Cyclic AMP|Dictyostelium|Models, Biological|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1003041', '23658506', 'We develop a coarse-grained stochastic model for the influence of signal relay on the collective behavior of migrating Dictyostelium discoideum cells. In the experiment, cells display a range of collective migration patterns, including uncorrelated motion, formation of partially localized streams, and clumping, depending on the type of cell and the strength of the external, linear concentration gradient of the signaling molecule cyclic adenosine monophosphate (cAMP). From our model, we find that the pattern of migration can be quantitatively described by the competition of two processes, the secretion rate of cAMP by the cells and the degradation rate of cAMP in the gradient chamber. Model simulations are compared to experiments for a wide range of strengths of an external linear-gradient signal. With degradation, the model secreting cells form streams and efficiently transverse the gradient, but without degradation, we find that model secreting cells form clumps without streaming. This indicates that the observed effective collective migration in streams requires not only signal relay but also degradation of the signal. In addition, our model allows us to detect and quantify precursors of correlated motion, even when cells do not exhibit obvious streaming.'),
(86015, 2013, 'plos', 'Bioinformatics and computational biology in Poland', 'Bujnicki, Janusz M|Tiuryn, Jerzy', 'Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland. iamb@genesilico.pl|Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland. iamb@genesilico.pl', 'Poland|Poland', 2, 'Computational Biology|History, 20th Century|History, 21st Century|Humans|Poland|Societies, Scientific', 'Historical Article', '10.1371/journal.pcbi.1003048', '23658507', '-'),
(86016, 2013, 'plos', 'A kinetic platform to determine the fate of nitric oxide in Escherichia coli', 'Robinson, Jonathan L|Brynildsen, Mark P', 'Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey, USA.|Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey, USA.', 'Jersey|Jersey', 33, 'Aerobiosis|Computational Biology|Computer Simulation|Escherichia coli|Kinetics|Metabolic Networks and Pathways|Models, Biological|Nitric Oxide|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1003049', '23658508', 'Nitric oxide (NO•) is generated by the innate immune response to neutralize pathogens. NO• and its autoxidation products have an extensive biochemical reaction network that includes reactions with iron-sulfur clusters, DNA, and thiols. The fate of NO• inside a pathogen depends on a kinetic competition among its many targets, and is of critical importance to infection outcomes. Due to the complexity of the NO• biochemical network, where many intermediates are short-lived and at extremely low concentrations, several species can be measured, but stable products are non-unique, and damaged biomolecules are continually repaired or regenerated, kinetic models are required to understand and predict the outcome of NO• treatment. Here, we have constructed a comprehensive kinetic model that encompasses the broad reactivity of NO• in Escherichia coli. The incorporation of spontaneous and enzymatic reactions, as well as damage and repair of biomolecules, allowed for a detailed analysis of how NO• distributes in E. coli cultures. The model was informed with experimental measurements of NO• dynamics, and used to identify control parameters of the NO• distribution. Simulations predicted that NO• dioxygenase (Hmp) functions as a dominant NO• consumption pathway at O2 concentrations as low as 35 µM (microaerobic), and interestingly, loses utility as the NO• delivery rate increases. We confirmed these predictions experimentally by measuring NO• dynamics in wild-type and mutant cultures at different NO• delivery rates and O2 concentrations. These data suggest that the kinetics of NO• metabolism must be considered when assessing the importance of cellular components to NO• tolerance, and that models such as the one described here are necessary to rigorously investigate NO• stress in microbes. This model provides a platform to identify novel strategies to potentiate the effects of NO•, and will serve as a template from which analogous models can be generated for other organisms.'),
(86017, 2013, 'plos', 'Long-range order in canary song', 'Markowitz, Jeffrey E|Ivie, Elizabeth|Kligler, Laura|Gardner, Timothy J', 'Department of Cognitive and Neural Systems, Boston University, Boston, Massachusetts, USA.|Department of Cognitive and Neural Systems, Boston University, Boston, Massachusetts, USA.|Department of Cognitive and Neural Systems, Boston University, Boston, Massachusetts, USA.|Department of Cognitive and Neural Systems, Boston University, Boston, Massachusetts, USA.', 'United States|United States|United States|United States', 31, 'Animals|Canaries|Computational Biology|Computer Simulation|Models, Biological|Models, Statistical|Reproducibility of Results|Vocalization, Animal', 'Journal Article', '10.1371/journal.pcbi.1003052', '23658509', 'Bird songs range in form from the simple notes of a Chipping Sparrow to the rich performance of the nightingale. Non-adjacent correlations can be found in the syntax of some birdsongs, indicating that the choice of what to sing next is determined not only by the current syllable, but also by previous syllables sung. Here we examine the song of the domesticated canary, a complex singer whose song consists of syllables, grouped into phrases that are arranged in flexible sequences. Phrases are defined by a fundamental time-scale that is independent of the underlying syllable duration. We show that the ordering of phrases is governed by long-range rules: the choice of what phrase to sing next in a given context depends on the history of the song, and for some syllables, highly specific rules produce correlations in song over timescales of up to ten seconds. The neural basis of these long-range correlations may provide insight into how complex behaviors are assembled from more elementary, stereotyped modules.'),
(86018, 2013, 'plos', 'Probing the energy landscape of activation gating of the bacterial potassium channel KcsA', 'Linder, Tobias|de Groot, Bert L|Stary-Weinzinger, Anna', 'Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria.|Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria.|Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria.', 'Austria|Austria|Austria', 0, 'Bacterial Proteins|Molecular Dynamics Simulation|Potassium Channels|Principal Component Analysis|Protein Conformation|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003058', '23658510', 'The bacterial potassium channel KcsA, which has been crystallized in several conformations, offers an ideal model to investigate activation gating of ion channels. In this study, essential dynamics simulations are applied to obtain insights into the transition pathways and the energy profile of KcsA pore gating. In agreement with previous hypotheses, our simulations reveal a two phasic activation gating process. In the first phase, local structural rearrangements in TM2 are observed leading to an intermediate channel conformation, followed by large structural rearrangements leading to full opening of KcsA. Conformational changes of a highly conserved phenylalanine, F114, at the bundle crossing region are crucial for the transition from a closed to an intermediate state. 3.9 µs umbrella sampling calculations reveal that there are two well-defined energy barriers dividing closed, intermediate, and open channel states. In agreement with mutational studies, the closed state was found to be energetically more favorable compared to the open state. Further, the simulations provide new insights into the dynamical coupling effects of F103 between the activation gate and the selectivity filter. Investigations on individual subunits support cooperativity of subunits during activation gating.'),
(86019, 2013, 'plos', 'Detection of mixed infection from bacterial whole genome sequence data allows assessment of its role in Clostridium difficile transmission', 'Eyre, David W|Cule, Madeleine L|Griffiths, David|Crook, Derrick W|Peto, Tim E A|Walker, A Sarah|Wilson, Daniel J', 'Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. david.eyre@ndm.ox.ac.uk|Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. david.eyre@ndm.ox.ac.uk|Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. david.eyre@ndm.ox.ac.uk|Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. david.eyre@ndm.ox.ac.uk|Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. david.eyre@ndm.ox.ac.uk|Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. david.eyre@ndm.ox.ac.uk|Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. david.eyre@ndm.ox.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Bacterial Infections|Clostridium difficile|Coinfection|Computational Biology|Computer Simulation|Cross Infection|Databases, Genetic|Disease Outbreaks|Genome, Bacterial|Humans|Molecular Typing|Phylogeny|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1003059', '23658511', 'Bacterial whole genome sequencing offers the prospect of rapid and high precision investigation of infectious disease outbreaks. Close genetic relationships between microorganisms isolated from different infected cases suggest transmission is a strong possibility, whereas transmission between cases with genetically distinct bacterial isolates can be excluded. However, undetected mixed infections-infection with xe2x89xa52 unrelated strains of the same species where only one is sequenced-potentially impairs exclusion of transmission with certainty, and may therefore limit the utility of this technique. We investigated the problem by developing a computationally efficient method for detecting mixed infection without the need for resource-intensive independent sequencing of multiple bacterial colonies. Given the relatively low density of single nucleotide polymorphisms within bacterial sequence data, direct reconstruction of mixed infection haplotypes from current short-read sequence data is not consistently possible. We therefore use a two-step maximum likelihood-based approach, assuming each sample contains up to two infecting strains. We jointly estimate the proportion of the infection arising from the dominant and minor strains, and the sequence divergence between these strains. In cases where mixed infection is confirmed, the dominant and minor haplotypes are then matched to a database of previously sequenced local isolates. We demonstrate the performance of our algorithm with in silico and in vitro mixed infection experiments, and apply it to transmission of an important healthcare-associated pathogen, Clostridium difficile. Using hospital ward movement data in a previously described stochastic transmission model, 15 pairs of cases enriched for likely transmission events associated with mixed infection were selected. Our method identified four previously undetected mixed infections, and a previously undetected transmission event, but no direct transmission between the pairs of cases under investigation. These results demonstrate that mixed infections can be detected without additional sequencing effort, and this will be important in assessing the extent of cryptic transmission in our hospitals.'),
(86020, 2013, 'plos', 'Estimation of vaccine efficacy and critical vaccination coverage in partially observed outbreaks', 'van Boven, Michiel|Ruijs, Wilhelmina L M|Wallinga, Jacco|ONeill, Philip D|Hahnxc3xa9, Susan', 'Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands. michiel.van.boven@rivm.nl|Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands. michiel.van.boven@rivm.nl|Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands. michiel.van.boven@rivm.nl|Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands. michiel.van.boven@rivm.nl|Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands. michiel.van.boven@rivm.nl', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 7, 'Bayes Theorem|Computational Biology|Computer Simulation|Disease Outbreaks|Humans|Models, Biological|Models, Statistical|Mumps|Netherlands|Risk|Schools|Vaccination', 'Journal Article', '10.1371/journal.pcbi.1003061', '23658512', 'Classical approaches to estimate vaccine efficacy are based on the assumption that a persons risk of infection does not depend on the infection status of others. This assumption is untenable for infectious disease data where such dependencies abound. We present a novel approach to estimating vaccine efficacy in a Bayesian framework using disease transmission models. The methodology is applied to outbreaks of mumps in primary schools in the Netherlands. The total study population consisted of 2,493 children in ten primary schools, of which 510 (20%) were known to have been infected, and 832 (33%) had unknown infection status. The apparent vaccination coverage ranged from 12% to 93%, and the apparent infection attack rate varied from 1% to 76%. Our analyses show that vaccination reduces the probability of infection per contact substantially but not perfectly ([Formula: see text]xe2x80x8a=xe2x80x8a0.933, 95CrI: 0.908-0.954). Mumps virus appears to be moderately transmissible in the school setting, with each case yielding an estimated 2.5 secondary cases in an unvaccinated population ([Formula: see text]xe2x80x8a=xe2x80x8a2.49, 95%CrI: 2.36-2.63), resulting in moderate estimates of the critical vaccination coverage (64.2%, 95%CrI: 61.7-66.7%). The indirect benefits of vaccination are highest in populations with vaccination coverage just below the critical vaccination coverage. In these populations, it is estimated that almost two infections can be prevented per vaccination. We discuss the implications for the optimal control of mumps in heterogeneously vaccinated populations.'),
(86021, 2013, 'plos', 'Novel developmental analyses identify longitudinal patterns of early gut microbiota that affect infant growth', 'White, Richard A|Bjørnholt, Jørgen V|Baird, Donna D|Midtvedt, Tore|Harris, Jennifer R|Pagano, Marcello|Hide, Winston|Rudi, Knut|Moen, Birgitte|Iszatt, Nina|Peddada, Shyamal D|Eggesbø, Merete', 'Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.|Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.|Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.|Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.|Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.|Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.|Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.|Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.|Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.|Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.|Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.|Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.', 'Norway|Norway|Norway|Norway|Norway|Norway|Norway|Norway|Norway|Norway|Norway|Norway', 43, 'Bacteria|Birth Weight|Cohort Studies|Computational Biology|Feces|Female|Gastrointestinal Tract|Humans|Infant|Infant, Newborn|Male|Models, Statistical|Weight Gain', 'Journal Article', '10.1371/journal.pcbi.1003042', '23671411', 'It is acknowledged that some obesity trajectories are set early in life, and that rapid weight gain in infancy is a risk factor for later development of obesity. Identifying modifiable factors associated with early rapid weight gain is a prerequisite for curtailing the growing worldwide obesity epidemic. Recently, much attention has been given to findings indicating that gut microbiota may play a role in obesity development. We aim at identifying how the development of early gut microbiota is associated with expected infant growth. We developed a novel procedure that allows for the identification of longitudinal gut microbiota patterns (corresponding to the gut ecosystem developing), which are associated with an outcome of interest, while appropriately controlling for the false discovery rate. Our method identified developmental pathways of Staphylococcus species and Escherichia coli that were associated with expected growth, and traditional methods indicated that the detection of Bacteroides species at day 30 was associated with growth. Our method should have wide future applicability for studying gut microbiota, and is particularly important for translational considerations, as it is critical to understand the timing of microbiome transitions prior to attempting to manipulate gut microbiota in early life.'),
(86022, 2013, 'plos', 'Improving breast cancer survival analysis through competition-based multidimensional modeling', 'Bilal, Erhan|Dutkowski, Janusz|Guinney, Justin|Jang, In Sock|Logsdon, Benjamin A|Pandey, Gaurav|Sauerwine, Benjamin A|Shimoni, Yishai|Moen Vollan, Hans Kristian|Mecham, Brigham H|Rueda, Oscar M|Tost, Jorg|Curtis, Christina|Alvarez, Mariano J|Kristensen, Vessela N|Aparicio, Samuel|Børresen-Dale, Anne-Lise|Caldas, Carlos|Califano, Andrea|Friend, Stephen H|Ideker, Trey|Schadt, Eric E|Stolovitzky, Gustavo A|Margolin, Adam A', 'IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.|IBM TJ Watson Research, Yorktown Heights, New York, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|Uni', 55, 'Algorithms|Breast Neoplasms|Cluster Analysis|Computational Biology|Databases, Factual|Female|Gene Expression Profiling|Humans|Models, Biological|Models, Statistical|Prognosis|Survival Analysis', 'Journal Article', '10.1371/journal.pcbi.1003047', '23671412', 'Breast cancer is the most common malignancy in women and is responsible for hundreds of thousands of deaths annually. As with most cancers, it is a heterogeneous disease and different breast cancer subtypes are treated differently. Understanding the difference in prognosis for breast cancer based on its molecular and phenotypic features is one avenue for improving treatment by matching the proper treatment with molecular subtypes of the disease. In this work, we employed a competition-based approach to modeling breast cancer prognosis using large datasets containing genomic and clinical information and an online real-time leaderboard program used to speed feedback to the modeling team and to encourage each modeler to work towards achieving a higher ranked submission. We find that machine learning methods combined with molecular features selected based on expert prior knowledge can improve survival predictions compared to current best-in-class methodologies and that ensemble models trained across multiple user submissions systematically outperform individual models within the ensemble. We also find that model scores are highly consistent across multiple independent evaluations. This study serves as the pilot phase of a much larger competition open to the whole research community, with the goal of understanding general strategies for model optimization using clinical and molecular profiling data and providing an objective, transparent system for assessing prognostic models.'),
(86023, 2013, 'plos', 'Selection for replicases in protocells', 'Bianconi, Ginestra|Zhao, Kun|Chen, Irene A|Nowak, Martin A', 'School of Mathematical Sciences, Queen Mary University of London, London, United Kingdom.|School of Mathematical Sciences, Queen Mary University of London, London, United Kingdom.|School of Mathematical Sciences, Queen Mary University of London, London, United Kingdom.|School of Mathematical Sciences, Queen Mary University of London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 20, 'Artificial Cells|Biochemical Phenomena|Cell Division|Evolution, Molecular|Models, Biological|Nucleotidyltransferases|Origin of Life|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.1003051', '23671413', 'We consider a world of nucleotide sequences and protocells. The sequences have the property of spontaneous self-replication. Some sequences - so-called replicases - have enzymatic activity in the sense of enhancing the replication rate of all (or almost all) sequences. In a well-mixed medium, natural selection would not favor such replicases because their presence equally benefits sequences with or without replicase activity. Here we show that protocells can select for replicases. We assume that sequences replicate within protocells and that protocells undergo spontaneous division. This leads to particular population structures which can augment the abundance of replicases. We explore various assumptions regarding replicase activity and protocell division. We calculate the error threshold that is compatible with selecting for replicases.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86024, 2013, 'plos', 'Effect of regulatory architecture on broad versus narrow sense heritability', 'Wang, Yunpeng|Vik, Jon Olav|Omholt, Stig W|Gjuvsland, Arne B', 'Centre for Integrative Genetics (CIGENE), Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Ås, Norway.|Centre for Integrative Genetics (CIGENE), Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Ås, Norway.|Centre for Integrative Genetics (CIGENE), Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Ås, Norway.|Centre for Integrative Genetics (CIGENE), Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Ås, Norway.', 'Norway|Norway|Norway|Norway', 4, 'Animals|Cell Cycle|Circadian Rhythm|Computational Biology|Computer Simulation|Cyclic AMP|Genotype|Glycolysis|Inheritance Patterns|Models, Genetic|Monte Carlo Method|Myocytes, Cardiac|Phenotype|Plants', 'Journal Article', '10.1371/journal.pcbi.1003053', '23671414', 'Additive genetic variance (VA ) and total genetic variance (VG ) are core concepts in biomedical, evolutionary and production-biology genetics. What determines the large variation in reported VA /VG ratios from line-cross experiments is not well understood. Here we report how the VA /VG ratio, and thus the ratio between narrow and broad sense heritability (h(2) /H(2) ), varies as a function of the regulatory architecture underlying genotype-to-phenotype (GP) maps. We studied five dynamic models (of the cAMP pathway, the glycolysis, the circadian rhythms, the cell cycle, and heart cell dynamics). We assumed genetic variation to be reflected in model parameters and extracted phenotypes summarizing the system dynamics. Even when imposing purely linear genotype to parameter maps and no environmental variation, we observed quite low VA /VG ratios. In particular, systems with positive feedback and cyclic dynamics gave more non-monotone genotype-phenotype maps and much lower VA /VG ratios than those without. The results show that some regulatory architectures consistently maintain a transparent genotype-to-phenotype relationship, whereas other architectures generate more subtle patterns. Our approach can be used to elucidate these relationships across a whole range of biological systems in a systematic fashion.'),
(86025, 2013, 'plos', 'Sparse coding can predict primary visual cortex receptive field changes induced by abnormal visual input', 'Hunt, Jonathan J|Dayan, Peter|Goodhill, Geoffrey J', 'Queensland Brain Institute, University of Queensland, St Lucia, Australia.|Queensland Brain Institute, University of Queensland, St Lucia, Australia.|Queensland Brain Institute, University of Queensland, St Lucia, Australia.', 'Australia|Australia|Australia', 19, 'Algorithms|Animals|Cats|Models, Neurological|Strabismus|Vision, Ocular|Visual Cortex|Visual Fields', 'Journal Article', '10.1371/journal.pcbi.1003005', '23675290', 'Receptive fields acquired through unsupervised learning of sparse representations of natural scenes have similar properties to primary visual cortex (V1) simple cell receptive fields. However, what drives in vivo development of receptive fields remains controversial. The strongest evidence for the importance of sensory experience in visual development comes from receptive field changes in animals reared with abnormal visual input. However, most sparse coding accounts have considered only normal visual input and the development of monocular receptive fields. Here, we applied three sparse coding models to binocular receptive field development across six abnormal rearing conditions. In every condition, the changes in receptive field properties previously observed experimentally were matched to a similar and highly faithful degree by all the models, suggesting that early sensory development can indeed be understood in terms of an impetus towards sparsity. As previously predicted in the literature, we found that asymmetries in inter-ocular correlation across orientations lead to orientation-specific binocular receptive fields. Finally we used our models to design a novel stimulus that, if present during rearing, is predicted by the sparsity principle to lead robustly to radically abnormal receptive fields.'),
(86026, 2013, 'plos', 'Host resistance, population structure and the long-term persistence of bubonic plague: contributions of a modelling approach in the Malagasy focus', 'Gascuel, Fanny|Choisy, Marc|Duplantier, Jean-Marc|Débarre, Florence|Brouat, Carine', 'IRD, CBGP (UMR IRD/INRA/CIRAD/MontpellierSupAgro), Montferrier-sur-Lez, France. fanny.gascuel@college-de-france.fr|IRD, CBGP (UMR IRD/INRA/CIRAD/MontpellierSupAgro), Montferrier-sur-Lez, France. fanny.gascuel@college-de-france.fr|IRD, CBGP (UMR IRD/INRA/CIRAD/MontpellierSupAgro), Montferrier-sur-Lez, France. fanny.gascuel@college-de-france.fr|IRD, CBGP (UMR IRD/INRA/CIRAD/MontpellierSupAgro), Montferrier-sur-Lez, France. fanny.gascuel@college-de-france.fr|IRD, CBGP (UMR IRD/INRA/CIRAD/MontpellierSupAgro), Montferrier-sur-Lez, France. fanny.gascuel@college-de-france.fr', 'France|France|France|France|France', 13, 'Animals|Computer Simulation|Disease Resistance|Ecology|Endemic Diseases|Fertility|Madagascar|Markov Chains|Models, Biological|Plague|Rats|Siphonaptera', 'Journal Article', '10.1371/journal.pcbi.1003039', '23675291', 'Although bubonic plague is an endemic zoonosis in many countries around the world, the factors responsible for the persistence of this highly virulent disease remain poorly known. Classically, the endemic persistence of plague is suspected to be due to the coexistence of plague resistant and plague susceptible rodents in natural foci, and/or to a metapopulation structure of reservoirs. Here, we test separately the effect of each of these factors on the long-term persistence of plague. We analyse the dynamics and equilibria of a model of plague propagation, consistent with plague ecology in Madagascar, a major focus where this disease is endemic since the 1920s in central highlands. By combining deterministic and stochastic analyses of this model, and including sensitivity analyses, we show that (i) endemicity is favoured by intermediate host population sizes, (ii) in large host populations, the presence of resistant rats is sufficient to explain long-term persistence of plague, and (iii) the metapopulation structure of susceptible host populations alone can also account for plague endemicity, thanks to both subdivision and the subsequent reduction in the size of subpopulations, and extinction-recolonization dynamics of the disease. In the light of these results, we suggest scenarios to explain the localized presence of plague in Madagascar.'),
(86027, 2013, 'plos', 'STL-based analysis of TRAIL-induced apoptosis challenges the notion of type I/type II cell line classification', 'Stoma, Szymon|Donzé, Alexandre|Bertaux, François|Maler, Oded|Batt, Gregory', 'INRIA Paris-Rocquencourt, Le Chesnay, France.|INRIA Paris-Rocquencourt, Le Chesnay, France.|INRIA Paris-Rocquencourt, Le Chesnay, France.|INRIA Paris-Rocquencourt, Le Chesnay, France.|INRIA Paris-Rocquencourt, Le Chesnay, France.', 'France|France|France|France|France', 12, 'Apoptosis|Caspases|Cell Line, Tumor|Computational Biology|Computer Simulation|Humans|Logic|Membrane Proteins|Mitochondrial Membranes|Models, Biological|Proto-Oncogene Proteins c-bcl-2|Semantics|Signal Transduction|TNF-Related Apoptosis-Inducing Ligand|Terminology as Topic', 'Journal Article', '10.1371/journal.pcbi.1003056', '23675292', 'Extrinsic apoptosis is a programmed cell death triggered by external ligands, such as the TNF-related apoptosis inducing ligand (TRAIL). Depending on the cell line, the specific molecular mechanisms leading to cell death may significantly differ. Precise characterization of these differences is crucial for understanding and exploiting extrinsic apoptosis. Cells show distinct behaviors on several aspects of apoptosis, including (i) the relative order of caspases activation, (ii) the necessity of mitochondria outer membrane permeabilization (MOMP) for effector caspase activation, and (iii) the survival of cell lines overexpressing Bcl2. These differences are attributed to the activation of one of two pathways, leading to classification of cell lines into two groups: type I and type II. In this work we challenge this type I/type II cell line classification. We encode the three aforementioned distinguishing behaviors in a formal language, called signal temporal logic (STL), and use it to extensively test the validity of a previously-proposed model of TRAIL-induced apoptosis with respect to experimental observations made on different cell lines. After having solved a few inconsistencies using STL-guided parameter search, we show that these three criteria do not define consistent cell line classifications in type I or type II, and suggest mutants that are predicted to exhibit ambivalent behaviors. In particular, this finding sheds light on the role of a feedback loop between caspases, and reconciliates two apparently-conflicting views regarding the importance of either upstream or downstream processes for cell-type determination. More generally, our work suggests that these three distinguishing behaviors should be merely considered as type I/II features rather than cell-type defining criteria. On the methodological side, this work illustrates the biological relevance of STL-diagrams, STL population data, and STL-guided parameter search implemented in the tool Breach. Such tools are well-adapted to the ever-increasing availability of heterogeneous knowledge on complex signal transduction pathways.'),
(86028, 2013, 'plos', 'A mechanistic understanding of allosteric immune escape pathways in the HIV-1 envelope glycoprotein', 'Sethi, Anurag|Tian, Jianhui|Derdeyn, Cynthia A|Korber, Bette|Gnanakaran, S', 'Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.', 'Mexico|Mexico|Mexico|Mexico|Mexico', 36, 'Binding Sites|CD4 Antigens|Computational Biology|HIV Envelope Protein gp120|HIV Infections|HIV-1|Humans|Immune Evasion|Molecular Dynamics Simulation|Principal Component Analysis|Protein Conformation|Reproducibility of Results|Structural Homology, Protein', 'Journal Article', '10.1371/journal.pcbi.1003046', '23696718', 'The HIV-1 envelope (Env) spike, which consists of a compact, heterodimeric trimer of the glycoproteins gp120 and gp41, is the target of neutralizing antibodies. However, the high mutation rate of HIV-1 and plasticity of Env facilitates viral evasion from neutralizing antibodies through various mechanisms. Mutations that are distant from the antibody binding site can lead to escape, probably by changing the conformation or dynamics of Env, however, these changes are difficult to identify and define mechanistically. Here we describe a network analysis-based approach to identify potential allosteric immune evasion mechanisms using three known HIV-1 Env gp120 protein structures from two different clades, B and C. First, correlation and principal component analyses of molecular dynamics (MD) simulations identified a high degree of long-distance coupled motions that exist between functionally distant regions within the intrinsic dynamics of the gp120 core, supporting the presence of long-distance communication in the protein. Then, by integrating MD simulations with network theory, we identified the optimal and suboptimal communication pathways and modules within the gp120 core. The results unveil both strain-dependent and -independent characteristics of the communication pathways in gp120. We show that within the context of three structurally homologous gp120 cores, the optimal pathway for communication is sequence sensitive, i.e. a suboptimal pathway in one strain becomes the optimal pathway in another strain. Yet the identification of conserved elements within these communication pathways, termed inter-modular hotspots, could present a new opportunity for immunogen design, as this could be an additional mechanism that HIV-1 uses to shield vulnerable antibody targets in Env that induce neutralizing antibody breadth.'),
(86029, 2013, 'plos', 'The emergence of environmental homeostasis in complex ecosystems', 'Dyke, James G|Weaver, Iain S', 'School of Electronics and Computer Science, University of Southampton, Southampton, United Kingdom. jd4@ecs.soton.ac.uk|School of Electronics and Computer Science, University of Southampton, Southampton, United Kingdom. jd4@ecs.soton.ac.uk', 'United Kingdom|United Kingdom', 18, 'Computational Biology|Computer Simulation|Earth (Planet)|Ecosystem|Homeostasis|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1003050', '23696719', 'The Earth, with its core-driven magnetic field, convective mantle, mobile lid tectonics, oceans of liquid water, dynamic climate and abundant life is arguably the most complex system in the known universe. This system has exhibited stability in the sense of, bar a number of notable exceptions, surface temperature remaining within the bounds required for liquid water and so a significant biosphere. Explanations for this range from anthropic principles in which the Earth was essentially lucky, to homeostatic Gaia in which the abiotic and biotic components of the Earth system self-organise into homeostatic states that are robust to a wide range of external perturbations. Here we present results from a conceptual model that demonstrates the emergence of homeostasis as a consequence of the feedback loop operating between life and its environment. Formulating the model in terms of Gaussian processes allows the development of novel computational methods in order to provide solutions. We find that the stability of this system will typically increase then remain constant with an increase in biological diversity and that the number of attractors within the phase space exponentially increases with the number of environmental variables while the probability of the system being in an attractor that lies within prescribed boundaries decreases approximately linearly. We argue that the cybernetic concept of rein control provides insights into how this model system, and potentially any system that is comprised of biological to environmental feedback loops, self-organises into homeostatic states.'),
(86030, 2013, 'plos', 'Connection between oligomeric state and gating characteristics of mechanosensitive ion channels', 'Haselwandter, Christoph A|Phillips, Rob', 'Department of Physics and Astronomy, University of Southern California, Los Angeles, California, USA. cah77@usc.edu|Department of Physics and Astronomy, University of Southern California, Los Angeles, California, USA. cah77@usc.edu', 'United States|United States', 18, 'Computational Biology|Escherichia coli Proteins|Ion Channels|Lipid Bilayers|Mechanotransduction, Cellular|Models, Biological|Models, Molecular|Protein Conformation|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003055', '23696720', 'The mechanosensitive channel of large conductance (MscL) is capable of transducing mechanical stimuli such as membrane tension into an electrochemical response. MscL provides a widely-studied model system for mechanotransduction and, more generally, for how bilayer mechanical properties regulate protein conformational changes. Much effort has been expended on the detailed experimental characterization of the molecular structure and biological function of MscL. However, despite its central significance, even basic issues such as the physiologically relevant oligomeric states and molecular structures of MscL remain a matter of debate. In particular, tetrameric, pentameric, and hexameric oligomeric states of MscL have been proposed, together with a range of detailed molecular structures of MscL in the closed and open channel states. Previous theoretical work has shown that the basic phenomenology of MscL gating can be understood using an elastic model describing the energetic cost of the thickness deformations induced by MscL in the surrounding lipid bilayer. Here, we generalize this elastic model to account for the proposed oligomeric states and hydrophobic shapes of MscL. We find that the oligomeric state and hydrophobic shape of MscL are reflected in the energetic cost of lipid bilayer deformations. We make quantitative predictions pertaining to the gating characteristics associated with various structural models of MscL and, in particular, show that different oligomeric states and hydrophobic shapes of MscL yield distinct membrane contributions to the gating energy and gating tension. Thus, the functional properties of MscL provide a signature of the oligomeric state and hydrophobic shape of MscL. Our results suggest that, in addition to the hydrophobic mismatch between membrane proteins and the surrounding lipid bilayer, the symmetry and shape of the hydrophobic surfaces of membrane proteins play an important role in the regulation of protein function by bilayer membranes.'),
(86031, 2013, 'plos', 'Two misfolding routes for the prion protein around pH 45', 'Garrec, Julian|Tavernelli, Ivano|Rothlisberger, Ursula', 'Laboratory of Computational Chemistry and Biochemistry - Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Laboratory of Computational Chemistry and Biochemistry - Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Laboratory of Computational Chemistry and Biochemistry - Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.', 'Switzerland|Switzerland|Switzerland', 16, 'Computer Simulation|Hydrogen-Ion Concentration|Molecular Dynamics Simulation|Nuclear Magnetic Resonance, Biomolecular|Prions|Protein Folding|Protons', 'Journal Article', '10.1371/journal.pcbi.1003057', '23696721', 'Using molecular dynamics simulations, we show that the prion protein (PrP) exhibits a dual behavior, with two possible transition routes, upon protonation of H187 around pH 4.5, which mimics specific conditions encountered in endosomes. Our results suggest a picture in which the protonated imidazole ring of H187 experiences an electrostatic repulsion with the nearby guanidinium group of R136, to which the system responds by pushing either H187 or R136 sidechains away from their native cavities. The regions to which H187 and R136 are linked, namely the C-terminal part of H2 and the loop connecting S1 to H1, respectively, are affected in a different manner depending on which pathway is taken. Specific in vivo or in vitro conditions, such as the presence of molecular chaperones or a particular experimental setup, may favor one transition pathway over the other, which can result in very different [Formula: see text] monomers. This has some possible connections with the observation of various fibril morphologies and the outcome of prion strains. In addition, the finding that the interaction of H187 with R136 is a weak point in mammalian PrP is supported by the absence of the [Formula: see text] residue pair in non-mammalian species that are known to be resistant to prion diseases.'),
(86032, 2013, 'plos', 'Coalescent tree imbalance and a simple test for selective sweeps based on microsatellite variation', 'Li, Haipeng|Wiehe, Thomas', 'Department of Computational Genomics, CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Department of Computational Genomics, CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.', 'China|China', 15, 'Computational Biology|Computer Simulation|Databases, Genetic|Genetic Variation|Genetics, Population|Microsatellite Repeats|Models, Genetic|Plasmodium falciparum', 'Journal Article', '10.1371/journal.pcbi.1003060', '23696722', 'Selective sweeps are at the core of adaptive evolution. We study how the shape of coalescent trees is affected by recent selective sweeps. To do so we define a coarse-grained measure of tree topology. This measure has appealing analytical properties, its distribution is derived from a uniform, and it is easy to estimate from experimental data. We show how it can be cast into a test for recent selective sweeps using microsatellite markers and present an application to an experimental data set from Plasmodium falciparum.'),
(86033, 2013, 'plos', 'Multiple estimates of transmissibility for the 2009 influenza pandemic based on influenza-like-illness data from small US military populations', 'Riley, Pete|Ben-Nun, Michal|Armenta, Richard|Linker, Jon A|Eick, Angela A|Sanchez, Jose L|George, Dylan|Bacon, David P|Riley, Steven', 'Predictive Science Inc., San Diego, California, USA. pete@predsci.com|Predictive Science Inc., San Diego, California, USA. pete@predsci.com|Predictive Science Inc., San Diego, California, USA. pete@predsci.com|Predictive Science Inc., San Diego, California, USA. pete@predsci.com|Predictive Science Inc., San Diego, California, USA. pete@predsci.com|Predictive Science Inc., San Diego, California, USA. pete@predsci.com|Predictive Science Inc., San Diego, California, USA. pete@predsci.com|Predictive Science Inc., San Diego, California, USA. pete@predsci.com|Predictive Science Inc., San Diego, California, USA. pete@predsci.com', 'United States|United States|United States|United States|United States|United States|United States|United States|United States', 10, 'Computational Biology|Humans|Incidence|Influenza, Human|Military Personnel|Models, Biological|Models, Statistical|Pandemics|United States', 'Journal Article', '10.1371/journal.pcbi.1003064', '23696723', 'Rapidly characterizing the amplitude and variability in transmissibility of novel human influenza strains as they emerge is a key public health priority. However, comparison of early estimates of the basic reproduction number during the 2009 pandemic were challenging because of inconsistent data sources and methods. Here, we define and analyze influenza-like-illness (ILI) case data from 2009-2010 for the 50 largest spatially distinct US military installations (military population defined by zip code, MPZ). We used publicly available data from non-military sources to show that patterns of ILI incidence in many of these MPZs closely followed the pattern of their enclosing civilian population. After characterizing the broad patterns of incidence (e.g. single-peak, double-peak), we defined a parsimonious SIR-like model with two possible values for intrinsic transmissibility across three epochs. We fitted the parameters of this model to data from all 50 MPZs, finding them to be reasonably well clustered with a median (mean) value of 1.39 (1.57) and standard deviation of 0.41. An increasing temporal trend in transmissibility ([Formula: see text], p-value: 0.013) during the period of our study was robust to the removal of high transmissibility outliers and to the removal of the smaller 20 MPZs. Our results demonstrate the utility of rapidly available - and consistent - data from multiple populations.'),
(86034, 2013, 'plos', 'Interface-resolved network of protein-protein interactions', 'Johnson, Margaret E|Hummer, Gerhard', 'Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. JohnsonME@niddk.nih.gov|Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. JohnsonME@niddk.nih.gov', 'United States|United States', 20, 'Clathrin|Computational Biology|Databases, Protein|Drug Discovery|Endocytosis|Models, Molecular|Mutation|Protein Binding|Protein Interaction Mapping|Proteins|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1003065', '23696724', 'We define an interface-interaction network (IIN) to capture the specificity and competition between protein-protein interactions (PPI). This new type of network represents interactions between individual interfaces used in functional protein binding and thereby contains the detail necessary to describe the competition and cooperation between any pair of binding partners. Here we establish a general framework for the construction of IINs that merges computational structure-based interface assignment with careful curation of available literature. To complement limited structural data, the inclusion of biochemical data is critical for achieving the accuracy and completeness necessary to analyze the specificity and competition between the protein interactions. Firstly, this procedure provides a means to clarify the information content of existing data on purported protein interactions and to remove indirect and spurious interactions. Secondly, the IIN we have constructed here for proteins involved in clathrin-mediated endocytosis (CME) exhibits distinctive topological properties. In contrast to PPI networks with their global and relatively dense connectivity, the fragmentation of the IIN into distinctive network modules suggests that different functional pressures act on the evolution of its topology. Large modules in the IIN are formed by interfaces sharing specificity for certain domain types, such as SH3 domains distributed across different proteins. The shared and distinct specificity of an interface is necessary for effective negative and positive design of highly selective binding targets. Lastly, the organization of detailed structural data in a network format allows one to identify pathways of specific binding interactions and thereby predict effects of mutations at specific surfaces on a protein and of specific binding inhibitors, as we explore in several examples. Overall, the endocytosis IIN is remarkably complex and rich in features masked in the coarser PPI, and collects relevant detail of protein association in a readily interpretable format.'),
(86035, 2013, 'plos', 'Polymorphisms in the F8 gene and MHC-II variants as risk factors for the development of inhibitory anti-factor VIII antibodies during the treatment of hemophilia a: a computational assessment', 'Pandey, Gouri Shankar|Yanover, Chen|Howard, Tom E|Sauna, Zuben E', 'Laboratory of Hemostasis, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA.|Laboratory of Hemostasis, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA.|Laboratory of Hemostasis, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA.|Laboratory of Hemostasis, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA.', 'United States|United States|United States|United States', 22, 'African Continental Ancestry Group|Amino Acid Sequence|Antibodies|Computational Biology|Factor VIII|Haplotypes|Hemophilia A|Histocompatibility Antigens Class II|Humans|Molecular Sequence Data|Peptide Fragments|Polymorphism, Single Nucleotide|Protein Binding|Risk Factors', 'Journal Article', '10.1371/journal.pcbi.1003066', '23696725', 'The development of neutralizing anti-drug-antibodies to the Factor VIII protein-therapeutic is currently the most significant impediment to the effective management of hemophilia A. Common non-synonymous single nucleotide polymorphisms (ns-SNPs) in the F8 gene occur as six haplotypes in the human population (denoted H1 to H6) of which H3 and H4 have been associated with an increased risk of developing anti-drug antibodies. There is evidence that CD4+ T-cell response is essential for the development of anti-drug antibodies and such a response requires the presentation of the peptides by the MHC-class-II (MHC-II) molecules of the patient. We measured the binding and half-life of peptide-MHC-II complexes using synthetic peptides from regions of the Factor VIII protein where ns-SNPs occur and showed that these wild type peptides form stable complexes with six common MHC-II alleles, representing 46.5% of the North American population. Next, we compared the affinities computed by NetMHCIIpan, a neural network-based algorithm for MHC-II peptide binding prediction, to the experimentally measured values and concluded that these are in good agreement (area under the ROC-curve of 0.778 to 0.972 for the six MHC-II variants). Using a computational binding predictor, we were able to expand our analysis to (a) include all wild type peptides spanning each polymorphic position, and (b) consider more MHC-II variants, thus allowing for a better estimation of the risk for clinical manifestation of anti-drug antibodies in the entire population (or a specific sub-population). Analysis of these computational data confirmed that peptides which have the wild type sequence at positions where the polymorphisms associated with haplotypes H3, H4 and H5 occur bind MHC-II proteins significantly more than a negative control. Taken together, the experimental and computational results suggest that wild type peptides from polymorphic regions of FVIII constitute potential T-cell epitopes and thus could explain the increased incidence of anti-drug antibodies in hemophilia A patients with haplotypes H3 and H4.'),
(86036, 2013, 'plos', 'Hybrid equation/agent-based model of ischemia-induced hyperemia and pressure ulcer formation predicts greater propensity to ulcerate in subjects with spinal cord injury', 'Solovyev, Alexey|Mi, Qi|Tzen, Yi-Ting|Brienza, David|Vodovotz, Yoram', 'Department of Mathematics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Mathematics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Mathematics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Mathematics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Mathematics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.', 'United States|United States|United States|United States|United States', 22, 'Adult|Computational Biology|Computer Simulation|Humans|Hyperemia|Ischemia|Middle Aged|Models, Biological|Models, Statistical|Pressure Ulcer|Regional Blood Flow|Skin|Spinal Cord Injuries', 'Journal Article', '10.1371/journal.pcbi.1003070', '23696726', 'Pressure ulcers are costly and life-threatening complications for people with spinal cord injury (SCI). People with SCI also exhibit differential blood flow properties in non-ulcerated skin. We hypothesized that a computer simulation of the pressure ulcer formation process, informed by data regarding skin blood flow and reactive hyperemia in response to pressure, could provide insights into the pathogenesis and effective treatment of post-SCI pressure ulcers. Agent-Based Models (ABM) are useful in settings such as pressure ulcers, in which spatial realism is important. Ordinary Differential Equation-based (ODE) models are useful when modeling physiological phenomena such as reactive hyperemia. Accordingly, we constructed a hybrid model that combines ODEs related to blood flow along with an ABM of skin injury, inflammation, and ulcer formation. The relationship between pressure and the course of ulcer formation, as well as several other important characteristic patterns of pressure ulcer formation, was demonstrated in this model. The ODE portion of this model was calibrated to data related to blood flow following experimental pressure responses in non-injured human subjects or to data from people with SCI. This model predicted a higher propensity to form ulcers in response to pressure in people with SCI vs. non-injured control subjects, and thus may serve as novel diagnostic platform for post-SCI ulcer formation.'),
(86037, 2013, 'plos', 'Quantifying the molecular origins of opposite solvent effects on protein-protein interactions', 'Vagenende, Vincent|Han, Alvin X|Pek, Han B|Loo, Bernard L W', 'Bioprocessing Technology Institute, ASTAR (Agency for Science, Technology and Research), Singapore. Vincent_Vagenende@bti.a-star.edu.sg|Bioprocessing Technology Institute, ASTAR (Agency for Science, Technology and Research), Singapore. Vincent_Vagenende@bti.a-star.edu.sg|Bioprocessing Technology Institute, ASTAR (Agency for Science, Technology and Research), Singapore. Vincent_Vagenende@bti.a-star.edu.sg|Bioprocessing Technology Institute, ASTAR (Agency for Science, Technology and Research), Singapore. Vincent_Vagenende@bti.a-star.edu.sg', 'Singapore|Singapore|Singapore|Singapore', 6, 'Computational Biology|Databases, Protein|Glycerol|Models, Chemical|Molecular Dynamics Simulation|Protein Binding|Proteins|Solvents', 'Journal Article', '10.1371/journal.pcbi.1003072', '23696727', 'Although the nature of solvent-protein interactions is generally weak and non-specific, addition of cosolvents such as denaturants and osmolytes strengthens protein-protein interactions for some proteins, whereas it weakens protein-protein interactions for others. This is exemplified by the puzzling observation that addition of glycerol oppositely affects the association constants of two antibodies, D1.3 and D44.1, with lysozyme. To resolve this conundrum, we develop a methodology based on the thermodynamic principles of preferential interaction theory and the quantitative characterization of local protein solvation from molecular dynamics simulations. We find that changes of preferential solvent interactions at the protein-protein interface quantitatively account for the opposite effects of glycerol on the antibody-antigen association constants. Detailed characterization of local protein solvation in the free and associated protein states reveals how opposite solvent effects on protein-protein interactions depend on the extent of dewetting of the protein-protein contact region and on structural changes that alter cooperative solvent-protein interactions at the periphery of the protein-protein interface. These results demonstrate the direct relationship between macroscopic solvent effects on protein-protein interactions and atom-scale solvent-protein interactions, and establish a general methodology for predicting and understanding solvent effects on protein-protein interactions in diverse biological environments.'),
(86038, 2013, 'plos', 'Human monogenic disease genes have frequently functionally redundant paralogs', 'Chen, Wei-Hua|Zhao, Xing-Ming|van Noort, Vera|Bork, Peer', 'European Molecular Biology Laboratory (EMBL) Heidelberg, Heidelberg, Germany.|European Molecular Biology Laboratory (EMBL) Heidelberg, Heidelberg, Germany.|European Molecular Biology Laboratory (EMBL) Heidelberg, Heidelberg, Germany.|European Molecular Biology Laboratory (EMBL) Heidelberg, Heidelberg, Germany.', 'Germany|Germany|Germany|Germany', 23, 'Databases, Genetic|Disease|Evolution, Molecular|Gene Expression Profiling|Genes, Duplicate|Genome, Human|Genomics|Humans|Models, Genetic|Mutation', 'Journal Article', '10.1371/journal.pcbi.1003073', '23696728', 'Mendelian disorders are often caused by mutations in genes that are not lethal but induce functional distortions leading to diseases. Here we study the extent of gene duplicates that might compensate genes causing monogenic diseases. We provide evidence for pervasive functional redundancy of human monogenic disease genes (MDs) by duplicates by manifesting 1) genes involved in human genetic disorders are enriched in duplicates and 2) duplicated disease genes tend to have higher functional similarities with their closest paralogs in contrast to duplicated non-disease genes of similar age. We propose that functional compensation by duplication of genes masks the phenotypic effects of deleterious mutations and reduces the probability of purging the defective genes from the human population, this functional compensation could be further enhanced by higher purification selection between disease genes and their duplicates as well as their orthologous counterpart compared to non-disease genes. However, due to the intrinsic expression stochasticity among individuals, the deleterious mutations could still be present as genetic diseases in some subpopulations where the duplicate copies are expressed at low abundances. Consequently the defective genes are linked to genetic disorders while they continue propagating within the population. Our results provide insight into the molecular basis underlying the spreading of duplicated disease genes.'),
(86039, 2013, 'plos', 'The impact of a ligand binding on strand migration in the SAM-I riboswitch', 'Huang, Wei|Kim, Joohyun|Jha, Shantenu|Aboul-ela, Fareed', 'Department of Biological Science, Louisiana State University, Baton Rouge, Louisiana, USA.|Department of Biological Science, Louisiana State University, Baton Rouge, Louisiana, USA.|Department of Biological Science, Louisiana State University, Baton Rouge, Louisiana, USA.|Department of Biological Science, Louisiana State University, Baton Rouge, Louisiana, USA.', 'United States|United States|United States|United States', 0, 'Cluster Analysis|Computational Biology|Hydrogen Bonding|Ligands|Models, Genetic|Molecular Dynamics Simulation|Nucleic Acid Conformation|RNA, Bacterial|Riboswitch|S-Adenosylmethionine', 'Journal Article', '10.1371/journal.pcbi.1003069', '23704854', 'Riboswitches sense cellular concentrations of small molecules and use this information to adjust synthesis rates of related metabolites. Riboswitches include an aptamer domain to detect the ligand and an expression platform to control gene expression. Previous structural studies of riboswitches largely focused on aptamers, truncating the expression domain to suppress conformational switching. To link ligand/aptamer binding to conformational switching, we constructed models of an S-adenosyl methionine (SAM)-I riboswitch RNA segment incorporating elements of the expression platform, allowing formation of an antiterminator (AT) helix. Using Anton, a computer specially developed for long timescale Molecular Dynamics (MD), we simulated an extended (three microseconds) MD trajectory with SAM bound to a modeled riboswitch RNA segment. Remarkably, we observed a strand migration, converting three base pairs from an antiterminator (AT) helix, characteristic of the transcription ON state, to a P1 helix, characteristic of the OFF state. This conformational switching towards the OFF state is observed only in the presence of SAM. Among seven extended trajectories with three starting structures, the presence of SAM enhances the trend towards the OFF state for two out of three starting structures tested. Our simulation provides a visual demonstration of how a small molecule (<500 MW) binding to a limited surface can trigger a large scale conformational rearrangement in a 40 kDa RNA by perturbing the Free Energy Landscape. Such a mechanism can explain minimal requirements for SAM binding and transcription termination for SAM-I riboswitches previously reported experimentally.'),
(86040, 2013, 'plos', 'A balance equation determines a switch in neuronal excitability', 'Franci, Alessio|Drion, Guillaume|Seutin, Vincent|Sepulchre, Rodolphe', 'INRIA Lille-Nord Europe, Orchestron Project, Villeneuve dAscq, France.|INRIA Lille-Nord Europe, Orchestron Project, Villeneuve dAscq, France.|INRIA Lille-Nord Europe, Orchestron Project, Villeneuve dAscq, France.|INRIA Lille-Nord Europe, Orchestron Project, Villeneuve dAscq, France.', 'France|France|France|France', 0, 'Action Potentials|Algorithms|Animals|Axons|Decapodiformes|Feedback, Physiological|Ion Channels|Models, Neurological|Neurons|Rats', 'Journal Article', '10.1371/journal.pcbi.1003040', '23717194', 'We use the qualitative insight of a planar neuronal phase portrait to detect an excitability switch in arbitrary conductance-based models from a simple mathematical condition. The condition expresses a balance between ion channels that provide a negative feedback at resting potential (restorative channels) and those that provide a positive feedback at resting potential (regenerative channels). Geometrically, the condition imposes a transcritical bifurcation that rules the switch of excitability through the variation of a single physiological parameter. Our analysis of six different published conductance based models always finds the transcritical bifurcation and the associated switch in excitability, which suggests that the mathematical predictions have a physiological relevance and that a same regulatory mechanism is potentially involved in the excitability and signaling of many neurons.'),
(86041, 2013, 'plos', 'Simultaneous identification of multiple driver pathways in cancer', 'Leiserson, Mark D M|Blokh, Dima|Sharan, Roded|Raphael, Benjamin J', 'Department of Computer Science and Center for Computational Molecular Biology, Brown University, Providence, RI, USA.|Department of Computer Science and Center for Computational Molecular Biology, Brown University, Providence, RI, USA.|Department of Computer Science and Center for Computational Molecular Biology, Brown University, Providence, RI, USA.|Department of Computer Science and Center for Computational Molecular Biology, Brown University, Providence, RI, USA.', 'United States|United States|United States|United States', 136, 'Algorithms|Computational Biology|Computer Simulation|Databases, Genetic|Humans|Models, Genetic|Mutation|Neoplasms|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1003054', '23717195', 'Distinguishing the somatic mutations responsible for cancer (driver mutations) from random, passenger mutations is a key challenge in cancer genomics. Driver mutations generally target cellular signaling and regulatory pathways consisting of multiple genes. This heterogeneity complicates the identification of driver mutations by their recurrence across samples, as different combinations of mutations in driver pathways are observed in different samples. We introduce the Multi-Dendrix algorithm for the simultaneous identification of multiple driver pathways de novo in somatic mutation data from a cohort of cancer samples. The algorithm relies on two combinatorial properties of mutations in a driver pathway: high coverage and mutual exclusivity. We derive an integer linear program that finds set of mutations exhibiting these properties. We apply Multi-Dendrix to somatic mutations from glioblastoma, breast cancer, and lung cancer samples. Multi-Dendrix identifies sets of mutations in genes that overlap with known pathways - including Rb, p53, PI(3)K, and cell cycle pathways - and also novel sets of mutually exclusive mutations, including mutations in several transcription factors or other genes involved in transcriptional regulation. These sets are discovered directly from mutation data with no prior knowledge of pathways or gene interactions. We show that Multi-Dendrix outperforms other algorithms for identifying combinations of mutations and is also orders of magnitude faster on genome-scale data. Software available at: http://compbio.cs.brown.edu/software.'),
(86042, 2013, 'plos', 'Inference of gene regulatory networks with sparse structural equation models exploiting genetic perturbations', 'Cai, Xiaodong|Bazerque, Juan Andrés|Giannakis, Georgios B', 'Department of Electrical and Computer Engineering, University of Miami, Coral Gables, FL, USA. x.cai@miami.edu|Department of Electrical and Computer Engineering, University of Miami, Coral Gables, FL, USA. x.cai@miami.edu|Department of Electrical and Computer Engineering, University of Miami, Coral Gables, FL, USA. x.cai@miami.edu', 'United States|United States|United States', 77, 'Algorithms|Cell Line|Computational Biology|Computer Simulation|Gene Regulatory Networks|HapMap Project|Humans|Immune System Phenomena|Models, Genetic|Quantitative Trait Loci', 'Journal Article', '10.1371/journal.pcbi.1003068', '23717196', 'Integrating genetic perturbations with gene expression data not only improves accuracy of regulatory network topology inference, but also enables learning of causal regulatory relations between genes. Although a number of methods have been developed to integrate both types of data, the desiderata of efficient and powerful algorithms still remains. In this paper, sparse structural equation models (SEMs) are employed to integrate both gene expression data and cis-expression quantitative trait loci (cis-eQTL), for modeling gene regulatory networks in accordance with biological evidence about genes regulating or being regulated by a small number of genes. A systematic inference method named sparsity-aware maximum likelihood (SML) is developed for SEM estimation. Using simulated directed acyclic or cyclic networks, the SML performance is compared with that of two state-of-the-art algorithms: the adaptive Lasso (AL) based scheme, and the QTL-directed dependency graph (QDG) method. Computer simulations demonstrate that the novel SML algorithm offers significantly better performance than the AL-based and QDG algorithms across all sample sizes from 100 to 1,000, in terms of detection power and false discovery rate, in all the cases tested that include acyclic or cyclic networks of 10, 30 and 300 genes. The SML method is further applied to infer a network of 39 human genes that are related to the immune function and are chosen to have a reliable eQTL per gene. The resulting network consists of 9 genes and 13 edges. Most of the edges represent interactions reasonably expected from experimental evidence, while the remaining may just indicate the emergence of new interactions. The sparse SEM and efficient SML algorithm provide an effective means of exploiting both gene expression and perturbation data to infer gene regulatory networks. An open-source computer program implementing the SML algorithm is freely available upon request.'),
(86043, 2013, 'plos', 'Gate-keeper residues and active-site rearrangements in DNA polymerase xcexbc help discriminate non-cognate nucleotides', 'Li, Yunlang|Schlick, Tamar', 'Department of Chemistry and Courant Institute of Mathematical Sciences, New York University, New York, NY, USA.|Department of Chemistry and Courant Institute of Mathematical Sciences, New York University, New York, NY, USA.', 'United States|United States', 0, 'Amino Acids|Base Pairing|Catalytic Domain|DNA|DNA-Directed DNA Polymerase|Molecular Dynamics Simulation|Nucleotides|Protein Binding|Protein Conformation|Static Electricity', 'Journal Article', '10.1371/journal.pcbi.1003074', '23717197', 'Incorporating the cognate instead of non-cognate substrates is crucial for DNA polymerase function. Here we analyze molecular dynamics simulations of DNA polymerase xcexbc (pol xcexbc) bound to different non-cognate incoming nucleotides including A:dCTP, A:dGTP, A(syn):dGTP, A:dATP, A(syn):dATP, T:dCTP, and T:dGTP to study the structure-function relationships involved with aberrant base pairs in the conformational pathway, while a pol xcexbc complex with the A:dTTP base pair is available, no solved non-cognate structures are available. We observe distinct differences of the non-cognate systems compared to the cognate system. Specifically, the motions of active-site residue His329 and Asp330 distort the active site, and Trp436, Gln440, Glu443 and Arg444 tend to tighten the nucleotide-binding pocket when non-cognate nucleotides are bound, the latter effect may further lead to an altered electrostatic potential within the active site. That most of these gate-keeper residues are located farther apart from the upstream primer in pol xcexbc, compared to other X family members, also suggests an interesting relation to pol xcexbcs ability to incorporate nucleotides when the upstream primer is not paired. By examining the correlated motions within pol xcexbc complexes, we also observe different patterns of correlations between non-cognate systems and the cognate system, especially decreased interactions between the incoming nucleotides and the nucleotide-binding pocket. Altered correlated motions in non-cognate systems agree with our recently proposed hybrid conformational selection/induced-fit models. Taken together, our studies propose the following order for difficulty of non-cognate system insertions by pol xcexbc: T:dGTP<A(syn):dATP<T:dCTP<A:dGTP<A(syn):dGTP<A:dCTP<A:dATP. This sequence agrees with available kinetic data for non-cognate nucleotide insertions, with the exception of A:dGTP, which may be more sensitive to the template sequence. The structures and conformational aspects predicted here are experimentally testable.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86044, 2013, 'plos', 'Testing whether humans have an accurate model of their own motor uncertainty in a speeded reaching task', 'Zhang, Hang|Daw, Nathaniel D|Maloney, Laurence T', 'Department of Psychology, New York University, New York, NY, USA. hang.zhang@nyu.edu|Department of Psychology, New York University, New York, NY, USA. hang.zhang@nyu.edu|Department of Psychology, New York University, New York, NY, USA. hang.zhang@nyu.edu', 'United States|United States|United States', 20, 'Choice Behavior|Computational Biology|Feedback|Female|Humans|Male|Models, Biological|Models, Statistical|Normal Distribution|Psychomotor Performance', 'Journal Article', '10.1371/journal.pcbi.1003080', '23717198', 'In many motor tasks, optimal performance presupposes that human movement planning is based on an accurate internal model of the subjects own motor error. We developed a motor choice task that allowed us to test whether the internal model implicit in a subjects choices differed from the actual in isotropy (elongation) and variance. Subjects were first trained to hit a circular target on a touch screen within a time limit. After training, subjects were repeatedly shown pairs of targets differing in size and shape and asked to choose the target that was easier to hit. On each trial they simply chose a target - they did not attempt to hit the chosen target. For each subject, we tested whether the internal model implicit in her target choices was consistent with her true error distribution in isotropy and variance. For all subjects, movement end points were anisotropic, distributed as vertically elongated bivariate Gaussians. However, in choosing targets, almost all subjects effectively assumed an isotropic distribution rather than their actual anisotropic distribution. Roughly half of the subjects chose as though they correctly estimated their own variance and the other half effectively assumed a variance that was more than four times larger than the actual, essentially basing their choices merely on the areas of the targets. The task and analyses we developed allowed us to characterize the internal model of motor error implicit in how humans plan reaching movements. In this task, human movement planning - even after extensive training - is based on an internal model of human motor error that includes substantial and qualitative inaccuracies.'),
(86045, 2013, 'plos', 'Biases in the experimental annotations of protein function and their effect on our understanding of protein function space', 'Schnoes, Alexandra M|Ream, David C|Thorman, Alexander W|Babbitt, Patricia C|Friedberg, Iddo', 'Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.|Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.|Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.|Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.|Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.', 'United States|United States|United States|United States|United States', 0, 'Animals|Computational Biology|Databases, Protein|High-Throughput Screening Assays|Humans|Molecular Sequence Annotation|Proteins', 'Journal Article', '10.1371/journal.pcbi.1003063', '23737737', 'The ongoing functional annotation of proteins relies upon the work of curators to capture experimental findings from scientific literature and apply them to protein sequence and structure data. However, with the increasing use of high-throughput experimental assays, a small number of experimental studies dominate the functional protein annotations collected in databases. Here, we investigate just how prevalent is the few articles - many proteins phenomenon. We examine the experimentally validated annotation of proteins provided by several groups in the GO Consortium, and show that the distribution of proteins per published study is exponential, with 0.14% of articles providing the source of annotations for 25% of the proteins in the UniProt-GOA compilation. Since each of the dominant articles describes the use of an assay that can find only one function or a small group of functions, this leads to substantial biases in what we know about the function of many proteins. Mass-spectrometry, microscopy and RNAi experiments dominate high throughput experiments. Consequently, the functional information derived from these experiments is mostly of the subcellular location of proteins, and of the participation of proteins in embryonic developmental pathways. For some organisms, the information provided by different studies overlap by a large amount. We also show that the information provided by high throughput experiments is less specific than those provided by low throughput experiments. Given the experimental techniques available, certain biases in protein function annotation due to high-throughput experiments are unavoidable. Knowing that these biases exist and understanding their characteristics and extent is important for database curators, developers of function annotation programs, and anyone who uses protein function annotation data to plan experiments.'),
(86046, 2013, 'plos', 'Computational assessment of the cooperativity between RNA binding proteins and MicroRNAs in Transcript Decay', 'Jiang, Peng|Singh, Mona|Coller, Hilary A', 'Department of Computer Science, Princeton University, Princeton, New Jersey, USA.|Department of Computer Science, Princeton University, Princeton, New Jersey, USA.|Department of Computer Science, Princeton University, Princeton, New Jersey, USA.', 'Jersey|Jersey|Jersey', 19, 'Amino Acid Motifs|Animals|Computational Biology|Humans|Mice|MicroRNAs|Models, Genetic|RNA Stability|RNA-Binding Proteins', 'Journal Article', '10.1371/journal.pcbi.1003075', '23737738', 'Transcript degradation is a widespread and important mechanism for regulating protein abundance. Two major regulators of transcript degradation are RNA Binding Proteins (RBPs) and microRNAs (miRNAs). We computationally explored whether RBPs and miRNAs cooperate to promote transcript decay. We defined five RBP motifs based on the evolutionary conservation of their recognition sites in 3UTRs as the binding motifs for Pumilio (PUM), U1A, Fox-1, Nova, and UAUUUAU. Recognition sites for some of these RBPs tended to localize at the end of long 3UTRs. A specific group of miRNA recognition sites were enriched within 50 nts from the RBP recognition sites for PUM and UAUUUAU. The presence of both a PUM recognition site and a recognition site for preferentially co-occurring miRNAs was associated with faster decay of the associated transcripts. For PUM and its co-occurring miRNAs, binding of the RBP to its recognition sites was predicted to release nearby miRNA recognition sites from RNA secondary structures. The mammalian miRNAs that preferentially co-occur with PUM binding sites have recognition seeds that are reverse complements to the PUM recognition motif. Their binding sites have the potential to form hairpin secondary structures with proximal PUM binding sites that would normally limit RISC accessibility, but would be more accessible to miRNAs in response to the binding of PUM. In sum, our computational analyses suggest that a specific set of RBPs and miRNAs work together to affect transcript decay, with the rescue of miRNA recognition sites via RBP binding as one possible mechanism of cooperativity.'),
(86047, 2013, 'plos', 'Rocky mountain conference on bioinformatics celebrates 10 years', 'Hunter, Lawrence E', 'Center for Computational Pharmacology & Computational Bioscience Program, University of Colorado Denver, Aurora, Colorado, USA. Larry.Hunter@ucdenver.edu', 'United States', 0, 'Colorado|Computational Biology|Congresses as Topic|History, 21st Century|Humans', 'Historical Article', '10.1371/journal.pcbi.1003076', '23737739', '-'),
(86048, 2013, 'plos', 'Coordination of rapid sphingolipid responses to heat stress in yeast', 'Chen, Po-Wei|Fonseca, Luis L|Hannun, Yusuf A|Voit, Eberhard O', 'Integrative BioSystems Institute and Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA.|Integrative BioSystems Institute and Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA.|Integrative BioSystems Institute and Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA.|Integrative BioSystems Institute and Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA.', 'Georgia|Georgia|Georgia|Georgia', 0, 'Alkaline Ceramidase|Coenzyme A Ligases|Fungal Proteins|Heat-Shock Response|Metabolic Networks and Pathways|Models, Biological|Saccharomyces cerevisiae|Sphingolipids', 'Journal Article', '10.1371/journal.pcbi.1003078', '23737740', 'The regulatory roles of sphingolipids in diverse cell functions have been characterized extensively. However, the dynamics and interactions among the different sphingolipid species are difficult to assess, because de novo biosynthesis, metabolic inter-conversions, and the retrieval of sphingolipids from membranes form a complex, highly regulated pathway system. Here we analyze the heat stress response of this system in the yeast Saccharomyces cerevisiae and demonstrate how the cell dynamically adjusts its enzyme profile so that it is appropriate for operation under stress conditions before changes in gene expression become effective. The analysis uses metabolic time series data, a complex mathematical model, and a custom-tailored optimization strategy. The results demonstrate that all enzyme activities rapidly increase in an immediate response to the elevated temperature. After just a few minutes, different functional clusters of enzymes follow distinct activity patterns. Interestingly, starting after about six minutes, both de novo biosynthesis and all exit routes from central sphingolipid metabolism become blocked, and the remaining metabolic activity consists entirely of an internal redistribution among different sphingoid base and ceramide pools. After about 30 minutes, heat stress is still in effect and the enzyme activity profile is still significantly changed. Importantly, however, the metabolites have regained concentrations that are essentially the same as those under optimal conditions.'),
(86049, 2013, 'plos', 'A two-stage cascade model of BOLD responses in human visual cortex', 'Kay, Kendrick N|Winawer, Jonathan|Rokem, Ariel|Mezer, Aviv|Wandell, Brian A', 'Department of Psychology, Stanford University, Stanford, California, USA. kendrick@post.harvard.edu|Department of Psychology, Stanford University, Stanford, California, USA. kendrick@post.harvard.edu|Department of Psychology, Stanford University, Stanford, California, USA. kendrick@post.harvard.edu|Department of Psychology, Stanford University, Stanford, California, USA. kendrick@post.harvard.edu|Department of Psychology, Stanford University, Stanford, California, USA. kendrick@post.harvard.edu', 'United States|United States|United States|United States|United States', 0, 'Adult|Bayes Theorem|Computational Biology|Humans|Linear Models|Magnetic Resonance Imaging|Male|Models, Neurological|Nonlinear Dynamics|Photic Stimulation|Signal Processing, Computer-Assisted|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1003079', '23737741', 'Visual neuroscientists have discovered fundamental properties of neural representation through careful analysis of responses to controlled stimuli. Typically, different properties are studied and modeled separately. To integrate our knowledge, it is necessary to build general models that begin with an input image and predict responses to a wide range of stimuli. In this study, we develop a model that accepts an arbitrary band-pass grayscale image as input and predicts blood oxygenation level dependent (BOLD) responses in early visual cortex as output. The model has a cascade architecture, consisting of two stages of linear and nonlinear operations. The first stage involves well-established computations-local oriented filters and divisive normalization-whereas the second stage involves novel computations-compressive spatial summation (a form of normalization) and a variance-like nonlinearity that generates selectivity for second-order contrast. The parameters of the model, which are estimated from BOLD data, vary systematically across visual field maps: compared to primary visual cortex, extrastriate maps generally have larger receptive field size, stronger levels of normalization, and increased selectivity for second-order contrast. Our results provide insight into how stimuli are encoded and transformed in successive stages of visual processing.'),
(86050, 2013, 'plos', 'A mechanical design principle for tissue structure and function in the airway tree', 'LaPrad, Adam S|Lutchen, Kenneth R|Suki, Béla', 'Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA.|Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA.|Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA.', 'United States|United States|United States', 0, 'Adult|Animals|Biomechanical Phenomena|Cattle|Child, Preschool|Computational Biology|Elastic Modulus|Homeostasis|Humans|Infant|Lung|Models, Biological|Total Lung Capacity', 'Journal Article', '10.1371/journal.pcbi.1003083', '23737742', 'With every breath, the dynamically changing mechanical pressures must work in unison with the cells and soft tissue structures of the lung to permit air to efficiently traverse the airway tree and undergo gas exchange in the alveoli. The influence of mechanics on cell and tissue function is becoming apparent, raising the question: how does the airway tree co-exist within its mechanical environment to maintain normal cell function throughout its branching structure of diminishing dimensions? We introduce a new mechanical design principle for the conducting airway tree in which mechanotransduction at the level of cells is driven to orchestrate airway wall structural changes that can best maintain a preferred mechanical microenvironment. To support this principle, we report in vitro radius-transmural pressure relations for a range of airway radii obtained from healthy bovine lungs and model the data using a strain energy function together with a thick-walled cylinder description. From this framework, we estimate circumferential stresses and incremental Youngs moduli throughout the airway tree. Our results indicate that the conducting airways consistently operate within a preferred mechanical homeostatic state, termed mechanical homeostasis, that is characterized by a narrow range of circumferential stresses and Youngs moduli. This mechanical homeostatic state is maintained for all airways throughout the tree via airway wall dimensional and mechanical relationships. As a consequence, cells within the airway walls throughout the airway tree experience similar oscillatory strains during breathing that are much smaller than previously thought. Finally, we discuss the potential implications of how the maintenance of mechanical homeostasis, while facilitating healthy tissue-level alterations necessary for maturation, may lead to airway wall structural changes capable of chronic asthma.'),
(86051, 2013, 'plos', 'Critical role of transient activity of MT1-MMP for ECM degradation in invadopodia', 'Watanabe, Ayako|Hoshino, Daisuke|Hosino, Daisuke|Koshikawa, Naohiko|Seiki, Motoharu|Suzuki, Takashi|Ichikawa, Kazuhisa', 'Division of Mathematical Oncology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.|Division of Mathematical Oncology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.|Division of Mathematical Oncology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.|Division of Mathematical Oncology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.|Division of Mathematical Oncology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.|Division of Mathematical Oncology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.|Division of Mathematical Oncology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.', 'Japan|Japan|Japan|Japan|Japan|Japan|Japan', 28, 'Cell Line, Tumor|Computational Biology|Computer Simulation|Extracellular Matrix|Humans|Matrix Metalloproteinase 14|Models, Biological|Neoplastic Processes', 'Journal Article', '10.1371/journal.pcbi.1003086', '23737743', 'Focal degradation of extracellular matrix (ECM) is the first step in the invasion of cancer cells. MT1-MMP is a potent membrane proteinase employed by aggressive cancer cells. In our previous study, we reported that MT1-MMP was preferentially located at membrane protrusions called invadopodia, where MT1-MMP underwent quick turnover. Our computer simulation and experiments showed that this quick turnover was essential for the degradation of ECM at invadopodia (Hoshino, D., et al., (2012) PLoS Comp. Biol., 8: e1002479). Here we report on characterization and analysis of the ECM-degrading activity of MT1-MMP, aiming at elucidating a possible reason for its repetitive insertion in the ECM degradation. First, in our computational model, we found a very narrow transient peak in the activity of MT1-MMP followed by steady state activity. This transient activity was due to the inhibition by TIMP-2, and the steady state activity of MT1-MMP decreased dramatically at higher TIMP-2 concentrations. Second, we evaluated the role of the narrow transient activity in the ECM degradation. When the transient activity was forcibly suppressed in computer simulations, the ECM degradation was heavily suppressed, indicating the essential role of this transient peak in the ECM degradation. Third, we compared continuous and pulsatile turnover of MT1-MMP in the ECM degradation at invadopodia. The pulsatile insertion showed basically consistent results with the continuous insertion in the ECM degradation, and the ECM degrading efficacy depended heavily on the transient activity of MT1-MMP in both models. Unexpectedly, however, low-frequency/high-concentration insertion of MT1-MMP was more effective in ECM degradation than high-frequency/low-concentration pulsatile insertion even if the time-averaged amount of inserted MT1-MMP was the same. The present analysis and characterization of ECM degradation by MT1-MMP together with our previous report indicate a dynamic nature of MT1-MMP at invadopodia and the importance of its transient peak in the degradation of the ECM.'),
(86052, 2013, 'plos', 'Are v1 simple cells optimized for visual occlusions? A comparative study', 'Bornschein, Jörg|Henniges, Marc|Lücke, Jörg', 'Frankfurt Institute for Advanced Studies, Goethe-Universität Frankfurt, Frankfurt, Germany.|Frankfurt Institute for Advanced Studies, Goethe-Universität Frankfurt, Frankfurt, Germany.|Frankfurt Institute for Advanced Studies, Goethe-Universität Frankfurt, Frankfurt, Germany.', 'Germany|Germany|Germany', 0, 'Animals|Computational Biology|Humans|Models, Theoretical|Vision, Ocular|Visual Cortex', 'Comparative Study', '10.1371/journal.pcbi.1003062', '23754938', 'Simple cells in primary visual cortex were famously found to respond to low-level image components such as edges. Sparse coding and independent component analysis (ICA) emerged as the standard computational models for simple cell coding because they linked their receptive fields to the statistics of visual stimuli. However, a salient feature of image statistics, occlusions of image components, is not considered by these models. Here we ask if occlusions have an effect on the predicted shapes of simple cell receptive fields. We use a comparative approach to answer this question and investigate two models for simple cells: a standard linear model and an occlusive model. For both models we simultaneously estimate optimal receptive fields, sparsity and stimulus noise. The two models are identical except for their component superposition assumption. We find the image encoding and receptive fields predicted by the models to differ significantly. While both models predict many Gabor-like fields, the occlusive model predicts a much sparser encoding and high percentages of globular receptive fields. This relatively new center-surround type of simple cell response is observed since reverse correlation is used in experimental studies. While high percentages of globular fields can be obtained using specific choices of sparsity and overcompleteness in linear sparse coding, no or only low proportions are reported in the vast majority of studies on linear models (including all ICA models). Likewise, for the here investigated linear model and optimal sparsity, only low proportions of globular fields are observed. In comparison, the occlusive model robustly infers high proportions and can match the experimentally observed high proportions of globular fields well. Our computational study, therefore, suggests that globular fields may be evidence for an optimal encoding of visual occlusions in primary visual cortex.'),
(86053, 2013, 'plos', 'Combinatorial clustering of residue position subsets predicts inhibitor affinity across the human kinome', 'Bryant, Drew H|Moll, Mark|Finn, Paul W|Kavraki, Lydia E', 'Department of Computer Science, Rice University, Houston, Texas, United States of America.|Department of Computer Science, Rice University, Houston, Texas, United States of America.|Department of Computer Science, Rice University, Houston, Texas, United States of America.|Department of Computer Science, Rice University, Houston, Texas, United States of America.', 'United States|United States|United States|United States', 13, 'Cluster Analysis|Humans|Models, Theoretical|Protein Kinases|Proteome|Support Vector Machine', 'Journal Article', '10.1371/journal.pcbi.1003087', '23754939', 'The protein kinases are a large family of enzymes that play fundamental roles in propagating signals within the cell. Because of the high degree of binding site similarity shared among protein kinases, designing drug compounds with high specificity among the kinases has proven difficult. However, computational approaches to comparing the 3-dimensional geometry and physicochemical properties of key binding site residue positions have been shown to be informative of inhibitor selectivity. The Combinatorial Clustering Of Residue Position Subsets (ccorps) method, introduced here, provides a semi-supervised learning approach for identifying structural features that are correlated with a given set of annotation labels. Here, ccorps is applied to the problem of identifying structural features of the kinase atp binding site that are informative of inhibitor binding. ccorps is demonstrated to make perfect or near-perfect predictions for the binding affinity profile of 8 of the 38 kinase inhibitors studied, while only having overall poor predictive ability for 1 of the 38 compounds. Additionally, ccorps is shown to identify shared structural features across phylogenetically diverse groups of kinases that are correlated with binding affinity for particular inhibitors, such instances of structural similarity among phylogenetically diverse kinases are also shown to not be rare among kinases. Finally, these function-specific structural features may serve as potential starting points for the development of highly specific kinase inhibitors.'),
(86054, 2013, 'plos', 'Scrutinizing MHC-I binding peptides and their limits of variation', 'Koch, Christian P|Perna, Anna M|Pillong, Max|Todoroff, Nickolay K|Wrede, Paul|Folkers, Gerd|Hiss, Jan A|Schneider, Gisbert', 'ETH Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zürich, Switzerland.|ETH Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zürich, Switzerland.|ETH Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zürich, Switzerland.|ETH Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zürich, Switzerland.|ETH Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zürich, Switzerland.|ETH Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zürich, Switzerland.|ETH Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zürich, Switzerland.|ETH Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zürich, Switzerland.', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 0, 'Animals|Artificial Intelligence|Computational Biology|Histocompatibility Antigens Class I|Mice|Peptides|Protein Binding', 'Journal Article', '10.1371/journal.pcbi.1003088', '23754940', 'Designed peptides that bind to major histocompatibility protein I (MHC-I) allomorphs bear the promise of representing epitopes that stimulate a desired immune response. A rigorous bioinformatical exploration of sequence patterns hidden in peptides that bind to the mouse MHC-I allomorph H-2K(b) is presented. We exemplify and validate these motif findings by systematically dissecting the epitope SIINFEKL and analyzing the resulting fragments for their binding potential to H-2K(b) in a thermal denaturation assay. The results demonstrate that only fragments exclusively retaining the carboxy- or amino-terminus of the reference peptide exhibit significant binding potential, with the N-terminal pentapeptide SIINF as shortest ligand. This study demonstrates that sophisticated machine-learning algorithms excel at extracting fine-grained patterns from peptide sequence data and predicting MHC-I binding peptides, thereby considerably extending existing linear prediction models and providing a fresh view on the computer-based molecular design of future synthetic vaccines. The server for prediction is available at http://modlab-cadd.ethz.ch (SLiDER tool, MHC-I version 2012).'),
(86055, 2013, 'plos', 'Gag-Pol processing during HIV-1 virion maturation: a systems biology approach', 'Kxc3xb6nnyxc5xb1, Balxc3xa1zs|Sadiq, S Kashif|Turxc3xa1nyi, Tamxc3xa1s|Hxc3xadrmondxc3xb3, Rita|Mxc3xbcller, Barbara|Krxc3xa4usslich, Hans-Georg|Coveney, Peter V|Mxc3xbcller, Viktor', 'Institute of Biology, Exc3xb6tvxc3xb6s Lorxc3xa1nd University, Budapest, Hungary.|Institute of Biology, Exc3xb6tvxc3xb6s Lorxc3xa1nd University, Budapest, Hungary.|Institute of Biology, Exc3xb6tvxc3xb6s Lorxc3xa1nd University, Budapest, Hungary.|Institute of Biology, Exc3xb6tvxc3xb6s Lorxc3xa1nd University, Budapest, Hungary.|Institute of Biology, Exc3xb6tvxc3xb6s Lorxc3xa1nd University, Budapest, Hungary.|Institute of Biology, Exc3xb6tvxc3xb6s Lorxc3xa1nd University, Budapest, Hungary.|Institute of Biology, Exc3xb6tvxc3xb6s Lorxc3xa1nd University, Budapest, Hungary.|Institute of Biology, Exc3xb6tvxc3xb6s Lorxc3xa1nd University, Budapest, Hungary.', 'Hungary|Hungary|Hungary|Hungary|Hungary|Hungary|Hungary|Hungary', 0, 'Genes, gag|Genes, pol|HIV-1|Proteolysis|Systems Biology|Virion', 'Journal Article', '10.1371/journal.pcbi.1003103', '23754941', 'Proteolytic processing of Gag and Gag-Pol polyproteins by the viral protease (PR) is crucial for the production of infectious HIV-1, and inhibitors of the viral PR are an integral part of current antiretroviral therapy. The process has several layers of complexity (multiple cleavage sites and substrates, multiple enzyme forms, PR auto-processing), which calls for a systems level approach to identify key vulnerabilities and optimal treatment strategies. Here we present the first full reaction kinetics model of proteolytic processing by HIV-1 PR, taking into account all canonical cleavage sites within Gag and Gag-Pol, intermediate products and enzyme forms, enzyme dimerization, the initial auto-cleavage of full-length Gag-Pol as well as self-cleavage of PR. The model allows us to identify the rate limiting step of virion maturation and the parameters with the strongest effect on maturation kinetics. Using the modelling framework, we predict interactions and compensatory potential between individual cleavage rates and drugs, characterize the time course of the process, explain the steep dose response curves associated with PR inhibitors and gain new insights into drug action. While the results of the model are subject to limitations arising from the simplifying assumptions used and from the uncertainties in the parameter estimates, the developed framework provides an extendable open-access platform to incorporate new data and hypotheses in the future.'),
(86056, 2013, 'plos', 'Theta coordinated error-driven learning in the hippocampus', 'Ketz, Nicholas|Morkonda, Srinimisha G|OReilly, Randall C', 'Department of Psychology, University of Colorado Boulder, Boulder, Colorado, United States of America.|Department of Psychology, University of Colorado Boulder, Boulder, Colorado, United States of America.|Department of Psychology, University of Colorado Boulder, Boulder, Colorado, United States of America.', 'United States|United States|United States', 24, 'Hippocampus|Humans|Learning|Models, Biological|Theta Rhythm', 'Journal Article', '10.1371/journal.pcbi.1003067', '23762019', 'The learning mechanism in the hippocampus has almost universally been assumed to be Hebbian in nature, where individual neurons in an engram join together with synaptic weight increases to support facilitated recall of memories later. However, it is also widely known that Hebbian learning mechanisms impose significant capacity constraints, and are generally less computationally powerful than learning mechanisms that take advantage of error signals. We show that the differential phase relationships of hippocampal subfields within the overall theta rhythm enable a powerful form of error-driven learning, which results in significantly greater capacity, as shown in computer simulations. In one phase of the theta cycle, the bidirectional connectivity between CA1 and entorhinal cortex can be trained in an error-driven fashion to learn to effectively encode the cortical inputs in a compact and sparse form over CA1. In a subsequent portion of the theta cycle, the system attempts to recall an existing memory, via the pathway from entorhinal cortex to CA3 and CA1. Finally the full theta cycle completes when a strong target encoding representation of the current input is imposed onto the CA1 via direct projections from entorhinal cortex. The difference between this target encoding and the attempted recall of the same representation on CA1 constitutes an error signal that can drive the learning of CA3 to CA1 synapses. This CA3 to CA1 pathway is critical for enabling full reinstatement of recalled hippocampal memories out in cortex. Taken together, these new learning dynamics enable a much more robust, high-capacity model of hippocampal learning than was available previously under the classical Hebbian model.'),
(86057, 2013, 'plos', 'Constraint and contingency in multifunctional gene regulatory circuits', 'Payne, Joshua L|Wagner, Andreas', 'University of Zurich, Institute of Evolutionary Biology and Environmental Studies, Zurich, Switzerland.|University of Zurich, Institute of Evolutionary Biology and Environmental Studies, Zurich, Switzerland.', 'Switzerland|Switzerland', 0, 'Gene Expression|Gene Regulatory Networks|Genotype|Humans|Models, Genetic', 'Journal Article', '10.1371/journal.pcbi.1003071', '23762020', 'Gene regulatory circuits drive the development, physiology, and behavior of organisms from bacteria to humans. The phenotypes or functions of such circuits are embodied in the gene expression patterns they form. Regulatory circuits are typically multifunctional, forming distinct gene expression patterns in different embryonic stages, tissues, or physiological states. Any one circuit with a single function can be realized by many different regulatory genotypes. Multifunctionality presumably constrains this number, but we do not know to what extent. We here exhaustively characterize a genotype space harboring millions of model regulatory circuits and all their possible functions. As a circuits number of functions increases, the number of genotypes with a given number of functions decreases exponentially but can remain very large for a modest number of functions. However, the sets of circuits that can form any one set of functions becomes increasingly fragmented. As a result, historical contingency becomes widespread in circuits with many functions. Whether a circuit can acquire an additional function in the course of its evolution becomes increasingly dependent on the function it already has. Circuits with many functions also become increasingly brittle and sensitive to mutation. These observations are generic properties of a broad class of circuits and independent of any one circuit genotype or phenotype.'),
(86058, 2013, 'plos', 'Quantitative analysis of glycerol accumulation, glycolysis and growth under hyper osmotic stress', 'Petelenz-Kurdziel, Elzbieta|Kuehn, Clemens|Nordlander, Bodil|Klein, Dagmara|Hong, Kuk-Ki|Jacobson, Therese|Dahl, Peter|Schaber, Jörg|Nielsen, Jens|Hohmann, Stefan|Klipp, Edda', 'Department of Chemistry and Molecular Biology/Microbiology, University of Gothenburg, Göteborg, Sweden.|Department of Chemistry and Molecular Biology/Microbiology, University of Gothenburg, Göteborg, Sweden.|Department of Chemistry and Molecular Biology/Microbiology, University of Gothenburg, Göteborg, Sweden.|Department of Chemistry and Molecular Biology/Microbiology, University of Gothenburg, Göteborg, Sweden.|Department of Chemistry and Molecular Biology/Microbiology, University of Gothenburg, Göteborg, Sweden.|Department of Chemistry and Molecular Biology/Microbiology, University of Gothenburg, Göteborg, Sweden.|Department of Chemistry and Molecular Biology/Microbiology, University of Gothenburg, Göteborg, Sweden.|Department of Chemistry and Molecular Biology/Microbiology, University of Gothenburg, Göteborg, Sweden.|Department of Chemistry and Molecular Biology/Microbiology, University of Gothenburg, Göteborg, Sweden.|Department of Chemistry and Molecular Biology/Microbiology, University of Gothenburg, Göteborg, Sweden.|Department of Chemistry and Molecular Biology/Microbiology, University of Gothenburg, Göteborg, Sweden.', 'Sweden|Sweden|Sweden|Sweden|Sweden|Sweden|Sweden|Sweden|Sweden|Sweden|Sweden', 0, 'Glycerol|Glycolysis|Models, Biological|Osmotic Pressure|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1003084', '23762021', 'We provide an integrated dynamic view on a eukaryotic osmolyte system, linking signaling with regulation of gene expression, metabolic control and growth. Adaptation to osmotic changes enables cells to adjust cellular activity and turgor pressure to an altered environment. The yeast Saccharomyces cerevisiae adapts to hyperosmotic stress by activating the HOG signaling cascade, which controls glycerol accumulation. The Hog1 kinase stimulates transcription of genes encoding enzymes required for glycerol production (Gpd1, Gpp2) and glycerol import (Stl1) and activates a regulatory enzyme in glycolysis (Pfk26/27). In addition, glycerol outflow is prevented by closure of the Fps1 glycerol facilitator. In order to better understand the contributions to glycerol accumulation of these different mechanisms and how redox and energy metabolism as well as biomass production are maintained under such conditions we collected an extensive dataset. Over a period of 180 min after hyperosmotic shock we monitored in wild type and different mutant cells the concentrations of key metabolites and proteins relevant for osmoadaptation. The dataset was used to parameterize an ODE model that reproduces the generated data very well. A detailed computational analysis using time-dependent response coefficients showed that Pfk26/27 contributes to rerouting glycolytic flux towards lower glycolysis. The transient growth arrest following hyperosmotic shock further adds to redirecting almost all glycolytic flux from biomass towards glycerol production. Osmoadaptation is robust to loss of individual adaptation pathways because of the existence and upregulation of alternative routes of glycerol accumulation. For instance, the Stl1 glycerol importer contributes to glycerol accumulation in a mutant with diminished glycerol production capacity. In addition, our observations suggest a role for trehalose accumulation in osmoadaptation and that Hog1 probably directly contributes to the regulation of the Fps1 glycerol facilitator. Taken together, we elucidated how different metabolic adaptation mechanisms cooperate and provide hypotheses for further experimental studies.'),
(86059, 2013, 'plos', 'Leveraging prior information to detect causal variants via multi-variant regression', 'Long, Nanye|Dickson, Samuel P|Maia, Jessica M|Kim, Hee Shin|Zhu, Qianqian|Allen, Andrew S', 'Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, United States of America. n.long@duke.edu|Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, United States of America. n.long@duke.edu|Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, United States of America. n.long@duke.edu|Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, United States of America. n.long@duke.edu|Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, United States of America. n.long@duke.edu|Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, United States of America. n.long@duke.edu', 'United States|United States|United States|United States|United States|United States', 0, 'Causality|Exome|Genome-Wide Association Study|Genotype|Models, Theoretical|Regression Analysis', 'Journal Article', '10.1371/journal.pcbi.1003093', '23762022', 'Although many methods are available to test sequence variants for association with complex diseases and traits, methods that specifically seek to identify causal variants are less developed. Here we develop and evaluate a Bayesian hierarchical regression method that incorporates prior information on the likelihood of variant causality through weighting of variant effects. By simulation studies using both simulated and real sequence variants, we compared a standard single variant test for analyzing variant-disease association with the proposed method using different weighting schemes. We found that by leveraging linkage disequilibrium of variants with known GWAS signals and sequence conservation (phastCons), the proposed method provides a powerful approach for detecting causal variants while controlling false positives.'),
(86060, 2013, 'plos', 'Patterns of proliferative activity in the colonic crypt determine crypt stability and rates of somatic evolution', 'Zhao, Rui|Michor, Franziska', 'Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America.', 'United States|United States', 0, 'Biological Evolution|Cell Proliferation|Chromosomal Instability|Colon|Humans|Intestinal Mucosa|Models, Biological|Mutation', 'Journal Article', '10.1371/journal.pcbi.1003082', '23785264', 'Epithelial cells in the colon are arranged in cylindrical structures called crypts in which cellular proliferation and migration are tightly regulated. We hypothesized that the proliferation patterns of cells may determine the stability of crypts as well as the rates of somatic evolution towards colorectal tumorigenesis. Here, we propose a linear process model of colonic epithelial cells that explicitly takes into account the proliferation kinetics of cells as a function of cell position within the crypt. Our results indicate that proliferation kinetics has significant influence on the speed of cell movement, kinetics of mutation propagation, and sensitivity of the system to selective effects of mutated cells. We found that, of all proliferation curves tested, those with mitotic activities concentrated near the stem cell, including the actual proliferation kinetics determined in in vivo labeling experiments, have a greater ability of delaying the rate of mutation accumulation in colonic stem cells compared to hypothetical proliferation curves with mitotic activities focused near the top of the crypt column. Our model can be used to investigate the dynamics of proliferation and mutation accumulation in spatially arranged tissues.'),
(86061, 2013, 'plos', 'Unsupervised clustering of subcellular protein expression patterns in high-throughput microscopy images reveals protein complexes and functional relationships between proteins', 'Handfield, Louis-François|Chong, Yolanda T|Simmons, Jibril|Andrews, Brenda J|Moses, Alan M', 'Department of Computer Science, University of Toronto, Ontario, Canada.|Department of Computer Science, University of Toronto, Ontario, Canada.|Department of Computer Science, University of Toronto, Ontario, Canada.|Department of Computer Science, University of Toronto, Ontario, Canada.|Department of Computer Science, University of Toronto, Ontario, Canada.', 'Canada|Canada|Canada|Canada|Canada', 0, 'Cluster Analysis|High-Throughput Screening Assays|Microscopy|Protein Binding|Proteins|Subcellular Fractions', 'Journal Article', '10.1371/journal.pcbi.1003085', '23785265', 'Protein subcellular localization has been systematically characterized in budding yeast using fluorescently tagged proteins. Based on the fluorescence microscopy images, subcellular localization of many proteins can be classified automatically using supervised machine learning approaches that have been trained to recognize predefined image classes based on statistical features. Here, we present an unsupervised analysis of protein expression patterns in a set of high-resolution, high-throughput microscope images. Our analysis is based on 7 biologically interpretable features which are evaluated on automatically identified cells, and whose cell-stage dependency is captured by a continuous model for cell growth. We show that it is possible to identify most previously identified localization patterns in a cluster analysis based on these features and that similarities between the inferred expression patterns contain more information about protein function than can be explained by a previous manual categorization of subcellular localization. Furthermore, the inferred cell-stage associated to each fluorescence measurement allows us to visualize large groups of proteins entering the bud at specific stages of bud growth. These correspond to proteins localized to organelles, revealing that the organelles must be entering the bud in a stereotypical order. We also identify and organize a smaller group of proteins that show subtle differences in the way they move around the bud during growth. Our results suggest that biologically interpretable features based on explicit models of cell morphology will yield unprecedented power for pattern discovery in high-resolution, high-throughput microscopy images.'),
(86062, 2013, 'plos', 'Bioinformatics goes to school--new avenues for teaching contemporary biology', 'Wood, Louisa|Gebhardt, Philipp', 'EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom.|EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom.', 'United Kingdom|United Kingdom', 8, 'Biology|Computational Biology|Teaching', 'Journal Article', '10.1371/journal.pcbi.1003089', '23785266', 'Since 2010, the European Molecular Biology Laboratorys (EMBL) Heidelberg laboratory and the European Bioinformatics Institute (EMBL-EBI) have jointly run bioinformatics training courses developed specifically for secondary school science teachers within Europe and EMBL member states. These courses focus on introducing bioinformatics, databases, and data-intensive biology, allowing participants to explore resources and providing classroom-ready materials to support them in sharing this new knowledge with their students. In this article, we chart our progress made in creating and running three bioinformatics training courses, including how the course resources are received by participants and how these, and bioinformatics in general, are subsequently used in the classroom. We assess the strengths and challenges of our approach, and share what we have learned through our interactions with European science teachers.'),
(86063, 2013, 'plos', 'Exploring volatile general anesthetic binding to a closed membrane-bound bacterial voltage-gated sodium channel via computation', 'Raju, S G|Barber, Annika F|LeBard, David N|Klein, Michael L|Carnevale, Vincenzo', 'Institute for Computational Molecular Science, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, United States of America.|Institute for Computational Molecular Science, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, United States of America.|Institute for Computational Molecular Science, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, United States of America.|Institute for Computational Molecular Science, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, United States of America.|Institute for Computational Molecular Science, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Anesthetics, General|Anesthetics, Inhalation|Bacteria|Ion Channel Gating|Molecular Dynamics Simulation|Sodium Channels', 'Journal Article', '10.1371/journal.pcbi.1003090', '23785267', 'Despite the clinical ubiquity of anesthesia, the molecular basis of anesthetic action is poorly understood. Amongst the many molecular targets proposed to contribute to anesthetic effects, the voltage gated sodium channels (VGSCs) should also be considered relevant, as they have been shown to be sensitive to all general anesthetics tested thus far. However, binding sites for VGSCs have not been identified. Moreover, the mechanism of inhibition is still largely unknown. The recently reported atomic structures of several members of the bacterial VGSC family offer the opportunity to shed light on the mechanism of action of anesthetics on these important ion channels. To this end, we have performed a molecular dynamics flooding simulation on a membrane-bound structural model of the archetypal bacterial VGSC, NaChBac in a closed pore conformation. This computation allowed us to identify binding sites and access pathways for the commonly used volatile general anesthetic, isoflurane. Three sites have been characterized with binding affinities in a physiologically relevant range. Interestingly, one of the most favorable sites is in the pore of the channel, suggesting that the binding sites of local and general anesthetics may overlap. Surprisingly, even though the activation gate of the channel is closed, and therefore the pore and the aqueous compartment at the intracellular side are disconnected, we observe binding of isoflurane in the central cavity. Several sampled association and dissociation events in the central cavity provide consistent support to the hypothesis that the fenestrations present in the membrane-embedded region of the channel act as the long-hypothesized hydrophobic drug access pathway.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86064, 2013, 'plos', 'Mate choice and the origin of menopause', 'Morton, Richard A|Stone, Jonathan R|Singh, Rama S', 'Department of Biology, McMaster University, Hamilton, Ontario, Canada.|Department of Biology, McMaster University, Hamilton, Ontario, Canada.|Department of Biology, McMaster University, Hamilton, Ontario, Canada.', 'Canada|Canada|Canada', 0, 'Female|Humans|Male|Menopause|Mutation|Sexual Behavior', 'Journal Article', '10.1371/journal.pcbi.1003092', '23785268', 'Human menopause is an unsolved evolutionary puzzle, and relationships among the factors that produced it remain understood poorly. Classic theory, involving a one-sex (female) model of human demography, suggests that genes imparting deleterious effects on post-reproductive survival will accumulate. Thus, a death barrier should emerge beyond the maximum age for female reproduction. Under this scenario, few women would experience menopause (decreased fertility with continued survival) because few would survive much longer than they reproduced. However, no death barrier is observed in human populations. Subsequent theoretical research has shown that two-sex models, including male fertility at older ages, avoid the death barrier. Here we use a stochastic, two-sex computational model implemented by computer simulation to show how male mating preference for younger females could lead to the accumulation of mutations deleterious to female fertility and thus produce a menopausal period. Our model requires neither the initial assumption of a decline in older female fertility nor the effects of inclusive fitness through which older, non-reproducing women assist in the reproductive efforts of younger women. Our model helps to explain why such effects, observed in many societies, may be insufficient factors in elucidating the origin of menopause.'),
(86065, 2013, 'plos', 'Emotional valence and the free-energy principle', 'Joffily, Mateus|Coricelli, Giorgio', 'Center for Mind/Brain Sciences, University of Trento, Trento, Italy. joffily@gate.cnrs.fr|Center for Mind/Brain Sciences, University of Trento, Trento, Italy. joffily@gate.cnrs.fr', 'Italy|Italy', 78, 'Bayes Theorem|Emotions|Humans|Models, Theoretical|Uncertainty', 'Journal Article', '10.1371/journal.pcbi.1003094', '23785269', 'The free-energy principle has recently been proposed as a unified Bayesian account of perception, learning and action. Despite the inextricable link between emotion and cognition, emotion has not yet been formulated under this framework. A core concept that permeates many perspectives on emotion is valence, which broadly refers to the positive and negative character of emotion or some of its aspects. In the present paper, we propose a definition of emotional valence in terms of the negative rate of change of free-energy over time. If the second time-derivative of free-energy is taken into account, the dynamics of basic forms of emotion such as happiness, unhappiness, hope, fear, disappointment and relief can be explained. In this formulation, an important function of emotional valence turns out to regulate the learning rate of the causes of sensory inputs. When sensations increasingly violate the agents expectations, valence is negative and increases the learning rate. Conversely, when sensations increasingly fulfil the agents expectations, valence is positive and decreases the learning rate. This dynamic interaction between emotional valence and learning rate highlights the crucial role played by emotions in biological agents adaptation to unexpected changes in their world.'),
(86066, 2013, 'plos', 'Fibrin networks regulate protein transport during thrombus development', 'Kim, Oleg V|Xu, Zhiliang|Rosen, Elliot D|Alber, Mark S', 'Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, South Bend, Indiana, United States of America.|Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, South Bend, Indiana, United States of America.|Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, South Bend, Indiana, United States of America.|Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, South Bend, Indiana, United States of America.', 'India|India|India|India', 0, 'Animals|Fibrin|Hemodynamics|Mice|Microfluidics|Protein Transport|Proteins|Thrombosis', 'Journal Article', '10.1371/journal.pcbi.1003095', '23785270', 'Thromboembolic disease is a leading cause of morbidity and mortality worldwide. In the last several years there have been a number of studies attempting to identify mechanisms that stop thrombus growth. This paper identifies a novel mechanism related to formation of a fibrin cap. In particular, protein transport through a fibrin network, an important component of a thrombus, was studied by integrating experiments with model simulations. The network permeability and the protein diffusivity were shown to be important factors determining the transport of proteins through the fibrin network. Our previous in vivo studies in mice have shown that stabilized non-occluding thrombi are covered by a fibrin network (fibrin cap). Model simulations, calibrated using experiments in microfluidic devices and accounting for the permeable structure of the fibrin cap, demonstrated that thrombin generated inside the thrombus was washed downstream through the fibrin network, thus limiting exposure of platelets on the thrombus surface to thrombin. Moreover, by restricting the approach of resting platelets in the flowing blood to the thrombus core, the fibrin cap impaired platelets from reaching regions of high thrombin concentration necessary for platelet activation and limited thrombus growth. The formation of a fibrin cap prevents small thrombi that frequently develop in the absence of major injury in the 60000 km of vessels in the body from developing into life threatening events.'),
(86067, 2013, 'plos', 'Modelling co-infection with malaria and lymphatic filariasis', 'Slater, Hannah C|Gambhir, Manoj|Parham, Paul E|Michael, Edwin', 'Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom.|Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom.|Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom.|Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 15, 'Animals|Culicidae|Elephantiasis, Filarial|Humans|Insect Vectors|Malaria|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1003096', '23785271', 'Malaria and lymphatic filariasis (LF) continue to cause a considerable public health burden globally and are co-endemic in many regions of sub-Saharan Africa. These infections are transmitted by the same mosquito species which raises important questions about optimal vector control strategies in co-endemic regions, as well as the effect of the presence of each infection on endemicity of the other, there is currently little consensus on the latter. The need for comprehensive modelling studies to address such questions is therefore significant, yet very few have been undertaken to date despite the recognised explanatory power of reliable dynamic mathematical models. Here, we develop a malaria-LF co-infection modelling framework that accounts for two key interactions between these infections, namely the increase in vector mortality as LF mosquito prevalence increases and the antagonistic Th1/Th2 immune response that occurs in co-infected hosts. We consider the crucial interplay between these interactions on the resulting endemic prevalence when introducing each infection in regions where the other is already endemic (e.g. due to regional environmental change), and the associated timescale for such changes, as well as effects on the basic reproduction number Rxe2x82x80 of each disease. We also highlight potential perverse effects of vector controls on human infection prevalence in co-endemic regions, noting that understanding such effects is critical in designing optimal integrated control programmes. Hence, as well as highlighting where better data are required to more reliably address such questions, we provide an important framework that will form the basis of future scenario analysis tools used to plan and inform policy decisions on intervention measures in different transmission settings.'),
(86068, 2013, 'plos', 'A forced damped oscillation framework for undulatory swimming provides new insights into how propulsion arises in active and passive swimming', 'Bhalla, Amneet Pal Singh|Griffith, Boyce E|Patankar, Neelesh A', 'Department of Mechanical Engineering, R. R. McCormick School of Engineering and Applied Science, Northwestern University, Evanston, Illinois, United States of America.|Department of Mechanical Engineering, R. R. McCormick School of Engineering and Applied Science, Northwestern University, Evanston, Illinois, United States of America.|Department of Mechanical Engineering, R. R. McCormick School of Engineering and Applied Science, Northwestern University, Evanston, Illinois, United States of America.', 'United States|United States|United States', 25, 'Animals|Models, Biological|Muscle Contraction|Swimming', 'Journal Article', '10.1371/journal.pcbi.1003097', '23785272', 'A fundamental issue in locomotion is to understand how muscle forcing produces apparently complex deformation kinematics leading to movement of animals like undulatory swimmers. The question of whether complicated muscle forcing is required to create the observed deformation kinematics is central to the understanding of how animals control movement. In this work, a forced damped oscillation framework is applied to a chain-link model for undulatory swimming to understand how forcing leads to deformation and movement. A unified understanding of swimming, caused by muscle contractions (active swimming) or by forces imparted by the surrounding fluid (passive swimming), is obtained. We show that the forcing triggers the first few deformation modes of the body, which in turn cause the translational motion. We show that relatively simple forcing patterns can trigger seemingly complex deformation kinematics that lead to movement. For given muscle activation, the forcing frequency relative to the natural frequency of the damped oscillator is important for the emergent deformation characteristics of the body. The proposed approach also leads to a qualitative understanding of optimal deformation kinematics for fast swimming. These results, based on a chain-link model of swimming, are confirmed by fully resolved computational fluid dynamics (CFD) simulations. Prior results from the literature on the optimal value of stiffness for maximum speed are explained.'),
(86069, 2013, 'plos', 'Neuronal functional connection graphs among multiple areas of the rat somatosensory system during spontaneous and evoked activities', 'Zippo, Antonio G|Storchi, Riccardo|Nencini, Sara|Caramenti, Gian Carlo|Valente, Maurizio|Biella, Gabriele Eliseo M', 'Institute of Molecular Bioimaging and Physiology, National Research Council, Segrate, Milan, Italy.|Institute of Molecular Bioimaging and Physiology, National Research Council, Segrate, Milan, Italy.|Institute of Molecular Bioimaging and Physiology, National Research Council, Segrate, Milan, Italy.|Institute of Molecular Bioimaging and Physiology, National Research Council, Segrate, Milan, Italy.|Institute of Molecular Bioimaging and Physiology, National Research Council, Segrate, Milan, Italy.|Institute of Molecular Bioimaging and Physiology, National Research Council, Segrate, Milan, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy', 0, 'Animals|Evoked Potentials, Somatosensory|Neurons|Rats|Somatosensory Cortex', 'Journal Article', '10.1371/journal.pcbi.1003104', '23785273', 'Small-World Networks (SWNs) represent a fundamental model for the comprehension of many complex man-made and biological networks. In the central nervous system, SWN models have been shown to fit well both anatomical and functional maps at the macroscopic level. However, the functional microscopic level, where the nodes of a network are represented by single neurons, is still poorly understood. At this level, although recent evidences suggest that functional connection graphs exhibit small-world organization, it is not known whether and how these maps, potentially distributed in multiple brain regions, change across different conditions, such as spontaneous and stimulus-evoked activities. We addressed these questions by analyzing the data from simultaneous multi-array extracellular recordings in three brain regions of rats, diversely involved in somatosensory information processing: the ventropostero-lateral thalamic nuclei, the primary somatosensory cortex and the centro-median thalamic nuclei. From both spike and Local Field Potential (LFP) recordings, we estimated the functional connection graphs by using the Normalized Compression Similarity for spikes and the Phase Synchrony for LFPs. Then, by using graph-theoretical statistics, we characterized the functional topology both during spontaneous activity and sensory stimulation. Our main results show that: (i) spikes and LFPs show SWN organization during spontaneous activity, (ii) after stimulation onset, while substantial functional graph reconfigurations occur both in spike and LFPs, small-worldness is nonetheless preserved, (iii) the stimulus triggers a significant increase of inter-area LFP connections without modifying the topology of intra-area functional connections. Finally, investigating computationally the functional substrate that supports the observed phenomena, we found that (iv) the fundamental concept of cell assemblies, transient groups of activating neurons, can be described by small-world networks. Our results suggest that activity of neurons from multiple areas of the rat somatosensory system contributes to the integration of local computations arisen in distributed functional cell assemblies according to the principles of SWNs.'),
(86070, 2013, 'plos', 'Impact of ribosomal modification on the binding of the antibiotic telithromycin using a combined grand canonical monte carlo/molecular dynamics simulation approach', 'Small, Meagan C|Lopes, Pedro|Andrade, Rodrigo B|Mackerell, Alexander D', 'Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, United States of America.|Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, United States of America.|Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, United States of America.|Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, United States of America.', 'United States|United States|United States|United States', 14, 'Anti-Bacterial Agents|Ketolides|Molecular Dynamics Simulation|Monte Carlo Method', 'Journal Article', '10.1371/journal.pcbi.1003113', '23785274', 'Resistance to macrolide antibiotics is conferred by mutation of A2058 to G or methylation by Erm methyltransferases of the exocyclic N6 of A2058 (E. coli numbering) that forms the macrolide binding site in the 50S subunit of the ribosome. Ketolides such as telithromycin mitigate A2058G resistance yet remain susceptible to Erm-based resistance. Molecular details associated with macrolide resistance due to the A2058G mutation and methylation at N6 of A2058 by Erm methyltransferases were investigated using empirical force field-based simulations. To address the buried nature of the macrolide binding site, the number of waters within the pocket was allowed to fluctuate via the use of a Grand Canonical Monte Carlo (GCMC) methodology. The GCMC water insertion/deletion steps were alternated with Molecular Dynamics (MD) simulations to allow for relaxation of the entire system. From this GCMC/MD approach information on the interactions between telithromycin and the 50S ribosome was obtained. In the wild-type (WT) ribosome, the 2-OH to A2058 N1 hydrogen bond samples short distances with a higher probability, while the effectiveness of telithromycin against the A2058G mutation is explained by a rearrangement of the hydrogen bonding pattern of the 2-OH to 2058 that maintains the overall antibiotic-ribosome interactions. In both the WT and A2058G mutation there is significant flexibility in telithromycins imidazole-pyridine side chain (ARM), indicating that entropic effects contribute to the binding affinity. Methylated ribosomes show lower sampling of short 2-OH to 2058 distances and also demonstrate enhanced G2057-A2058 stacking leading to disrupted A752-U2609 Watson-Crick (WC) interactions as well as hydrogen bonding between telithromycins ARM and U2609. This information will be of utility in the rational design of novel macrolide analogs with improved activity against methylated A2058 ribosomes.'),
(86071, 2013, 'plos', 'The ability of flux balance analysis to predict evolution of central metabolism scales with the initial distance to the optimum', 'Harcombe, William R|Delaney, Nigel F|Leiby, Nicholas|Klitgord, Niels|Marx, Christopher J', 'Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States', 41, 'Carbon Isotopes|Escherichia coli|Evolution, Molecular|Glucose|Lactic Acid|Metabolism', 'Journal Article', '10.1371/journal.pcbi.1003091', '23818838', 'The most powerful genome-scale framework to model metabolism, flux balance analysis (FBA), is an evolutionary optimality model. It hypothesizes selection upon a proposed optimality criterion in order to predict the set of internal fluxes that would maximize fitness. Here we present a direct test of the optimality assumption underlying FBA by comparing the central metabolic fluxes predicted by multiple criteria to changes measurable by a (13)C-labeling method for experimentally-evolved strains. We considered datasets for three Escherichia coli evolution experiments that varied in their length, consistency of environment, and initial optimality. For ten populations that were evolved for 50,000 generations in glucose minimal medium, we observed modest changes in relative fluxes that led to small, but significant decreases in optimality and increased the distance to the predicted optimal flux distribution. In contrast, seven populations evolved on the poor substrate lactate for 900 generations collectively became more optimal and had flux distributions that moved toward predictions. For three pairs of central metabolic knockouts evolved on glucose for 600-800 generations, there was a balance between cases where optimality and flux patterns moved toward or away from FBA predictions. Despite this variation in predictability of changes in central metabolism, two generalities emerged. First, improved growth largely derived from evolved increases in the rate of substrate use. Second, FBA predictions bore out well for the two experiments initiated with ancestors with relatively sub-optimal yield, whereas those begun already quite optimal tended to move somewhat away from predictions. These findings suggest that the tradeoff between rate and yield is surprisingly modest. The observed positive correlation between rate and yield when adaptation initiated further from the optimum resulted in the ability of FBA to use stoichiometric constraints to predict the evolution of metabolism despite selection for rate. '),
(86072, 2013, 'plos', 'Integrative analysis of deep sequencing data identifies estrogen receptor early response genes and links ATAD3B to poor survival in breast cancer', 'Ovaska, Kristian|Matarese, Filomena|Grote, Korbinian|Charapitsa, Iryna|Cervera, Alejandra|Liu, Chengyu|Reid, George|Seifert, Martin|Stunnenberg, Hendrik G|Hautaniemi, Sampsa', 'Research Programs Unit, Genome-Scale Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Genome-Scale Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Genome-Scale Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Genome-Scale Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Genome-Scale Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Genome-Scale Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Genome-Scale Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Genome-Scale Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Genome-Scale Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Genome-Scale Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.', 'Finland|Finland|Finland|Finland|Finland|Finland|Finland|Finland|Finland|Finland', 0, 'ATPases Associated with Diverse Cellular Activities|Adenosine Triphosphatases|Breast Neoplasms|Estrogen Receptor alpha|Female|Humans|MCF-7 Cells|Membrane Proteins|Mitochondrial Proteins|Survival Analysis|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1003100', '23818839', 'Identification of responsive genes to an extra-cellular cue enables characterization of pathophysiologically crucial biological processes. Deep sequencing technologies provide a powerful means to identify responsive genes, which creates a need for computational methods able to analyze dynamic and multi-level deep sequencing data. To answer this need we introduce here a data-driven algorithm, SPINLONG, which is designed to search for genes that match the user-defined hypotheses or models. SPINLONG is applicable to various experimental setups measuring several molecular markers in parallel. To demonstrate the SPINLONG approach, we analyzed ChIP-seq data reporting PolII, estrogen receptor xcexb1 (ERxcexb1), H3K4me3 and H2A.Z occupancy at five time points in the MCF-7 breast cancer cell line after estradiol stimulus. We obtained 777 ERa early responsive genes and compared the biological functions of the genes having ERxcexb1 binding within 20 kb of the transcription start site (TSS) to genes without such binding site. Our results show that the non-genomic action of ERxcexb1 via the MAPK pathway, instead of direct ERa binding, may be responsible for early cell responses to ERxcexb1 activation. Our results also indicate that the ERxcexb1 responsive genes triggered by the genomic pathway are transcribed faster than those without ERxcexb1 binding sites. The survival analysis of the 777 ERxcexb1 responsive genes with 150 primary breast cancer tumors and in two independent validation cohorts indicated the ATAD3B gene, which does not have ERxcexb1 binding site within 20 kb of its TSS, to be significantly associated with poor patient survival.'),
(86073, 2013, 'plos', 'How the dynamics and structure of sexual contact networks shape pathogen phylogenies', 'Robinson, Katy|Fyson, Nick|Cohen, Ted|Fraser, Christophe|Colijn, Caroline', 'University of Bristol, Bristol, United Kingdom.|University of Bristol, Bristol, United Kingdom.|University of Bristol, Bristol, United Kingdom.|University of Bristol, Bristol, United Kingdom.|University of Bristol, Bristol, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 32, 'Biological Evolution|Cluster Analysis|Microbiota|Phylogeny', 'Journal Article', '10.1371/journal.pcbi.1003105', '23818840', 'The characteristics of the host contact network over which a pathogen is transmitted affect both epidemic spread and the projected effectiveness of control strategies. Given the importance of understanding these contact networks, it is unfortunate that they are very difficult to measure directly. This challenge has led to an interest in methods to infer information about host contact networks from pathogen phylogenies, because in shaping a pathogens opportunities for reproduction, contact networks also shape pathogen evolution. Host networks influence pathogen phylogenies both directly, through governing opportunities for evolution, and indirectly by changing the prevalence and incidence. Here, we aim to separate these two effects by comparing pathogen evolution on different host networks that share similar epidemic trajectories. This approach allows use to examine the direct effects of network structure on pathogen phylogenies, largely controlling for confounding differences arising from population dynamics. We find that networks with more heterogeneous degree distributions yield pathogen phylogenies with more variable cluster numbers, smaller mean cluster sizes, shorter mean branch lengths, and somewhat higher tree imbalance than networks with relatively homogeneous degree distributions. However, in particular for dynamic networks, we find that these direct effects are relatively modest. These findings suggest that the role of the epidemic trajectory, the dynamics of the network and the inherent variability of metrics such as cluster size must each be taken into account when trying to use pathogen phylogenies to understand characteristics about the underlying host contact network. '),
(86074, 2013, 'plos', 'Towards systematic discovery of signaling networks in budding yeast filamentous growth stress response using interventional phosphorylation data', 'Zhang, Yan|Kweon, Hye Kyong|Shively, Christian|Kumar, Anuj|Andrews, Philip C', 'Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.|Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.|Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.|Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.|Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.', 'United States|United States|United States|United States|United States', 14, 'Amino Acid Sequence|Bayes Theorem|Fungal Proteins|Mass Spectrometry|Molecular Sequence Data|Phosphopeptides|Phosphorylation|Saccharomyces cerevisiae|Signal Transduction|Stress, Physiological', 'Journal Article', '10.1371/journal.pcbi.1003077', '23825934', 'Reversible phosphorylation is one of the major mechanisms of signal transduction, and signaling networks are critical regulators of cell growth and development. However, few of these networks have been delineated completely. Towards this end, quantitative phosphoproteomics is emerging as a useful tool enabling large-scale determination of relative phosphorylation levels. However, phosphoproteomics differs from classical proteomics by a more extensive sampling limitation due to the limited number of detectable sites per protein. Here, we propose a comprehensive quantitative analysis pipeline customized for phosphoproteome data from interventional experiments for identifying key proteins in specific pathways, discovering the protein-protein interactions and inferring the signaling network. We also made an effort to partially compensate for the missing value problem, a chronic issue for proteomics studies. The dataset used for this study was generated using SILAC (Stable Isotope Labeling with Amino acids in Cell culture) technique with interventional experiments (kinase-dead mutations). The major components of the pipeline include phosphopeptide meta-analysis, correlation network analysis and causal relationship discovery. We have successfully applied our pipeline to interventional experiments identifying phosphorylation events underlying the transition to a filamentous growth form in Saccharomyces cerevisiae. We identified 5 high-confidence proteins from meta-analysis, and 19 hub proteins from correlation analysis (Pbi2p and Hsp42p were identified by both analyses). All these proteins are involved in stress responses. Nine of them have direct or indirect evidence of involvement in filamentous growth. In addition, we tested four of our predicted proteins, Nth1p, Pbi2p, Pdr12p and Rcn2p, by interventional phenotypic experiments and all of them present differential invasive growth, providing prospective validation of our approach. This comprehensive pipeline presents a systematic way for discovering signaling networks using interventional phosphoproteome data and can suggest candidate proteins for further investigation. We anticipate the methodology to be applicable as well to other interventional studies via different experimental platforms. '),
(86075, 2013, 'plos', 'Dynamic excitatory and inhibitory gain modulation can produce flexible, robust and optimal decision-making', 'Niyogi, Ritwik K|Wong-Lin, KongFatt', 'Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom.|Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom.', 'United Kingdom|United Kingdom', 0, 'Decision Making|Humans|Models, Theoretical|Reaction Time|Task Performance and Analysis', 'Journal Article', '10.1371/journal.pcbi.1003099', '23825935', 'Behavioural and neurophysiological studies in primates have increasingly shown the involvement of urgency signals during the temporal integration of sensory evidence in perceptual decision-making. Neuronal correlates of such signals have been found in the parietal cortex, and in separate studies, demonstrated attention-induced gain modulation of both excitatory and inhibitory neurons. Although previous computational models of decision-making have incorporated gain modulation, their abstract forms do not permit an understanding of the contribution of inhibitory gain modulation. Thus, the effects of co-modulating both excitatory and inhibitory neuronal gains on decision-making dynamics and behavioural performance remain unclear. In this work, we incorporate time-dependent co-modulation of the gains of both excitatory and inhibitory neurons into our previous biologically based decision circuit model. We base our computational study in the context of two classic motion-discrimination tasks performed in animals. Our model shows that by simultaneously increasing the gains of both excitatory and inhibitory neurons, a variety of the observed dynamic neuronal firing activities can be replicated. In particular, the model can exhibit winner-take-all decision-making behaviour with higher firing rates and within a significantly more robust model parameter range. It also exhibits short-tailed reaction time distributions even when operating near a dynamical bifurcation point. The model further shows that neuronal gain modulation can compensate for weaker recurrent excitation in a decision neural circuit, and support decision formation and storage. Higher neuronal gain is also suggested in the more cognitively demanding reaction time than in the fixed delay version of the task. Using the exact temporal delays from the animal experiments, fast recruitment of gain co-modulation is shown to maximize reward rate, with a timescale that is surprisingly near the experimentally fitted value. Our work provides insights into the simultaneous and rapid modulation of excitatory and inhibitory neuronal gains, which enables flexible, robust, and optimal decision-making. '),
(86076, 2013, 'plos', 'PUMA: a unified framework for penalized multiple regression analysis of GWAS data', 'Hoffman, Gabriel E|Logsdon, Benjamin A|Mezey, Jason G', 'Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America. gh258@cornell.edu|Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America. gh258@cornell.edu|Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America. gh258@cornell.edu', 'United States|United States|United States', 0, 'Genome-Wide Association Study|Humans|Models, Theoretical|Regression Analysis', 'Journal Article', '10.1371/journal.pcbi.1003101', '23825936', 'Penalized Multiple Regression (PMR) can be used to discover novel disease associations in GWAS datasets. In practice, proposed PMR methods have not been able to identify well-supported associations in GWAS that are undetectable by standard association tests and thus these methods are not widely applied. Here, we present a combined algorithmic and heuristic framework for PUMA (Penalized Unified Multiple-locus Association) analysis that solves the problems of previously proposed methods including computational speed, poor performance on genome-scale simulated data, and identification of too many associations for real data to be biologically plausible. The framework includes a new minorize-maximization (MM) algorithm for generalized linear models (GLM) combined with heuristic model selection and testing methods for identification of robust associations. The PUMA framework implements the penalized maximum likelihood penalties previously proposed for GWAS analysis (i.e. Lasso, Adaptive Lasso, NEG, MCP), as well as a penalty that has not been previously applied to GWAS (i.e. LOG). Using simulations that closely mirror real GWAS data, we show that our framework has high performance and reliably increases power to detect weak associations, while existing PMR methods can perform worse than single marker testing in overall performance. To demonstrate the empirical value of PUMA, we analyzed GWAS data for type 1 diabetes, Crohnss disease, and rheumatoid arthritis, three autoimmune diseases from the original Wellcome Trust Case Control Consortium. Our analysis replicates known associations for these diseases and we discover novel etiologically relevant susceptibility loci that are invisible to standard single marker tests, including six novel associations implicating genes involved in pancreatic function, insulin pathways and immune-cell function in type 1 diabetes, three novel associations implicating genes in pro- and anti-inflammatory pathways in Crohns disease, and one novel association implicating a gene involved in apoptosis pathways in rheumatoid arthritis. We provide software for applying our PUMA analysis framework. '),
(86077, 2013, 'plos', 'A design principle of group-level decision making in cell populations', 'Fujimoto, Koichi|Sawai, Satoshi', 'Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan. fujimoto@bio.sci.osaka-u.ac.jp|Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan. fujimoto@bio.sci.osaka-u.ac.jp', 'Japan|Japan', 10, 'Cell Biology|Decision Making|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1003110', '23825937', 'Populations of cells often switch states as a group to cope with environmental changes such as nutrient availability and cell density. Although the gene circuits that underlie the switches are well understood at the level of single cells, the ways in which such circuits work in concert among many cells to support group-level switches are not fully explored. Experimental studies of microbial quorum sensing show that group-level changes in cellular states occur in either a graded or an all-or-none fashion. Here, we show through numerical simulations and mathematical analysis that these behaviors generally originate from two distinct forms of bistability. The choice of bistability is uniquely determined by a dimensionless parameter that compares the synthesis and the transport of the inducing molecules. The role of the parameter is universal, such that it not only applies to the autoinducing circuits typically found in bacteria but also to the more complex gene circuits involved in transmembrane receptor signaling. Furthermore, in gene circuits with negative feedback, the same dimensionless parameter determines the coherence of group-level transitions from quiescence to a rhythmic state. The set of biochemical parameters in bacterial quorum-sensing circuits appear to be tuned so that the cells can use either type of transition. The design principle identified here serves as the basis for the analysis and control of cellular collective decision making. '),
(86078, 2013, 'plos', 'Dual delayed feedback provides sensitivity and robustness to the NF-xcexbaB signaling module', 'Longo, Diane M|Selimkhanov, Jangir|Kearns, Jeffrey D|Hasty, Jeff|Hoffmann, Alexander|Tsimring, Lev S', 'Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.', 'United States|United States|United States|United States|United States|United States', 0, 'Computer Simulation|Feedback|NF-kappa B|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1003112', '23825938', 'Many cellular stress-responsive signaling systems exhibit highly dynamic behavior with oscillatory features mediated by delayed negative feedback loops. What remains unclear is whether oscillatory behavior is the basis for a signaling code based on frequency modulation (FM) or whether the negative feedback control modules have evolved to fulfill other functional requirements. Here, we use experimentally calibrated computational models to interrogate the negative feedback loops that regulate the dynamic activity of the transcription factor NF-xcexbaB. Linear stability analysis of the model shows that oscillatory frequency is a hard-wired feature of the primary negative feedback loop and not a function of the stimulus, thus arguing against an FM signaling code. Instead, our modeling studies suggest that the two feedback loops may be tuned to provide for rapid activation and inactivation capabilities for transient input signals of a wide range of durations, by minimizing late phase oscillations response durations may be fine-tuned in a graded rather than quantized manner. Further, in the presence of molecular noise the dual delayed negative feedback system minimizes stochastic excursions of the output to produce a robust NF-xcexbaB response.'),
(86079, 2013, 'plos', 'Molecular mechanisms in the activation of abscisic acid receptor PYR1', 'Dorosh, Lyudmyla|Kharenko, Olesya A|Rajagopalan, Nandhakishore|Loewen, Michele C|Stepanova, Maria', 'National Research Council of Canada, Edmonton, Alberta, Canada.|National Research Council of Canada, Edmonton, Alberta, Canada.|National Research Council of Canada, Edmonton, Alberta, Canada.|National Research Council of Canada, Edmonton, Alberta, Canada.|National Research Council of Canada, Edmonton, Alberta, Canada.', 'Canada|Canada|Canada|Canada|Canada', 0, 'Abscisic Acid|Arabidopsis|Arabidopsis Proteins|Kinetics|Ligands|Membrane Transport Proteins|Molecular Dynamics Simulation|Protein Binding', 'Journal Article', '10.1371/journal.pcbi.1003114', '23825939', 'The pyrabactin resistance 1 (PYR1)/PYR1-like (PYL)/regulatory component of abscisic acid (ABA) response (RCAR) proteins comprise a well characterized family of ABA receptors. Recent investigations have revealed two subsets of these receptors that, in the absence of ABA, either form inactive homodimers (PYR1 and PYLs 1-3) or mediate basal inhibition of downstream target type 2C protein phosphatases (PP2Cs, PYLs 4-10) respectively in vitro. Addition of ABA has been shown to release the apo-homodimers yielding ABA-bound monomeric holo-receptors that can interact with PP2Cs, highlighting a competitive-interaction process. Interaction selectivity has been shown to be mediated by subtle structural variations of primary sequence and ligand binding effects. Now, the dynamical contributions of ligand binding on interaction selectivity are investigated through extensive molecular dynamics (MD) simulations of apo and holo-PYR1 in monomeric and dimeric form as well as in complex with a PP2C, homology to ABA insensitive 1 (HAB1). Robust comparative interpretations were enabled by a novel essential collective dynamics approach. In agreement with recent experimental findings, our analysis indicates that ABA-bound PYR1 should efficiently bind to HAB1. However, both ABA-bound and ABA-extracted PYR1-HAB1 constructs have demonstrated notable similarities in their dynamics, suggesting that apo-PYR1 should also be able to make a substantial interaction with PP2Cs, albeit likely with slower complex formation kinetics. Further analysis indicates that both ABA-bound and ABA-free PYR1 in complex with HAB1 exhibit a higher intra-molecular structural stability and stronger inter-molecular dynamic correlations, in comparison with either holo- or apo-PYR1 dimers, supporting a model that includes apo-PYR1 in complex with HAB1. This possibility of a conditional functional apo-PYR1-PP2C complex was validated in vitro. These findings are generally consistent with the competitive-interaction model for PYR1 but highlight dynamical contributions of the PYR1 structure in mediating interaction selectivity suggesting added degrees of complexity in the regulation of the competitive-inhibition. '),
(86080, 2013, 'plos', 'Understanding the molecular determinants driving the immunological specificity of the protective pilus 2a backbone protein of group B streptococcus', 'Nuccitelli, Annalisa|Rinaudo, C Daniela|Brogioni, Barbara|Cozzi, Roberta|Ferrer-Navarro, Mario|Yero, Daniel|Telford, John L|Grandi, Guido|Daura, Xavier|Zacharias, Martin|Maione, Domenico', 'Novartis Vaccines and Diagnostics, Siena, Italy.|Novartis Vaccines and Diagnostics, Siena, Italy.|Novartis Vaccines and Diagnostics, Siena, Italy.|Novartis Vaccines and Diagnostics, Siena, Italy.|Novartis Vaccines and Diagnostics, Siena, Italy.|Novartis Vaccines and Diagnostics, Siena, Italy.|Novartis Vaccines and Diagnostics, Siena, Italy.|Novartis Vaccines and Diagnostics, Siena, Italy.|Novartis Vaccines and Diagnostics, Siena, Italy.|Novartis Vaccines and Diagnostics, Siena, Italy.|Novartis Vaccines and Diagnostics, Siena, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy|Italy|Italy|Italy|Italy|Italy', 4, 'Amino Acid Sequence|Animals|Antibodies, Monoclonal|Bacterial Proteins|Epitope Mapping|Mice|Models, Molecular|Molecular Sequence Data|Phagocytosis|Sequence Homology, Amino Acid|Streptococcus agalactiae', 'Journal Article', '10.1371/journal.pcbi.1003115', '23825940', 'The pilus 2a backbone protein (BP-2a) is one of the most structurally and functionally characterized components of a potential vaccine formulation against Group B Streptococcus. It is characterized by six main immunologically distinct allelic variants, each inducing variant-specific protection. To investigate the molecular determinants driving the variant immunogenic specificity of BP-2a, in terms of single residue contributions, we generated six monoclonal antibodies against a specific protein variant based on their capability to recognize the polymerized pili structure on the bacterial surface. Three mAbs were also able to induce complement-dependent opsonophagocytosis killing of live GBS and target the same linear epitope present in the structurally defined and immunodominant domain D3 of the protein. Molecular docking between the modelled scFv antibody sequences and the BP-2a crystal structure revealed the potential role at the binding interface of some non-conserved antigen residues. Mutagenesis analysis confirmed the necessity of a perfect balance between charges, size and polarity at the binding interface to obtain specific binding of mAbs to the protein antigen for a neutralizing response. '),
(86081, 2013, 'plos', 'Bacteria-human somatic cell lateral gene transfer is enriched in cancer samples', 'Riley, David R|Sieber, Karsten B|Robinson, Kelly M|White, James Robert|Ganesan, Ashwinkumar|Nourbakhsh, Syrus|Dunning Hotopp, Julie C', 'Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 78, 'Bacteria|Base Sequence|DNA, Bacterial|Gene Transfer, Horizontal|Genes, Bacterial|Genome, Human|Humans|Molecular Sequence Data|Neoplasms|Sequence Homology, Nucleic Acid', 'Journal Article', '10.1371/journal.pcbi.1003107', '23840181', 'There are 10× more bacterial cells in our bodies from the microbiome than human cells. Viral DNA is known to integrate in the human genome, but the integration of bacterial DNA has not been described. Using publicly available sequence data from the human genome project, the 1000 Genomes Project, and The Cancer Genome Atlas (TCGA), we examined bacterial DNA integration into the human somatic genome. Here we present evidence that bacterial DNA integrates into the human somatic genome through an RNA intermediate, and that such integrations are detected more frequently in (a) tumors than normal samples, (b) RNA than DNA samples, and (c) the mitochondrial genome than the nuclear genome. Hundreds of thousands of paired reads support random integration of Acinetobacter-like DNA in the human mitochondrial genome in acute myeloid leukemia samples. Numerous read pairs across multiple stomach adenocarcinoma samples support specific integration of Pseudomonas-like DNA in the 5-UTR and 3-UTR of four proto-oncogenes that are up-regulated in their transcription, consistent with conversion to an oncogene. These data support our hypothesis that bacterial integrations occur in the human somatic genome and may play a role in carcinogenesis. We anticipate that the application of our approach to additional cancer genome projects will lead to the more frequent detection of bacterial DNA integrations in tumors that are in close proximity to the human microbiome. ');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86082, 2013, 'plos', 'Flux balance analysis of cyanobacterial metabolism: the metabolic network of Synechocystis sp PCC 6803', 'Knoop, Henning|Gründel, Marianne|Zilliges, Yvonne|Lehmann, Robert|Hoffmann, Sabrina|Lockau, Wolfgang|Steuer, Ralf', 'Humboldt-Universität zu Berlin, Institut für Theoretische Biologie, Berlin, Germany. henning.knoop@biologie.hu-berlin.de|Humboldt-Universität zu Berlin, Institut für Theoretische Biologie, Berlin, Germany. henning.knoop@biologie.hu-berlin.de|Humboldt-Universität zu Berlin, Institut für Theoretische Biologie, Berlin, Germany. henning.knoop@biologie.hu-berlin.de|Humboldt-Universität zu Berlin, Institut für Theoretische Biologie, Berlin, Germany. henning.knoop@biologie.hu-berlin.de|Humboldt-Universität zu Berlin, Institut für Theoretische Biologie, Berlin, Germany. henning.knoop@biologie.hu-berlin.de|Humboldt-Universität zu Berlin, Institut für Theoretische Biologie, Berlin, Germany. henning.knoop@biologie.hu-berlin.de|Humboldt-Universität zu Berlin, Institut für Theoretische Biologie, Berlin, Germany. henning.knoop@biologie.hu-berlin.de', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany', 0, 'Citric Acid Cycle|Darkness|Glyoxylates|Metabolic Networks and Pathways|Phototrophic Processes|Ribulose-Bisphosphate Carboxylase|Synechocystis', 'Journal Article', '10.1371/journal.pcbi.1003081', '23843751', 'Cyanobacteria are versatile unicellular phototrophic microorganisms that are highly abundant in many environments. Owing to their capability to utilize solar energy and atmospheric carbon dioxide for growth, cyanobacteria are increasingly recognized as a prolific resource for the synthesis of valuable chemicals and various biofuels. To fully harness the metabolic capabilities of cyanobacteria necessitates an in-depth understanding of the metabolic interconversions taking place during phototrophic growth, as provided by genome-scale reconstructions of microbial organisms. Here we present an extended reconstruction and analysis of the metabolic network of the unicellular cyanobacterium Synechocystis sp. PCC 6803. Building upon several recent reconstructions of cyanobacterial metabolism, unclear reaction steps are experimentally validated and the functional consequences of unknown or dissenting pathway topologies are discussed. The updated model integrates novel results with respect to the cyanobacterial TCA cycle, an alleged glyoxylate shunt, and the role of photorespiration in cellular growth. Going beyond conventional flux-balance analysis, we extend the computational analysis to diurnal light/dark cycles of cyanobacterial metabolism. '),
(86083, 2013, 'plos', 'Cooperative binding', 'Stefan, Melanie I|Le Novère, Nicolas', 'Division of Biology, California Institute of Technology, Pasadena, California, United States of America.|Division of Biology, California Institute of Technology, Pasadena, California, United States of America.', 'United States|United States', 73, 'Binding Sites|Models, Molecular|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1003106', '23843752', 'Molecular binding is an interaction between molecules that results in a stable association between those molecules. Cooperative binding occurs if the number of binding sites of a macromolecule that are occupied by a specific type of ligand is a nonlinear function of this ligands concentration. This can be due, for instance, to an affinity for the ligand that depends on the amount of ligand bound. Cooperativity can be positive (supralinear) or negative (infralinear). Cooperative binding is most often observed in proteins, but nucleic acids can also exhibit cooperative binding, for instance of transcription factors. Cooperative binding has been shown to be the mechanism underlying a large range of biochemical and physiological processes. '),
(86084, 2013, 'plos', 'Interaction of motility, directional sensing, and polarity modules recreates the behaviors of chemotaxing cells', 'Shi, Changji|Huang, Chuan-Hsiang|Devreotes, Peter N|Iglesias, Pablo A', 'Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland, USA.|Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland, USA.|Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland, USA.|Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland, USA.', 'United States|United States|United States|United States', 69, 'Cell Polarity|Chemotaxis', 'Journal Article', '10.1371/journal.pcbi.1003122', '23861660', 'Chemotaxis involves the coordinated action of separable but interrelated processes: motility, gradient sensing, and polarization. We have hypothesized that these are mediated by separate modules that account for these processes individually and that, when combined, recreate most of the behaviors of chemotactic cells. Here, we describe a mathematical model where the modules are implemented in terms of reaction-diffusion equations. Migration and the accompanying changes in cellular morphology are demonstrated in simulations using a mechanical model of the cell cortex implemented in the level set framework. The central module is an excitable network that accounts for random migration. The response to combinations of uniform stimuli and gradients is mediated by a local excitation, global inhibition module that biases the direction in which excitability is directed. A polarization module linked to the excitable network through the cytoskeleton allows unstimulated cells to move persistently and, for cells in gradients, to gradually acquire distinct sensitivity between front and back. Finally, by varying the strengths of various feedback loops in the model we obtain cellular behaviors that mirror those of genetically altered cell lines.'),
(86085, 2013, 'plos', 'Predicting network activity from high throughput metabolomics', 'Li, Shuzhao|Park, Youngja|Duraisingham, Sai|Strobel, Frederick H|Khan, Nooruddin|Soltow, Quinlyn A|Jones, Dean P|Pulendran, Bali', 'Emory Vaccine Center, Emory University, Atlanta, Georgia, USA. shuzhao.li@gmail.com|Emory Vaccine Center, Emory University, Atlanta, Georgia, USA. shuzhao.li@gmail.com|Emory Vaccine Center, Emory University, Atlanta, Georgia, USA. shuzhao.li@gmail.com|Emory Vaccine Center, Emory University, Atlanta, Georgia, USA. shuzhao.li@gmail.com|Emory Vaccine Center, Emory University, Atlanta, Georgia, USA. shuzhao.li@gmail.com|Emory Vaccine Center, Emory University, Atlanta, Georgia, USA. shuzhao.li@gmail.com|Emory Vaccine Center, Emory University, Atlanta, Georgia, USA. shuzhao.li@gmail.com|Emory Vaccine Center, Emory University, Atlanta, Georgia, USA. shuzhao.li@gmail.com', 'Georgia|Georgia|Georgia|Georgia|Georgia|Georgia|Georgia|Georgia', 0, 'Algorithms|Humans|Immunity, Innate|Mass Spectrometry|Metabolomics', 'Journal Article', '10.1371/journal.pcbi.1003123', '23861661', 'The functional interpretation of high throughput metabolomics by mass spectrometry is hindered by the identification of metabolites, a tedious and challenging task. We present a set of computational algorithms which, by leveraging the collective power of metabolic pathways and networks, predict functional activity directly from spectral feature tables without a priori identification of metabolites. The algorithms were experimentally validated on the activation of innate immune cells. '),
(86086, 2013, 'plos', 'Pathway-based screening strategy for multitarget inhibitors of diverse proteins in metabolic pathways', 'Hsu, Kai-Cheng|Cheng, Wen-Chi|Chen, Yen-Fu|Wang, Wen-Ching|Yang, Jinn-Moon', 'Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.|Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.|Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.|Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.|Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.', '-|-|-|-|-', 15, 'Biological Evolution|Models, Molecular|Mutagenesis, Site-Directed|Proteins', 'Journal Article', '10.1371/journal.pcbi.1003127', '23861662', 'Many virtual screening methods have been developed for identifying single-target inhibitors based on the strategy of one-disease, one-target, one-drug. The hit rates of these methods are often low because they cannot capture the features that play key roles in the biological functions of the target protein. Furthermore, single-target inhibitors are often susceptible to drug resistance and are ineffective for complex diseases such as cancers. Therefore, a new strategy is required for enriching the hit rate and identifying multitarget inhibitors. To address these issues, we propose the pathway-based screening strategy (called PathSiMMap) to derive binding mechanisms for increasing the hit rate and discovering multitarget inhibitors using site-moiety maps. This strategy simultaneously screens multiple target proteins in the same pathway, these proteins bind intermediates with common substructures. These proteins possess similar conserved binding environments (pathway anchors) when the product of one protein is the substrate of the next protein in the pathway despite their low sequence identity and structure similarity. We successfully discovered two multitarget inhibitors with IC50 of <10 µM for shikimate dehydrogenase and shikimate kinase in the shikimate pathway of Helicobacter pylori. Furthermore, we found two selective inhibitors (IC50 of <10 µM) for shikimate dehydrogenase using the specific anchors derived by our method. Our experimental results reveal that this strategy can enhance the hit rates and the pathway anchors are highly conserved and important for biological functions. We believe that our strategy provides a great value for elucidating protein binding mechanisms and discovering multitarget inhibitors. '),
(86087, 2013, 'plos', 'Engineering a more thermostable blue light photo receptor Bacillus subtilis YtvA LOV domain by a computer aided rational design method', 'Song, Xiangfei|Wang, Yefei|Shu, Zhiyu|Hong, Jingbo|Li, Tong|Yao, Lishan', 'Shandong Provincial Key Laboratory of Energy Genetics, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China.|Shandong Provincial Key Laboratory of Energy Genetics, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China.|Shandong Provincial Key Laboratory of Energy Genetics, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China.|Shandong Provincial Key Laboratory of Energy Genetics, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China.|Shandong Provincial Key Laboratory of Energy Genetics, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China.|Shandong Provincial Key Laboratory of Energy Genetics, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China.', 'China|China|China|China|China|China', 22, 'Bacillus subtilis|Cloning, Molecular|Computer-Aided Design|Fluorescence|Light|Models, Molecular|Photoreceptors, Microbial|Protein Engineering', 'Journal Article', '10.1371/journal.pcbi.1003129', '23861663', 'The ability to design thermostable proteins offers enormous potential for the development of novel protein bioreagents. In this work, a combined computational and experimental method was developed to increase the T m of the flavin mononucleotide based fluorescent protein Bacillus Subtilis YtvA LOV domain by 31 Celsius, thus extending its applicability in thermophilic systems. Briefly, the method includes five steps, the single mutant computer screening to identify thermostable mutant candidates, the experimental evaluation to confirm the positive selections, the computational redesign around the thermostable mutation regions, the experimental reevaluation and finally the multiple mutations combination. The adopted method is simple and effective, can be applied to other important proteins where other methods have difficulties, and therefore provides a new tool to improve protein thermostability. '),
(86088, 2013, 'plos', 'Predictors of hepatitis B cure using gene therapy to deliver DNA cleavage enzymes: a mathematical modeling approach', 'Schiffer, Joshua T|Swan, Dave A|Stone, Daniel|Jerome, Keith R', 'Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. jschiffe@fhcrc.org|Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. jschiffe@fhcrc.org|Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. jschiffe@fhcrc.org|Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. jschiffe@fhcrc.org', 'United States|United States|United States|United States', 31, 'DNA|DNA Repair|Genetic Therapy|Genetic Vectors|Hepatitis B|Humans|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1003131', '23861664', 'Most chronic viral infections are managed with small molecule therapies that inhibit replication but are not curative because non-replicating viral forms can persist despite decades of suppressive treatment. There are therefore numerous strategies in development to eradicate all non-replicating viruses from the body. We are currently engineering DNA cleavage enzymes that specifically target hepatitis B virus covalently closed circular DNA (HBV cccDNA), the episomal form of the virus that persists despite potent antiviral therapies. DNA cleavage enzymes, including homing endonucleases or meganucleases, zinc-finger nucleases (ZFNs), TAL effector nucleases (TALENs), and CRISPR-associated system 9 (Cas9) proteins, can disrupt specific regions of viral DNA. Because DNA repair is error prone, the virus can be neutralized after repeated cleavage events when a target sequence becomes mutated. DNA cleavage enzymes will be delivered as genes within viral vectors that enter hepatocytes. Here we develop mathematical models that describe the delivery and intracellular activity of DNA cleavage enzymes. Model simulations predict that high vector to target cell ratio, limited removal of delivery vectors by humoral immunity, and avid binding between enzyme and its DNA target will promote the highest level of cccDNA disruption. Development of de novo resistance to cleavage enzymes may occur if DNA cleavage and error prone repair does not render the viral episome replication incompetent: our model predicts that concurrent delivery of multiple enzymes which target different vital cccDNA regions, or sequential delivery of different enzymes, are both potentially useful strategies for avoiding multi-enzyme resistance. The underlying dynamics of cccDNA persistence are unlikely to impact the probability of cure provided that antiviral therapy is given concurrently during eradication trials. We conclude by describing experiments that can be used to validate the model, which will in turn provide vital information for dose selection for potential curative trials in animals and ultimately humans. '),
(86089, 2013, 'plos', 'Consistent estimation of Gibbs energy using component contributions', 'Noor, Elad|Haraldsdóttir, Hulda S|Milo, Ron|Fleming, Ronan M T', 'Plant Sciences Department, Weizmann Institute of Science, Rehovot, Israel.|Plant Sciences Department, Weizmann Institute of Science, Rehovot, Israel.|Plant Sciences Department, Weizmann Institute of Science, Rehovot, Israel.|Plant Sciences Department, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel|Israel|Israel', 109, 'Energy Metabolism|Genome|Models, Biological|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003098', '23874165', 'Standard Gibbs energies of reactions are increasingly being used in metabolic modeling for applying thermodynamic constraints on reaction rates, metabolite concentrations and kinetic parameters. The increasing scope and diversity of metabolic models has led scientists to look for genome-scale solutions that can estimate the standard Gibbs energy of all the reactions in metabolism. Group contribution methods greatly increase coverage, albeit at the price of decreased precision. We present here a way to combine the estimations of group contribution with the more accurate reactant contributions by decomposing each reaction into two parts and applying one of the methods on each of them. This method gives priority to the reactant contributions over group contributions while guaranteeing that all estimations will be consistent, i.e. will not violate the first law of thermodynamics. We show that there is a significant increase in the accuracy of our estimations compared to standard group contribution. Specifically, our cross-validation results show an 80% reduction in the median absolute residual for reactions that can be derived by reactant contributions only. We provide the full framework and source code for deriving estimates of standard reaction Gibbs energy, as well as confidence intervals, and believe this will facilitate the wide use of thermodynamic data for a better understanding of metabolism. '),
(86090, 2013, 'plos', 'Optimal dynamics for quality control in spatially distributed mitochondrial networks', 'Patel, Pinkesh K|Shirihai, Orian|Huang, Kerwyn Casey', 'Department of Bioengineering, Stanford University, Stanford, California, USA.|Department of Bioengineering, Stanford University, Stanford, California, USA.|Department of Bioengineering, Stanford University, Stanford, California, USA.', 'United States|United States|United States', 25, 'Autophagy|Membrane Potential, Mitochondrial|Mitochondria|Quality Control|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1003108', '23874166', 'Recent imaging studies of mitochondrial dynamics have implicated a cycle of fusion, fission, and autophagy in the quality control of mitochondrial function by selectively increasing the membrane potential of some mitochondria at the expense of the turnover of others. This complex, dynamical system creates spatially distributed networks that are dependent on active transport along cytoskeletal networks and on protein import leading to biogenesis. To study the relative impacts of local interactions between neighboring mitochondria and their reorganization via transport, we have developed a spatiotemporal mathematical model encompassing all of these processes in which we focus on the dynamics of a health parameter meant to mimic the functional state of mitochondria. In agreement with previous models, we show that both autophagy and the generation of membrane potential asymmetry following a fusion/fission cycle are required for maintaining a healthy mitochondrial population. This health maintenance is affected by mitochondrial density and motility primarily through changes in the frequency of fusion events. Health is optimized when the selectivity thresholds for fusion and fission are matched, providing a mechanistic basis for the observed coupling of the two processes through the protein OPA1. We also demonstrate that the discreteness of the components exchanged during fusion is critical for quality control, and that the effects of limiting total amounts of autophagy and biogenesis have distinct consequences on health and population size, respectively. Taken together, our results show that several general principles emerge from the complexity of the quality control cycle that can be used to focus and interpret future experimental studies, and our modeling framework provides a road-map for deconstructing the functional importance of local interactions in communities of cells as well as organelles. '),
(86091, 2013, 'plos', 'A family of algorithms for computing consensus about node state from network data', 'Brush, Eleanor R|Krakauer, David C|Flack, Jessica C', 'Program in Quantitative and Computational Biology, Princeton University, Princeton, New Jersey, USA. brush@princeton.edu|Program in Quantitative and Computational Biology, Princeton University, Princeton, New Jersey, USA. brush@princeton.edu|Program in Quantitative and Computational Biology, Princeton University, Princeton, New Jersey, USA. brush@princeton.edu', 'Jersey|Jersey|Jersey', 17, 'Algorithms|Neural Networks (Computer)|Social Support', 'Journal Article', '10.1371/journal.pcbi.1003109', '23874167', 'Biological and social networks are composed of heterogeneous nodes that contribute differentially to network structure and function. A number of algorithms have been developed to measure this variation. These algorithms have proven useful for applications that require assigning scores to individual nodes-from ranking websites to determining critical species in ecosystems-yet the mechanistic basis for why they produce good rankings remains poorly understood. We show that a unifying property of these algorithms is that they quantify consensus in the network about a nodes state or capacity to perform a function. The algorithms capture consensus by either taking into account the number of a target nodes direct connections, and, when the edges are weighted, the uniformity of its weighted in-degree distribution (breadth), or by measuring net flow into a target node (depth). Using data from communication, social, and biological networks we find that that how an algorithm measures consensus-through breadth or depth- impacts its ability to correctly score nodes. We also observe variation in sensitivity to source biases in interaction/adjacency matrices: errors arising from systematic error at the node level or direct manipulation of network connectivity by nodes. Our results indicate that the breadth algorithms, which are derived from information theory, correctly score nodes (assessed using independent data) and are robust to errors. However, in cases where nodes form opinions about other nodes using indirect information, like reputation, depth algorithms, like Eigenvector Centrality, are required. One caveat is that Eigenvector Centrality is not robust to error unless the network is transitive or assortative. In these cases the network structure allows the depth algorithms to effectively capture breadth as well as depth. Finally, we discuss the algorithms cognitive and computational demands. This is an important consideration in systems in which individuals use the collective opinions of others to make decisions. '),
(86092, 2013, 'plos', 'The minimal complexity of adapting agents increases with fitness', 'Joshi, Nikhil J|Tononi, Giulio|Koch, Christof', 'Computation and Neural Systems, California Institute of Technology, Pasadena, California, USA. nikhil.joshi@caltech.edu|Computation and Neural Systems, California Institute of Technology, Pasadena, California, USA. nikhil.joshi@caltech.edu|Computation and Neural Systems, California Institute of Technology, Pasadena, California, USA. nikhil.joshi@caltech.edu', 'United States|United States|United States', 24, 'Adaptation, Physiological|Animals|Biological Evolution|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.1003111', '23874168', 'What is the relationship between the complexity and the fitness of evolved organisms, whether natural or artificial? It has been asserted, primarily based on empirical data, that the complexity of plants and animals increases as their fitness within a particular environment increases via evolution by natural selection. We simulate the evolution of the brains of simple organisms living in a planar maze that they have to traverse as rapidly as possible. Their connectome evolves over 10,000s of generations. We evaluate their circuit complexity, using four information-theoretical measures, including one that emphasizes the extent to which any network is an irreducible entity. We find that their minimal complexity increases with their fitness. '),
(86093, 2013, 'plos', 'Target essentiality and centrality characterize drug side effects', 'Wang, Xiujuan|Thijssen, Bram|Yu, Haiyuan', 'Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, USA.|Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, USA.|Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, USA.', 'United States|United States|United States', 31, 'Drug-Related Side Effects and Adverse Reactions|Humans|Linear Models|Proteins', 'Journal Article', '10.1371/journal.pcbi.1003119', '23874169', 'To investigate factors contributing to drug side effects, we systematically examine relationships between 4,199 side effects associated with 996 drugs and their 647 human protein targets. We find that it is the number of essential targets, not the number of total targets, that determines the side effects of corresponding drugs. Furthermore, within the context of a three-dimensional interaction network with atomic-resolution interaction interfaces, we find that drugs causing more side effects are also characterized by high degree and betweenness of their targets and highly shared interaction interfaces on these targets. Our findings suggest that both essentiality and centrality of a drug target are key factors contributing to side effects and should be taken into consideration in rational drug design. '),
(86094, 2013, 'plos', 'Towards predicting the response of a solid tumour to chemotherapy and radiotherapy treatments: clinical insights from a computational model', 'Powathil, Gibin G|Adamson, Douglas J A|Chaplain, Mark A J', 'Division of Mathematics, University of Dundee, Dundee, United Kingdom. gibin@maths.dundee.ac.uk|Division of Mathematics, University of Dundee, Dundee, United Kingdom. gibin@maths.dundee.ac.uk|Division of Mathematics, University of Dundee, Dundee, United Kingdom. gibin@maths.dundee.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 60, 'Cell Cycle|Humans|Models, Biological|Neoplasms|Treatment Outcome', 'Journal Article', '10.1371/journal.pcbi.1003120', '23874170', 'In this paper we use a hybrid multiscale mathematical model that incorporates both individual cell behaviour through the cell-cycle and the effects of the changing microenvironment through oxygen dynamics to study the multiple effects of radiation therapy. The oxygenation status of the cells is considered as one of the important prognostic markers for determining radiation therapy, as hypoxic cells are less radiosensitive. Another factor that critically affects radiation sensitivity is cell-cycle regulation. The effects of radiation therapy are included in the model using a modified linear quadratic model for the radiation damage, incorporating the effects of hypoxia and cell-cycle in determining the cell-cycle phase-specific radiosensitivity. Furthermore, after irradiation, an individual cells cell-cycle dynamics are intrinsically modified through the activation of pathways responsible for repair mechanisms, often resulting in a delay/arrest in the cell-cycle. The model is then used to study various combinations of multiple doses of cell-cycle dependent chemotherapies and radiation therapy, as radiation may work better by the partial synchronisation of cells in the most radiosensitive phase of the cell-cycle. Moreover, using this multi-scale model, we investigate the optimum sequencing and scheduling of these multi-modality treatments, and the impact of internal and external heterogeneity on the spatio-temporal patterning of the distribution of tumour cells and their response to different treatment schedules. '),
(86095, 2013, 'plos', 'The role of multiple marks in epigenetic silencing and the emergence of a stable bivalent chromatin state', 'Mukhopadhyay, Swagatam|Sengupta, Anirvan M', 'Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. smukhopa@cshl.edu|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. smukhopa@cshl.edu', 'United States|United States', 9, 'Acetylation|Chromatin|DNA Methylation|Epigenesis, Genetic|Gene Silencing|Histones|Sirtuins', 'Journal Article', '10.1371/journal.pcbi.1003121', '23874171', 'We introduce and analyze a minimal model of epigenetic silencing in budding yeast, built upon known biomolecular interactions in the system. Doing so, we identify the epigenetic marks essential for the bistability of epigenetic states. The model explicitly incorporates two key chromatin marks, namely H4K16 acetylation and H3K79 methylation, and explores whether the presence of multiple marks lead to a qualitatively different systems behavior. We find that having both modifications is important for the robustness of epigenetic silencing. Besides the silenced and transcriptionally active fate of chromatin, our model leads to a novel state with bivalent (i.e., both active and silencing) marks under certain perturbations (knock-out mutations, inhibition or enhancement of enzymatic activity). The bivalent state appears under several perturbations and is shown to result in patchy silencing. We also show that the titration effect, owing to a limited supply of silencing proteins, can result in counter-intuitive responses. The design principles of the silencing system is systematically investigated and disparate experimental observations are assessed within a single theoretical framework. Specifically, we discuss the behavior of Sir protein recruitment, spreading and stability of silenced regions in commonly-studied mutants (e.g., sas2[Formula: see text], dot1[Formula: see text]) illuminating the controversial role of Dot1 in the systems biology of yeast silencing. '),
(86096, 2013, 'plos', 'Shared protein complex subunits contribute to explaining disrupted co-occurrence', 'Schneider, Adrian|Seidl, Michael F|Snel, Berend', 'Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, The Netherlands.|Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, The Netherlands.|Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, The Netherlands.', 'Netherlands|Netherlands|Netherlands', 10, 'Genome|Phylogeny|Proteins', 'Journal Article', '10.1371/journal.pcbi.1003124', '23874172', 'The gene composition of present-day genomes has been shaped by a complicated evolutionary history, resulting in diverse distributions of genes across genomes. The pattern of presence and absence of a gene in different genomes is called its phylogenetic profile. It has been shown that proteins whose encoding genes have highly similar profiles tend to be functionally related: As these genes were gained and lost together, their encoded proteins can probably only perform their full function if both are present. However, a large proportion of genes encoding interacting proteins do not have matching profiles. In this study, we analysed one possible reason for this, namely that phylogenetic profiles can be affected by multi-functional proteins such as shared subunits of two or more protein complexes. We found that by considering triplets of proteins, of which one protein is multi-functional, a large fraction of disturbed co-occurrence patterns can be explained. '),
(86097, 2013, 'plos', 'A model for the self-organization of vesicular flux and protein distributions in the Golgi apparatus', 'Ispolatov, Iaroslav|Müsch, Anne', 'Departamento de Física, Universidad de Santiago de Chile, Santiago, Chile. jaros007@gmail.com|Departamento de Física, Universidad de Santiago de Chile, Santiago, Chile. jaros007@gmail.com', 'Chile|Chile', 8, 'Golgi Apparatus|Models, Biological|Proteins', 'Journal Article', '10.1371/journal.pcbi.1003125', '23874173', 'The generation of two non-identical membrane compartments via exchange of vesicles is considered to require two types of vesicles specified by distinct cytosolic coats that selectively recruit cargo, and two membrane-bound SNARE pairs that specify fusion and differ in their affinities for each type of vesicles. The mammalian Golgi complex is composed of 6-8 non-identical cisternae that undergo gradual maturation and replacement yet features only two SNARE pairs. We present a model that explains how distinct composition of Golgi cisternae can be generated with two and even a single SNARE pair and one vesicle coat. A decay of active SNARE concentration in aging cisternae provides the seed for a cis[Formula: see text]trans SNARE gradient that generates the predominantly retrograde vesicle flux which further enhances the gradient. This flux in turn yields the observed inhomogeneous steady-state distribution of Golgi enzymes, which compete with each other and with the SNAREs for incorporation into transport vesicles. We show analytically that the steady state SNARE concentration decays exponentially with the cisterna number. Numerical solutions of rate equations reproduce the experimentally observed SNARE gradients, overlapping enzyme peaks in cis, medial and trans and the reported change in vesicle nature across the Golgi: Vesicles originating from younger cisternae mostly contain Golgi enzymes and SNAREs enriched in these cisternae and extensively recycle through the Endoplasmic Reticulum (ER), while the other subpopulation of vesicles contains Golgi proteins prevalent in older cisternae and hardly reaches the ER. '),
(86098, 2013, 'plos', 'Hierarchical modeling for rare event detection and cell subset alignment across flow cytometry samples', 'Cron, Andrew|Gouttefangeas, Cécile|Frelinger, Jacob|Lin, Lin|Singh, Satwinder K|Britten, Cedrik M|Welters, Marij J P|van der Burg, Sjoerd H|West, Mike|Chan, Cliburn', 'Department of Statistical Science, Duke University, Durham, North Carolina, USA.|Department of Statistical Science, Duke University, Durham, North Carolina, USA.|Department of Statistical Science, Duke University, Durham, North Carolina, USA.|Department of Statistical Science, Duke University, Durham, North Carolina, USA.|Department of Statistical Science, Duke University, Durham, North Carolina, USA.|Department of Statistical Science, Duke University, Durham, North Carolina, USA.|Department of Statistical Science, Duke University, Durham, North Carolina, USA.|Department of Statistical Science, Duke University, Durham, North Carolina, USA.|Department of Statistical Science, Duke University, Durham, North Carolina, USA.|Department of Statistical Science, Duke University, Durham, North Carolina, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States|United States|United States', 52, 'Flow Cytometry|Humans|Lymphocyte Subsets|Models, Biological|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1003130', '23874174', 'Flow cytometry is the prototypical assay for multi-parameter single cell analysis, and is essential in vaccine and biomarker research for the enumeration of antigen-specific lymphocytes that are often found in extremely low frequencies (0.1% or less). Standard analysis of flow cytometry data relies on visual identification of cell subsets by experts, a process that is subjective and often difficult to reproduce. An alternative and more objective approach is the use of statistical models to identify cell subsets of interest in an automated fashion. Two specific challenges for automated analysis are to detect extremely low frequency event subsets without biasing the estimate by pre-processing enrichment, and the ability to align cell subsets across multiple data samples for comparative analysis. In this manuscript, we develop hierarchical modeling extensions to the Dirichlet Process Gaussian Mixture Model (DPGMM) approach we have previously described for cell subset identification, and show that the hierarchical DPGMM (HDPGMM) naturally generates an aligned data model that captures both commonalities and variations across multiple samples. HDPGMM also increases the sensitivity to extremely low frequency events by sharing information across multiple samples analyzed simultaneously. We validate the accuracy and reproducibility of HDPGMM estimates of antigen-specific T cells on clinically relevant reference peripheral blood mononuclear cell (PBMC) samples with known frequencies of antigen-specific T cells. These cell samples take advantage of retrovirally TCR-transduced T cells spiked into autologous PBMC samples to give a defined number of antigen-specific T cells detectable by HLA-peptide multimer binding. We provide open source software that can take advantage of both multiple processors and GPU-acceleration to perform the numerically-demanding computations. We show that hierarchical modeling is a useful probabilistic approach that can provide a consistent labeling of cell subsets and increase the sensitivity of rare event detection in the context of quantifying antigen-specific immune responses. '),
(86099, 2013, 'plos', 'Transcription factor binding profiles reveal cyclic expression of human protein-coding genes and non-coding RNAs', 'Cheng, Chao|Ung, Matthew|Grant, Gavin D|Whitfield, Michael L', 'Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA. chao.cheng@dartmouth.edu|Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA. chao.cheng@dartmouth.edu|Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA. chao.cheng@dartmouth.edu|Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA. chao.cheng@dartmouth.edu', 'United States|United States|United States|United States', 5, 'Genes, cdc|Humans|Promoter Regions, Genetic|Protein Binding|RNA, Untranslated|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1003132', '23874175', 'Cell cycle is a complex and highly supervised process that must proceed with regulatory precision to achieve successful cellular division. Despite the wide application, microarray time course experiments have several limitations in identifying cell cycle genes. We thus propose a computational model to predict human cell cycle genes based on transcription factor (TF) binding and regulatory motif information in their promoters. We utilize ENCODE ChIP-seq data and motif information as predictors to discriminate cell cycle against non-cell cycle genes. Our results show that both the trans- TF features and the cis- motif features are predictive of cell cycle genes, and a combination of the two types of features can further improve prediction accuracy. We apply our model to a complete list of GENCODE promoters to predict novel cell cycle driving promoters for both protein-coding genes and non-coding RNAs such as lincRNAs. We find that a similar percentage of lincRNAs are cell cycle regulated as protein-coding genes, suggesting the importance of non-coding RNAs in cell cycle division. The model we propose here provides not only a practical tool for identifying novel cell cycle genes with high accuracy, but also new insights on cell cycle regulation by TFs and cis-regulatory elements. '),
(86100, 2013, 'plos', 'Gain control network conditions in early sensory coding', 'Serrano, Eduardo|Nowotny, Thomas|Levi, Rafael|Smith, Brian H|Huerta, Ramón', 'GNB, Escuela Politécnica Superior, Universidad Autónoma de Madrid, Madrid, Spain.|GNB, Escuela Politécnica Superior, Universidad Autónoma de Madrid, Madrid, Spain.|GNB, Escuela Politécnica Superior, Universidad Autónoma de Madrid, Madrid, Spain.|GNB, Escuela Politécnica Superior, Universidad Autónoma de Madrid, Madrid, Spain.|GNB, Escuela Politécnica Superior, Universidad Autónoma de Madrid, Madrid, Spain.', 'Spain|Spain|Spain|Spain|Spain', 18, 'Brain|Models, Neurological|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.1003133', '23874176', 'Gain control is essential for the proper function of any sensory system. However, the precise mechanisms for achieving effective gain control in the brain are unknown. Based on our understanding of the existence and strength of connections in the insect olfactory system, we analyze the conditions that lead to controlled gain in a randomly connected network of excitatory and inhibitory neurons. We consider two scenarios for the variation of input into the system. In the first case, the intensity of the sensory input controls the input currents to a fixed proportion of neurons of the excitatory and inhibitory populations. In the second case, increasing intensity of the sensory stimulus will both, recruit an increasing number of neurons that receive input and change the input current that they receive. Using a mean field approximation for the network activity we derive relationships between the parameters of the network that ensure that the overall level of activity of the excitatory population remains unchanged for increasing intensity of the external stimulation. We find that, first, the main parameters that regulate network gain are the probabilities of connections from the inhibitory population to the excitatory population and of the connections within the inhibitory population. Second, we show that strict gain control is not achievable in a random network in the second case, when the input recruits an increasing number of neurons. Finally, we confirm that the gain control conditions derived from the mean field approximation are valid in simulations of firing rate models and Hodgkin-Huxley conductance based models. '),
(86101, 2013, 'plos', 'Charles Bonnet syndrome: evidence for a generative model in the cortex?', 'Reichert, David P|Seriès, Peggy|Storkey, Amos J', 'Institute for Adaptive and Neural Computation, University of Edinburgh, Edinburgh, United Kingdom. david_reichert@brown.edu|Institute for Adaptive and Neural Computation, University of Edinburgh, Edinburgh, United Kingdom. david_reichert@brown.edu|Institute for Adaptive and Neural Computation, University of Edinburgh, Edinburgh, United Kingdom. david_reichert@brown.edu', 'United Kingdom|United Kingdom|United Kingdom', 26, 'Hallucinations|Homeostasis|Humans|Models, Biological|Nerve Net|Probability|Syndrome', 'Journal Article', '10.1371/journal.pcbi.1003134', '23874177', 'Several theories propose that the cortex implements an internal model to explain, predict, and learn about sensory data, but the nature of this model is unclear. One condition that could be highly informative here is Charles Bonnet syndrome (CBS), where loss of vision leads to complex, vivid visual hallucinations of objects, people, and whole scenes. CBS could be taken as indication that there is a generative model in the brain, specifically one that can synthesise rich, consistent visual representations even in the absence of actual visual input. The processes that lead to CBS are poorly understood. Here, we argue that a model recently introduced in machine learning, the deep Boltzmann machine (DBM), could capture the relevant aspects of (hypothetical) generative processing in the cortex. The DBM carries both the semantics of a probabilistic generative model and of a neural network. The latter allows us to model a concrete neural mechanism that could underlie CBS, namely, homeostatic regulation of neuronal activity. We show that homeostatic plasticity could serve to make the learnt internal model robust against e.g. degradation of sensory input, but overcompensate in the case of CBS, leading to hallucinations. We demonstrate how a wide range of features of CBS can be explained in the model and suggest a potential role for the neuromodulator acetylcholine. This work constitutes the first concrete computational model of CBS and the first application of the DBM as a model in computational neuroscience. Our results lend further credence to the hypothesis of a generative model in the brain. '),
(86102, 2013, 'plos', 'Genetic selection for context-dependent stochastic phenotypes: Sp1 and TATA mutations increase phenotypic noise in HIV-1 gene expression', 'Miller-Jensen, Kathryn|Skupsky, Ron|Shah, Priya S|Arkin, Adam P|Schaffer, David V', 'Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA. kathryn.miller-jensen@yale.edu|Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA. kathryn.miller-jensen@yale.edu|Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA. kathryn.miller-jensen@yale.edu|Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA. kathryn.miller-jensen@yale.edu|Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA. kathryn.miller-jensen@yale.edu', 'United States|United States|United States|United States|United States', 20, 'HIV-1|Humans|In Vitro Techniques|Mutation|Phenotype|Selection, Genetic|Sp1 Transcription Factor|Stochastic Processes|TATA Box|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1003135', '23874178', 'The sequence of a promoter within a genome does not uniquely determine gene expression levels and their variability, rather, promoter sequence can additionally interact with its location in the genome, or genomic context, to shape eukaryotic gene expression. Retroviruses, such as human immunodeficiency virus-1 (HIV), integrate their genomes into those of their host and thereby provide a biomedically-relevant model system to quantitatively explore the relationship between promoter sequence, genomic context, and noise-driven variability on viral gene expression. Using an in vitro model of the HIV Tat-mediated positive-feedback loop, we previously demonstrated that fluctuations in viral Tat-transactivating protein levels generate integration-site-dependent, stochastically-driven phenotypes, in which infected cells randomly switch between high and low expressing states in a manner that may be related to viral latency. Here we extended this model and designed a forward genetic screen to systematically identify genetic elements in the HIV LTR promoter that modulate the fraction of genomic integrations that specify Switching phenotypes. Our screen identified mutations in core promoter regions, including Sp1 and TATA transcription factor binding sites, which increased the Switching fraction several fold. By integrating single-cell experiments with computational modeling, we further investigated the mechanism of Switching-fraction enhancement for a selected Sp1 mutation. Our experimental observations demonstrated that the Sp1 mutation both impaired Tat-transactivated expression and also altered basal expression in the absence of Tat. Computational analysis demonstrated that the observed change in basal expression could contribute significantly to the observed increase in viral integrations that specify a Switching phenotype, provided that the selected mutation affected Tat-mediated noise amplification differentially across genomic contexts. Our study thus demonstrates a methodology to identify and characterize promoter elements that affect the distribution of stochastic phenotypes over genomic contexts, and advances our understanding of how promoter mutations may control the frequency of latent HIV infection. '),
(86103, 2013, 'plos', 'New universal rules of eukaryotic translation initiation fidelity', 'Zur, Hadas|Tuller, Tamir', 'Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv, Israel.|Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv, Israel.', 'Israel|Israel', 64, '5 Untranslated Regions|Codon|Genome|Peptide Initiation Factors', 'Journal Article', '10.1371/journal.pcbi.1003136', '23874179', 'The accepted model of eukaryotic translation initiation begins with the scanning of the transcript by the pre-initiation complex from the 5end until an ATG codon with a specific nucleotide (nt) context surrounding it is recognized (Kozak rule). According to this model, ATG codons upstream to the beginning of the ORF should affect translation. We perform for the first time, a genome-wide statistical analysis, uncovering a new, more comprehensive and quantitative, set of initiation rules for improving the cost of translation and its efficiency. Analyzing dozens of eukaryotic genomes, we find that in all frames there is a universal trend of selection for low numbers of ATG codons, specifically, 16-27 codons upstream, but also 5-11 codons downstream of the START ATG, include less ATG codons than expected. We further suggest that there is selection for anti optimal ATG contexts in the vicinity of the START ATG. Thus, the efficiency and fidelity of translation initiation is encoded in the 5UTR as required by the scanning model, but also at the beginning of the ORF. The observed nt patterns suggest that in all the analyzed organisms the pre-initiation complex often misses the START ATG of the ORF, and may start translation from an alternative initiation start-site. Thus, to prevent the translation of undesired proteins, there is selection for nucleotide sequences with low affinity to the pre-initiation complex near the beginning of the ORF. With the new suggested rules we were able to obtain a twice higher correlation with ribosomal density and protein levels in comparison to the Kozak rule alone (e.g. for protein levels r=0.7 vs. r=0.31, p<10(-12)).');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86104, 2013, 'plos', 'Frequency dependence of signal power and spatial reach of the local field potential', 'xc5x81xc4x99ski, Szymon|Lindxc3xa9n, Henrik|Tetzlaff, Tom|Pettersen, Klas H|Einevoll, Gaute T', 'Department of Mathematical Sciences and Technology, Norwegian University of Life Sciences, xc3x85s, Norway. s.leski@nencki.gov.pl|Department of Mathematical Sciences and Technology, Norwegian University of Life Sciences, xc3x85s, Norway. s.leski@nencki.gov.pl|Department of Mathematical Sciences and Technology, Norwegian University of Life Sciences, xc3x85s, Norway. s.leski@nencki.gov.pl|Department of Mathematical Sciences and Technology, Norwegian University of Life Sciences, xc3x85s, Norway. s.leski@nencki.gov.pl|Department of Mathematical Sciences and Technology, Norwegian University of Life Sciences, xc3x85s, Norway. s.leski@nencki.gov.pl', 'Norway|Norway|Norway|Norway|Norway', 0, 'Action Potentials|Brain|Models, Neurological', 'Journal Article', '10.1371/journal.pcbi.1003137', '23874180', 'Despite its century-old use, the interpretation of local field potentials (LFPs), the low-frequency part of electrical signals recorded in the brain, is still debated. In cortex the LFP appears to mainly stem from transmembrane neuronal currents following synaptic input, and obvious questions regarding the locality of the LFP are: What is the size of the signal-generating region, i.e., the spatial reach, around a recording contact? How far does the LFP signal extend outside a synaptically activated neuronal population? And how do the answers depend on the temporal frequency of the LFP signal? Experimental inquiries have given conflicting results, and we here pursue a modeling approach based on a well-established biophysical forward-modeling scheme incorporating detailed reconstructed neuronal morphologies in precise calculations of population LFPs including thousands of neurons. The two key factors determining the frequency dependence of LFP are the spatial decay of the single-neuron LFP contribution and the conversion of synaptic input correlations into correlations between single-neuron LFP contributions. Both factors are seen to give low-pass filtering of the LFP signal power. For uncorrelated input only the first factor is relevant, and here a modest reduction (<50%) in the spatial reach is observed for higher frequencies (>100 Hz) compared to the near-DC ([Formula: see text]) value of about [Formula: see text]. Much larger frequency-dependent effects are seen when populations of pyramidal neurons receive correlated and spatially asymmetric inputs: the low-frequency ([Formula: see text]) LFP power can here be an order of magnitude or more larger than at 60 Hz. Moreover, the low-frequency LFP components have larger spatial reach and extend further outside the active population than high-frequency components. Further, the spatial LFP profiles for such populations typically span the full vertical extent of the dendrites of neurons in the population. Our numerical findings are backed up by an intuitive simplified model for the generation of population LFP. '),
(86105, 2013, 'plos', 'Successful reconstruction of a physiological circuit with known connectivity from spiking activity alone', 'Gerhard, Felipe|Kispersky, Tilman|Gutierrez, Gabrielle J|Marder, Eve|Kramer, Mark|Eden, Uri', 'Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. felipe.gerhard@epfl.ch|Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. felipe.gerhard@epfl.ch|Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. felipe.gerhard@epfl.ch|Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. felipe.gerhard@epfl.ch|Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. felipe.gerhard@epfl.ch|Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. felipe.gerhard@epfl.ch', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 41, 'Action Potentials|Biophysics|Models, Biological|Neurons', 'Journal Article', '10.1371/journal.pcbi.1003138', '23874181', 'Identifying the structure and dynamics of synaptic interactions between neurons is the first step to understanding neural network dynamics. The presence of synaptic connections is traditionally inferred through the use of targeted stimulation and paired recordings or by post-hoc histology. More recently, causal network inference algorithms have been proposed to deduce connectivity directly from electrophysiological signals, such as extracellularly recorded spiking activity. Usually, these algorithms have not been validated on a neurophysiological data set for which the actual circuitry is known. Recent work has shown that traditional network inference algorithms based on linear models typically fail to identify the correct coupling of a small central pattern generating circuit in the stomatogastric ganglion of the crab Cancer borealis. In this work, we show that point process models of observed spike trains can guide inference of relative connectivity estimates that match the known physiological connectivity of the central pattern generator up to a choice of threshold. We elucidate the necessary steps to derive faithful connectivity estimates from a model that incorporates the spike train nature of the data. We then apply the model to measure changes in the effective connectivity pattern in response to two pharmacological interventions, which affect both intrinsic neural dynamics and synaptic transmission. Our results provide the first successful application of a network inference algorithm to a circuit for which the actual physiological synapses between neurons are known. The point process methodology presented here generalizes well to larger networks and can describe the statistics of neural populations. In general we show that advanced statistical models allow for the characterization of effective network structure, deciphering underlying network dynamics and estimating information-processing capabilities. '),
(86106, 2013, 'plos', 'Distinct allelic patterns of nanog expression impart embryonic stem cell population heterogeneity', 'Wu, Jincheng|Tzanakakis, Emmanuel S', 'Department of Chemical and Biological Engineering, State University of New York at Buffalo, Buffalo, New York, USA.|Department of Chemical and Biological Engineering, State University of New York at Buffalo, Buffalo, New York, USA.', 'United States|United States', 9, 'Alleles|Animals|Embryonic Stem Cells|Gene Expression|Homeodomain Proteins|Mice|Nanog Homeobox Protein', 'Journal Article', '10.1371/journal.pcbi.1003140', '23874182', 'Nanog is a principal pluripotency regulator exhibiting a disperse distribution within stem cell populations in vivo and in vitro. Increasing evidence points to a functional role of Nanog heterogeneity on stem cell fate decisions. Allelic control of Nanog gene expression was reported recently in mouse embryonic stem cells. To better understand how this mode of regulation influences the observed heterogeneity of NANOG in stem cell populations, we assembled a multiscale stochastic population balance equation framework. In addition to allelic control, gene expression noise and random partitioning at cell division were considered. As a result of allelic Nanog expression, the distribution of Nanog exhibited three distinct states but when combined with transcriptional noise the profile became bimodal. Regardless of their allelic expression pattern, initially uniform populations of stem cells gave rise to the same Nanog heterogeneity within ten cell cycles. Depletion of NANOG content in cells switching off both gene alleles was slower than the accumulation of intracellular NANOG after cells turned on at least one of their Nanog gene copies pointing to Nanog state-dependent dynamics. Allelic transcription of Nanog also raises issues regarding the use of stem cell lines with reporter genes knocked in a single allelic locus. Indeed, significant divergence was observed in the reporter and native protein profiles depending on the difference in their half-lives and insertion of the reporter gene in one or both alleles. In stem cell populations with restricted Nanog expression, allelic regulation facilitates the maintenance of fractions of self-renewing cells with sufficient Nanog content to prevent aberrant loss of pluripotency. Our findings underline the role of allelic control of Nanog expression as a prime determinant of stem cell population heterogeneity and warrant further investigation in the contexts of stem cell specification and cell reprogramming. '),
(86107, 2013, 'plos', 'Dynamic fluctuations provide the basis of a conformational switch mechanism in apo cyclic AMP receptor protein', 'Aykaxc3xa7 Fas, Burcu|Tutar, Yusuf|Haliloxc4x9flu, Txc3xbcrkan', 'Department of Chemical Engineering and Polymer Research Center, Boxc4x9fazixc3xa7i University, Bebek, xc4xb0stanbul, Turkey.|Department of Chemical Engineering and Polymer Research Center, Boxc4x9fazixc3xa7i University, Bebek, xc4xb0stanbul, Turkey.|Department of Chemical Engineering and Polymer Research Center, Boxc4x9fazixc3xa7i University, Bebek, xc4xb0stanbul, Turkey.', 'Turkey|Turkey|Turkey', 0, 'Cyclic AMP Receptor Protein|Models, Molecular|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1003141', '23874183', 'Escherichia coli cyclic AMP Receptor Protein (CRP) undergoes conformational changes with cAMP binding and allosterically promotes CRP to bind specifically to the DNA. In that, the structural and dynamic properties of apo CRP prior to cAMP binding are of interest for the comprehension of the activation mechanism. Here, the dynamics of apo CRP monomer/dimer and holo CRP dimer were studied by Molecular Dynamics (MD) simulations and Gaussian Network Model (GNM). The interplay of the inter-domain hinge with the cAMP and DNA binding domains are pre-disposed in the apo state as a conformational switch in the CRPs allosteric communication mechanism. The hinge at L134-D138 displaying intra- and inter-subunit coupled fluctuations with the cAMP and DNA binding domains leads to the emergence of stronger coupled fluctuations between the two domains and describes an on state. The flexible regions at K52-E58, P154/D155 and I175 maintain the dynamic coupling of the two domains. With a shift in the inter-domain hinge position towards the N terminus, nevertheless, the latter correlations between the domains loosen and become disordered, L134-D138 dynamically interacts only with the cAMP and DNA binding domains of its own subunit, and an off state is assumed. We present a mechanistic view on how the structural dynamic units are hierarchically built for the allosteric functional mechanism, from apo CRP monomer to apo-to-holo CRP dimers. '),
(86108, 2013, 'plos', 'Epidemiologically optimal static networks from temporal network data', 'Holme, Petter', 'Department of Energy Science, Sungkyunkwan University, Suwon, Korea. holme@skku.edu', '-', 37, 'Computer Simulation|Disease Outbreaks|Epidemiologic Studies|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1003142', '23874184', 'One of network epidemiologys central assumptions is that the contact structure over which infectious diseases propagate can be represented as a static network. However, contacts are highly dynamic, changing at many time scales. In this paper, we investigate conceptually simple methods to construct static graphs for network epidemiology from temporal contact data. We evaluate these methods on empirical and synthetic model data. For almost all our cases, the network representation that captures most relevant information is a so-called exponential-threshold network. In these, each contact contributes with a weight decreasing exponentially with time, and there is an edge between a pair of vertices if the weight between them exceeds a threshold. Networks of aggregated contacts over an optimally chosen time window perform almost as good as the exponential-threshold networks. On the other hand, networks of accumulated contacts over the entire sampling time, and networks of concurrent partnerships, perform worse. We discuss these observations in the context of the temporal and topological structure of the data sets. '),
(86109, 2013, 'plos', 'Inferring nonlinear neuronal computation based on physiologically plausible inputs', 'McFarland, James M|Cui, Yuwei|Butts, Daniel A', 'Department of Biology and Program in Neuroscience and Cognitive Science, University of Maryland, College Park, Maryland, USA. jmmcfarl@umd.edu|Department of Biology and Program in Neuroscience and Cognitive Science, University of Maryland, College Park, Maryland, USA. jmmcfarl@umd.edu|Department of Biology and Program in Neuroscience and Cognitive Science, University of Maryland, College Park, Maryland, USA. jmmcfarl@umd.edu', 'United States|United States|United States', 71, 'Models, Biological|Neurons|Retinal Ganglion Cells', 'Journal Article', '10.1371/journal.pcbi.1003143', '23874185', 'The computation represented by a sensory neurons response to stimuli is constructed from an array of physiological processes both belonging to that neuron and inherited from its inputs. Although many of these physiological processes are known to be nonlinear, linear approximations are commonly used to describe the stimulus selectivity of sensory neurons (i.e., linear receptive fields). Here we present an approach for modeling sensory processing, termed the Nonlinear Input Model (NIM), which is based on the hypothesis that the dominant nonlinearities imposed by physiological mechanisms arise from rectification of a neurons inputs. Incorporating such upstream nonlinearities within the standard linear-nonlinear (LN) cascade modeling structure implicitly allows for the identification of multiple stimulus features driving a neurons response, which become directly interpretable as either excitatory or inhibitory. Because its form is analogous to an integrate-and-fire neuron receiving excitatory and inhibitory inputs, model fitting can be guided by prior knowledge about the inputs to a given neuron, and elements of the resulting model can often result in specific physiological predictions. Furthermore, by providing an explicit probabilistic model with a relatively simple nonlinear structure, its parameters can be efficiently optimized and appropriately regularized. Parameter estimation is robust and efficient even with large numbers of model components and in the context of high-dimensional stimuli with complex statistical structure (e.g. natural stimuli). We describe detailed methods for estimating the model parameters, and illustrate the advantages of the NIM using a range of example sensory neurons in the visual and auditory systems. We thus present a modeling framework that can capture a broad range of nonlinear response functions while providing physiologically interpretable descriptions of neural computation. '),
(86110, 2013, 'plos', 'Structural disorder provides increased adaptability for vesicle trafficking pathways', 'Pietrosemoli, Natalia|Pancsa, Rita|Tompa, Peter', 'National Centre for Biotechnology (CNB-CSIC), Madrid, Spain , Department of Bioengineering, Rice University, Houston, Texas, USA.|National Centre for Biotechnology (CNB-CSIC), Madrid, Spain , Department of Bioengineering, Rice University, Houston, Texas, USA.|National Centre for Biotechnology (CNB-CSIC), Madrid, Spain , Department of Bioengineering, Rice University, Houston, Texas, USA.', 'Spain|Spain|Spain', 0, 'Databases, Protein|Humans|Models, Molecular|Organelles|Protein Transport|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1003144', '23874186', 'Vesicle trafficking systems play essential roles in the communication between the organelles of eukaryotic cells and also between cells and their environment. Endocytosis and the late secretory route are mediated by clathrin-coated vesicles, while the COat Protein I and II (COPI and COPII) routes stand for the bidirectional traffic between the ER and the Golgi apparatus. Despite similar fundamental organizations, the molecular machinery, functions, and evolutionary characteristics of the three systems are very different. In this work, we compiled the basic functional protein groups of the three main routes for human and yeast and analyzed them from the structural disorder perspective. We found similar overall disorder content in yeast and human proteins, confirming the well-conserved nature of these systems. Most functional groups contain highly disordered proteins, supporting the general importance of structural disorder in these routes, although some of them seem to heavily rely on disorder, while others do not. Interestingly, the clathrin system is significantly more disordered (~23%) than the other two, COPI (~9%) and COPII (~8%). We show that this structural phenomenon enhances the inherent plasticity and increased evolutionary adaptability of the clathrin system, which distinguishes it from the other two routes. Since multi-functionality (moonlighting) is indicative of both plasticity and adaptability, we studied its prevalence in vesicle trafficking proteins and correlated it with structural disorder. Clathrin adaptors have the highest capability for moonlighting while also comprising the most highly disordered members. The ability to acquire tissue specific functions was also used to approach adaptability: clathrin route genes have the most tissue specific exons encoding for protein segments enriched in structural disorder and interaction sites. Overall, our results confirm the general importance of structural disorder in vesicle trafficking and suggest major roles for this structural property in shaping the differences of evolutionary adaptability in the three routes.'),
(86111, 2013, 'plos', 'Statistical analysis of molecular signal recording', 'Glaser, Joshua I|Zamft, Bradley M|Marblestone, Adam H|Moffitt, Jeffrey R|Tyo, Keith|Boyden, Edward S|Church, George|Kording, Konrad P', 'Department of Physical Medicine and Rehabilitation, Northwestern University and Rehabilitation Institute of Chicago, Chicago, Illinois, USA. j-glaser@u.northwestern.edu|Department of Physical Medicine and Rehabilitation, Northwestern University and Rehabilitation Institute of Chicago, Chicago, Illinois, USA. j-glaser@u.northwestern.edu|Department of Physical Medicine and Rehabilitation, Northwestern University and Rehabilitation Institute of Chicago, Chicago, Illinois, USA. j-glaser@u.northwestern.edu|Department of Physical Medicine and Rehabilitation, Northwestern University and Rehabilitation Institute of Chicago, Chicago, Illinois, USA. j-glaser@u.northwestern.edu|Department of Physical Medicine and Rehabilitation, Northwestern University and Rehabilitation Institute of Chicago, Chicago, Illinois, USA. j-glaser@u.northwestern.edu|Department of Physical Medicine and Rehabilitation, Northwestern University and Rehabilitation Institute of Chicago, Chicago, Illinois, USA. j-glaser@u.northwestern.edu|Department of Physical Medicine and Rehabilitation, Northwestern University and Rehabilitation Institute of Chicago, Chicago, Illinois, USA. j-glaser@u.northwestern.edu|Department of Physical Medicine and Rehabilitation, Northwestern University and Rehabilitation Institute of Chicago, Chicago, Illinois, USA. j-glaser@u.northwestern.edu', 'United States|United States|United States|United States|United States|United States|United States|United States', 14, 'Algorithms|DNA|DNA-Directed DNA Polymerase|Kinetics', 'Journal Article', '10.1371/journal.pcbi.1003145', '23874187', 'A molecular device that records time-varying signals would enable new approaches in neuroscience. We have recently proposed such a device, termed a molecular ticker tape, in which an engineered DNA polymerase (DNAP) writes time-varying signals into DNA in the form of nucleotide misincorporation patterns. Here, we define a theoretical framework quantifying the expected capabilities of molecular ticker tapes as a function of experimental parameters. We present a decoding algorithm for estimating time-dependent input signals, and DNAP kinetic parameters, directly from misincorporation rates as determined by sequencing. We explore the requirements for accurate signal decoding, particularly the constraints on (1) the polymerase biochemical parameters, and (2) the amplitude, temporal resolution, and duration of the time-varying input signals. Our results suggest that molecular recording devices with kinetic properties similar to natural polymerases could be used to perform experiments in which neural activity is compared across several experimental conditions, and that devices engineered by combining favorable biochemical properties from multiple known polymerases could potentially measure faster phenomena such as slow synchronization of neuronal oscillations. Sophisticated engineering of DNAPs is likely required to achieve molecular recording of neuronal activity with single-spike temporal resolution over experimentally relevant timescales. '),
(86112, 2013, 'plos', 'Dynamics of SIN asymmetry establishment', 'Bajpai, Archana|Feoktistova, Anna|Chen, Jun-Song|McCollum, Dannel|Sato, Masamitsu|Carazo-Salas, Rafael E|Gould, Kathleen L|Csikász-Nagy, Attila', 'Microsoft Research-University of Trento Centre for Computational Systems Biology, Piazza Manifattura 1, Rovereto, Italy.|Microsoft Research-University of Trento Centre for Computational Systems Biology, Piazza Manifattura 1, Rovereto, Italy.|Microsoft Research-University of Trento Centre for Computational Systems Biology, Piazza Manifattura 1, Rovereto, Italy.|Microsoft Research-University of Trento Centre for Computational Systems Biology, Piazza Manifattura 1, Rovereto, Italy.|Microsoft Research-University of Trento Centre for Computational Systems Biology, Piazza Manifattura 1, Rovereto, Italy.|Microsoft Research-University of Trento Centre for Computational Systems Biology, Piazza Manifattura 1, Rovereto, Italy.|Microsoft Research-University of Trento Centre for Computational Systems Biology, Piazza Manifattura 1, Rovereto, Italy.|Microsoft Research-University of Trento Centre for Computational Systems Biology, Piazza Manifattura 1, Rovereto, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy|Italy|Italy', 0, 'Cell Cycle|Cell Cycle Proteins|Phosphorylation|Schizosaccharomyces|Schizosaccharomyces pombe Proteins|Spindle Apparatus', 'Journal Article', '10.1371/journal.pcbi.1003147', '23874188', 'Timing of cell division is coordinated by the Septation Initiation Network (SIN) in fission yeast. SIN activation is initiated at the two spindle pole bodies (SPB) of the cell in metaphase, but only one of these SPBs contains an active SIN in anaphase, while SIN is inactivated in the other by the Cdc16-Byr4 GAP complex. Most of the factors that are needed for such asymmetry establishment have been already characterized, but we lack the molecular details that drive such quick asymmetric distribution of molecules at the two SPBs. Here we investigate the problem by computational modeling and, after establishing a minimal system with two antagonists that can drive reliable asymmetry establishment, we incorporate the current knowledge on the basic SIN regulators into an extended model with molecular details of the key regulators. The model can capture several peculiar earlier experimental findings and also predicts the behavior of double and triple SIN mutants. We experimentally tested one prediction, that phosphorylation of the scaffold protein Cdc11 by a SIN kinase and the core cell cycle regulatory Cyclin dependent kinase (Cdk) can compensate for mutations in the SIN inhibitor Cdc16 with different efficiencies. One aspect of the prediction failed, highlighting a potential hole in our current knowledge. Further experimental tests revealed that SIN induced Cdc11 phosphorylation might have two separate effects. We conclude that SIN asymmetry is established by the antagonistic interactions between SIN and its inhibitor Cdc16-Byr4, partially through the regulation of Cdc11 phosphorylation states. '),
(86113, 2013, 'plos', 'Ten simple rules for writing a literature review', 'Pautasso, Marco', 'Microsoft Research-University of Trento Centre for Computational Systems Biology, Piazza Manifattura 1, Rovereto, Italy.', 'Italy', 0, 'Guidelines as Topic|Review Literature as Topic|Writing', 'Editorial', '10.1371/journal.pcbi.1003149', '23874189', '-'),
(86114, 2013, 'plos', 'Improving pharmacokinetic-pharmacodynamic modeling to investigate anti-infective chemotherapy with application to the current generation of antimalarial drugs', 'Kay, Katherine|Hastings, Ian M', 'Parasitology Department, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom. kwinter@liverpool.ac.uk|Parasitology Department, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom. kwinter@liverpool.ac.uk', 'United Kingdom|United Kingdom', 22, 'Animals|Antimalarials|Half-Life|Humans|Models, Biological|Plasmodium', 'Journal Article', '10.1371/journal.pcbi.1003151', '23874190', 'Mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) modelling is the standard computational technique for simulating drug treatment of infectious diseases with the potential to enhance our understanding of drug treatment outcomes, drug deployment strategies, and dosing regimens. Standard methodologies assume only a single drug is used, it acts only in its unconverted form, and that oral drugs are instantaneously absorbed across the gut wall to their site of action. For drugs with short half-lives, this absorption period accounts for a significant period of their time in the body. Treatment of infectious diseases often uses combination therapies, so we refined and substantially extended the PK/PD methodologies to incorporate (i) time lags and drug concentration profiles resulting from absorption across the gut wall and, if required, conversion to another active form, (ii) multiple drugs within a treatment combination, (iii) differing modes of action of drugs in the combination: additive, synergistic, antagonistic, (iv) drugs converted to an active metabolite with a similar mode of action. This methodology was applied to a case study of two first-line malaria treatments based on artemisinin combination therapies (ACTs, artemether-lumefantrine and artesunate-mefloquine) where the likelihood of increased artemisinin tolerance/resistance has led to speculation on their continued long-term effectiveness. We note previous estimates of artemisinin kill rate were underestimated by a factor of seven, both the unconverted and converted form of the artemisinins kill parasites and the extended PK/PD methodology produced results consistent with field observations. The simulations predict that a potentially rapid decline in ACT effectiveness is likely to occur as artemisinin resistance spreads, emphasising the importance of containing the spread of artemisinin resistance before it results in widespread drug failure. We found that PK/PD data is generally very poorly reported in the malaria literature, severely reducing its value for subsequent re-application, and we make specific recommendations to improve this situation. '),
(86115, 2013, 'plos', 'GEMINI: integrative exploration of genetic variation and genome annotations', 'Paila, Umadevi|Chapman, Brad A|Kirchner, Rory|Quinlan, Aaron R', 'Department of Public Health Sciences and Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.|Department of Public Health Sciences and Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.|Department of Public Health Sciences and Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.|Department of Public Health Sciences and Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.', 'United States|United States|United States|United States', 0, 'Data Mining|Databases, Genetic|Genetic Variation|Genome, Human|Genomics|Genotype|Humans|Software', 'Journal Article', '10.1371/journal.pcbi.1003153', '23874191', 'Modern DNA sequencing technologies enable geneticists to rapidly identify genetic variation among many human genomes. However, isolating the minority of variants underlying disease remains an important, yet formidable challenge for medical genetics. We have developed GEMINI (GEnome MINIng), a flexible software package for exploring all forms of human genetic variation. Unlike existing tools, GEMINI integrates genetic variation with a diverse and adaptable set of genome annotations (e.g., dbSNP, ENCODE, UCSC, ClinVar, KEGG) into a unified database to facilitate interpretation and data exploration. Whereas other methods provide an inflexible set of variant filters or prioritization methods, GEMINI allows researchers to compose complex queries based on sample genotypes, inheritance patterns, and both pre-installed and custom genome annotations. GEMINI also provides methods for ad hoc queries and data exploration, a simple programming interface for custom analyses that leverage the underlying database, and both command line and graphical tools for common analyses. We demonstrate GEMINIs utility for exploring variation in personal genomes and family based genetic studies, and illustrate its ability to scale to studies involving thousands of human samples. GEMINI is designed for reproducibility and flexibility and our goal is to provide researchers with a standard framework for medical genomics. '),
(86116, 2013, 'plos', 'A systematic framework for molecular dynamics simulations of protein post-translational modifications', 'Petrov, Drazen|Margreitter, Christian|Grandits, Melanie|Oostenbrink, Chris|Zagrovic, Bojan', 'Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter, Vienna, Austria.|Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter, Vienna, Austria.|Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter, Vienna, Austria.|Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter, Vienna, Austria.|Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter, Vienna, Austria.', 'Austria|Austria|Austria|Austria|Austria', 47, 'Computational Biology|Molecular Dynamics Simulation|Protein Processing, Post-Translational|Proteins', 'Journal Article', '10.1371/journal.pcbi.1003154', '23874192', 'By directly affecting structure, dynamics and interaction networks of their targets, post-translational modifications (PTMs) of proteins play a key role in different cellular processes ranging from enzymatic activation to regulation of signal transduction to cell-cycle control. Despite the great importance of understanding how PTMs affect proteins at the atomistic level, a systematic framework for treating post-translationally modified amino acids by molecular dynamics (MD) simulations, a premier high-resolution computational biology tool, has never been developed. Here, we report and validate force field parameters (GROMOS 45a3 and 54a7) required to run and analyze MD simulations of more than 250 different types of enzymatic and non-enzymatic PTMs. The newly developed GROMOS 54a7 parameters in particular exhibit near chemical accuracy in matching experimentally measured hydration free energies (RMSE=4.2 kJ/mol over the validation set). Using this tool, we quantitatively show that the majority of PTMs greatly alter the hydrophobicity and other physico-chemical properties of target amino acids, with the extent of change in many cases being comparable to the complete range spanned by native amino acids.'),
(86117, 2013, 'plos', 'Variations within class-A xcexb2-lactamase physiochemical properties reflect evolutionary and environmental patterns, but not antibiotic specificity', 'Verma, Deeptak|Jacobs, Donald J|Livesay, Dennis R', 'Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, North Carolina, USA.|Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, North Carolina, USA.|Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, North Carolina, USA.', 'United States|United States|United States', 0, 'Amino Acid Sequence|Anti-Bacterial Agents|Bacteria|Biological Evolution|Models, Molecular|Molecular Sequence Data|Phylogeny|Sequence Homology, Amino Acid|Static Electricity|beta-Lactamases', 'Journal Article', '10.1371/journal.pcbi.1003155', '23874193', 'The bacterial enzyme xcexb2-lactamase hydrolyzes the xcexb2-lactam ring of penicillin and chemically related antibiotics, rendering them ineffective. Due to rampant antibiotic overuse, the enzyme is evolving new resistance activities at an alarming rate. Related, the enzymes global physiochemical properties exhibit various amounts of conservation and variability across the family. To that end, we characterize the extent of property conservation within twelve different class-A xcexb2-lactamases, and conclusively establish that the systematic variations therein parallel their evolutionary history. Large and systematic differences within electrostatic potential maps and pairwise residue-to-residue couplings are observed across the protein, which robustly reflect phylogenetic outgroups. Other properties are more conserved (such as residue pKa values, electrostatic networks, and backbone flexibility), yet they also have systematic variations that parallel the phylogeny in a statistically significant way. Similarly, the above properties also parallel the environmental condition of the bacteria they are from in a statistically significant way. However, it is interesting and surprising that the only one of the global properties (protein charge) parallels the functional specificity patterns, meaning antibiotic resistance activities are not significantly constraining the global physiochemical properties. Rather, extended spectrum activities can emerge from the background of nearly any set of electrostatic and dynamic properties. '),
(86118, 2013, 'plos', 'Expanding the druggable space of the LSD1/CoREST epigenetic target: new potential binding regions for drug-like molecules, peptides, protein partners, and chromatin', 'Robertson, James C|Hurley, Nate C|Tortorici, Marcello|Ciossani, Giuseppe|Borrello, Maria Teresa|Vellore, Nadeem A|Ganesan, A|Mattevi, Andrea|Baron, Riccardo', 'Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA.|Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA.|Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA.|Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA.|Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA.|Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA.|Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA.|Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA.|Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States|United States', 0, 'Binding Sites|Chromatin|Co-Repressor Proteins|Crystallography, X-Ray|Epigenesis, Genetic|Histone Demethylases|Molecular Dynamics Simulation|Nerve Tissue Proteins|Peptides|Repressor Proteins', 'Journal Article', '10.1371/journal.pcbi.1003158', '23874194', 'Lysine specific demethylase-1 (LSD1/KDM1A) in complex with its corepressor protein CoREST is a promising target for epigenetic drugs. No therapeutic that targets LSD1/CoREST, however, has been reported to date. Recently, extended molecular dynamics (MD) simulations indicated that LSD1/CoREST nanoscale clamp dynamics is regulated by substrate binding and highlighted key hinge points of this large-scale motion as well as the relevance of local residue dynamics. Prompted by the urgent need for new molecular probes and inhibitors to understand LSD1/CoREST interactions with small-molecules, peptides, protein partners, and chromatin, we undertake here a configurational ensemble approach to expand LSD1/CoREST druggability. The independent algorithms FTMap and SiteMap and our newly developed Druggable Site Visualizer (DSV) software tool were used to predict and inspect favorable binding sites. We find that the hinge points revealed by MD simulations at the SANT2/Tower interface, at the SWIRM/AOD interface, and at the AOD/Tower interface are new targets for the discovery of molecular probes to block association of LSD1/CoREST with chromatin or protein partners. A fourth region was also predicted from simulated configurational ensembles and was experimentally validated to have strong binding propensity. The observation that this prediction would be prevented when using only the X-ray structures available (including the X-ray structure bound to the same peptide) underscores the relevance of protein dynamics in protein interactions. A fifth region was highlighted corresponding to a small pocket on the AOD domain. This study sets the basis for future virtual screening campaigns targeting the five novel regions reported herein and for the design of LSD1/CoREST mutants to probe LSD1/CoREST binding with chromatin and various protein partners. '),
(86119, 2013, 'plos', 'Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection', 'Bains, Iren|van Santen, Hisse M|Seddon, Benedict|Yates, Andrew J', 'Immune Cell Biology, MRC National Institute for Medical Research, Mill Hill, London, United Kingdom.|Immune Cell Biology, MRC National Institute for Medical Research, Mill Hill, London, United Kingdom.|Immune Cell Biology, MRC National Institute for Medical Research, Mill Hill, London, United Kingdom.|Immune Cell Biology, MRC National Institute for Medical Research, Mill Hill, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 14, 'Animals|Cell Lineage|Major Histocompatibility Complex|Mice|Models, Biological|T-Lymphocytes|Thymus Gland', 'Journal Article', '10.1371/journal.pcbi.1003102', '23935465', 'Conventional and regulatory T cells develop in the thymus where they are exposed to samples of self-peptide MHC (pMHC) ligands. This probabilistic process selects for cells within a range of responsiveness that allows the detection of foreign antigen without excessive responses to self. Regulatory T cells are thought to lie at the higher end of the spectrum of acceptable self-reactivity and play a crucial role in the control of autoimmunity and tolerance to innocuous antigens. While many studies have elucidated key elements influencing lineage commitment, we still lack a full understanding of how thymocytes integrate signals obtained by sampling self-peptides to make fate decisions. To address this problem, we apply stochastic models of signal integration by T cells to data from a study quantifying the development of the two lineages using controllable levels of agonist peptide in the thymus. We find two models are able to explain the observations, one in which T cells continually re-assess fate decisions on the basis of multiple summed proximal signals from TCR-pMHC interactions, and another in which TCR sensitivity is modulated over time, such that contact with the same pMHC ligand may lead to divergent outcomes at different stages of development. Neither model requires that T(conv) and T(reg) are differentially susceptible to deletion or that the two lineages need qualitatively different signals for development, as have been proposed. We find additional support for the variable-sensitivity model, which is able to explain apparently paradoxical observations regarding the effect of partial and strong agonists on T(conv) and T(reg) development.'),
(86120, 2013, 'plos', 'HypothesisFinder: a strategy for the detection of speculative statements in scientific text', 'Malhotra, Ashutosh|Younesi, Erfan|Gurulingappa, Harsha|Hofmann-Apitius, Martin', 'Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing, Sankt Augustin, Germany.|Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing, Sankt Augustin, Germany.|Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing, Sankt Augustin, Germany.|Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing, Sankt Augustin, Germany.', 'Germany|Germany|Germany|Germany', 26, 'Alzheimer Disease|Automation|Humans|Models, Theoretical|Natural Language Processing', 'Journal Article', '10.1371/journal.pcbi.1003117', '23935466', 'Speculative statements communicating experimental findings are frequently found in scientific articles, and their purpose is to provide an impetus for further investigations into the given topic. Automated recognition of speculative statements in scientific text has gained interest in recent years as systematic analysis of such statements could transform speculative thoughts into testable hypotheses. We describe here a pattern matching approach for the detection of speculative statements in scientific text that uses a dictionary of speculative patterns to classify sentences as hypothetical. To demonstrate the practical utility of our approach, we applied it to the domain of Alzheimers disease and showed that our automated approach captures a wide spectrum of scientific speculations on Alzheimers disease. Subsequent exploration of derived hypothetical knowledge leads to generation of a coherent overview on emerging knowledge niches, and can thus provide added value to ongoing research activities. '),
(86121, 2013, 'plos', 'Reconstruction and validation of a genome-scale metabolic model for the filamentous fungus Neurospora crassa using FARM', 'Dreyfuss, Jonathan M|Zucker, Jeremy D|Hood, Heather M|Ocasio, Linda R|Sachs, Matthew S|Galagan, James E', 'Graduate Program in Bioinformatics, Boston University, Boston, Massachusetts, United States of America.|Graduate Program in Bioinformatics, Boston University, Boston, Massachusetts, United States of America.|Graduate Program in Bioinformatics, Boston University, Boston, Massachusetts, United States of America.|Graduate Program in Bioinformatics, Boston University, Boston, Massachusetts, United States of America.|Graduate Program in Bioinformatics, Boston University, Boston, Massachusetts, United States of America.|Graduate Program in Bioinformatics, Boston University, Boston, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States|United States', 34, 'Algorithms|Genome, Fungal|Models, Biological|Neurospora crassa', 'Journal Article', '10.1371/journal.pcbi.1003126', '23935467', 'The filamentous fungus Neurospora crassa played a central role in the development of twentieth-century genetics, biochemistry and molecular biology, and continues to serve as a model organism for eukaryotic biology. Here, we have reconstructed a genome-scale model of its metabolism. This model consists of 836 metabolic genes, 257 pathways, 6 cellular compartments, and is supported by extensive manual curation of 491 literature citations. To aid our reconstruction, we developed three optimization-based algorithms, which together comprise Fast Automated Reconstruction of Metabolism (FARM). These algorithms are: LInear MEtabolite Dilution Flux Balance Analysis (limed-FBA), which predicts flux while linearly accounting for metabolite dilution, One-step functional Pruning (OnePrune), which removes blocked reactions with a single compact linear program, and Consistent Reproduction Of growth/no-growth Phenotype (CROP), which reconciles differences between in silico and experimental gene essentiality faster than previous approaches. Against an independent test set of more than 300 essential/non-essential genes that were not used to train the model, the model displays 93% sensitivity and specificity. We also used the model to simulate the biochemical genetics experiments originally performed on Neurospora by comprehensively predicting nutrient rescue of essential genes and synthetic lethal interactions, and we provide detailed pathway-based mechanistic explanations of our predictions. Our model provides a reliable computational framework for the integration and interpretation of ongoing experimental efforts in Neurospora, and we anticipate that our methods will substantially reduce the manual effort required to develop high-quality genome-scale metabolic models for other organisms. '),
(86122, 2013, 'plos', 'Co-expression profiling of autism genes in the mouse brain', 'Menashe, Idan|Grange, Pascal|Larsen, Eric C|Banerjee-Basu, Sharmila|Mitra, Partha P', 'MindSpec, McLean, Virginia, United States of America. menashe.idan@gmail.com|MindSpec, McLean, Virginia, United States of America. menashe.idan@gmail.com|MindSpec, McLean, Virginia, United States of America. menashe.idan@gmail.com|MindSpec, McLean, Virginia, United States of America. menashe.idan@gmail.com|MindSpec, McLean, Virginia, United States of America. menashe.idan@gmail.com', 'United States|United States|United States|United States|United States', 31, 'Animals|Autistic Disorder|Brain|Gene Expression Profiling|Mice|Mice, Inbred C57BL', 'Journal Article', '10.1371/journal.pcbi.1003128', '23935468', 'Autism spectrum disorder (ASD) is one of the most prevalent and highly heritable neurodevelopmental disorders in humans. There is significant evidence that the onset and severity of ASD is governed in part by complex genetic mechanisms affecting the normal development of the brain. To date, a number of genes have been associated with ASD. However, the temporal and spatial co-expression of these genes in the brain remain unclear. To address this issue, we examined the co-expression network of 26 autism genes from AutDB (http://mindspec.org/autdb.html), in the framework of 3,041 genes whose expression energies have the highest correlation between the coronal and sagittal images from the Allen Mouse Brain Atlas database (http://mouse.brain-map.org). These data were derived from in situ hybridization experiments conducted on male, 56-day old C57BL/6J mice co-registered to the Allen Reference Atlas, and were used to generate a normalized co-expression matrix indicating the cosine similarity between expression vectors of genes in this database. The network formed by the autism-associated genes showed a higher degree of co-expression connectivity than seen for the other genes in this dataset (Kolmogorov-Smirnov Pxe2x80x8a=xe2x80x8a5xc3x9710xe2x81xbbxc2xb2xe2x81xb8). Using Monte Carlo simulations, we identified two cliques of co-expressed genes that were significantly enriched with autism genes (A Bonferroni corrected P<0.05). Genes in both these cliques were significantly over-expressed in the cerebellar cortex (Pxe2x80x8a=xe2x80x8a1xc3x9710xe2x81xbbxe2x81xb5) suggesting possible implication of this brain region in autism. In conclusion, our study provides a detailed profiling of co-expression patterns of autism genes in the mouse brain, and suggests specific brain regions and new candidate genes that could be involved in autism etiology.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86123, 2013, 'plos', 'Spatial stochastic dynamics enable robust cell polarization', 'Lawson, Michael J|Drawert, Brian|Khammash, Mustafa|Petzold, Linda|Yi, Tau-Mu', 'Department of BioMolecular Science and Engineering, University of California, Santa Barbara, California, United States of America.|Department of BioMolecular Science and Engineering, University of California, Santa Barbara, California, United States of America.|Department of BioMolecular Science and Engineering, University of California, Santa Barbara, California, United States of America.|Department of BioMolecular Science and Engineering, University of California, Santa Barbara, California, United States of America.|Department of BioMolecular Science and Engineering, University of California, Santa Barbara, California, United States of America.', 'United States|United States|United States|United States|United States', 38, 'Cell Polarity|Models, Biological|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1003139', '23935469', 'Although cell polarity is an essential feature of living cells, it is far from being well-understood. Using a combination of computational modeling and biological experiments we closely examine an important prototype of cell polarity: the pheromone-induced formation of the yeast polarisome. Focusing on the role of noise and spatial heterogeneity, we develop and investigate two mechanistic spatial models of polarisome formation, one deterministic and the other stochastic, and compare the contrasting predictions of these two models against experimental phenotypes of wild-type and mutant cells. We find that the stochastic model can more robustly reproduce two fundamental characteristics observed in wild-type cells: a highly polarized phenotype via a mechanism that we refer to as spatial stochastic amplification, and the ability of the polarisome to track a moving pheromone input. Moreover, we find that only the stochastic model can simultaneously reproduce these characteristics of the wild-type phenotype and the multi-polarisome phenotype of a deletion mutant of the scaffolding protein Spa2. Significantly, our analysis also demonstrates that higher levels of stochastic noise results in increased robustness of polarization to parameter variation. Furthermore, our work suggests a novel role for a polarisome protein in the stabilization of actin cables. These findings elucidate the intricate role of spatial stochastic effects in cell polarity, giving support to a cellular model where noise and spatial heterogeneity combine to achieve robust biological function. '),
(86124, 2013, 'plos', 'Efficient partitioning of memory systems and its importance for memory consolidation', 'Roxin, Alex|Fusi, Stefano', 'Center for Theoretical Neuroscience, Columbia University, New York, New York, United States of America.|Center for Theoretical Neuroscience, Columbia University, New York, New York, United States of America.', 'United States|United States', 21, 'Brain|Memory|Nerve Net|Synapses', 'Journal Article', '10.1371/journal.pcbi.1003146', '23935470', 'Long-term memories are likely stored in the synaptic weights of neuronal networks in the brain. The storage capacity of such networks depends on the degree of plasticity of their synapses. Highly plastic synapses allow for strong memories, but these are quickly overwritten. On the other hand, less labile synapses result in long-lasting but weak memories. Here we show that the trade-off between memory strength and memory lifetime can be overcome by partitioning the memory system into multiple regions characterized by different levels of synaptic plasticity and transferring memory information from the more to less plastic region. The improvement in memory lifetime is proportional to the number of memory regions, and the initial memory strength can be orders of magnitude larger than in a non-partitioned memory system. This model provides a fundamental computational reason for memory consolidation processes at the systems level. '),
(86125, 2013, 'plos', 'Multi-study integration of brain cancer transcriptomes reveals organ-level molecular signatures', 'Sung, Jaeyun|Kim, Pan-Jun|Ma, Shuyi|Funk, Cory C|Magis, Andrew T|Wang, Yuliang|Hood, Leroy|Geman, Donald|Price, Nathan D', 'Institute for Systems Biology, Seattle, Washington, United States of America.|Institute for Systems Biology, Seattle, Washington, United States of America.|Institute for Systems Biology, Seattle, Washington, United States of America.|Institute for Systems Biology, Seattle, Washington, United States of America.|Institute for Systems Biology, Seattle, Washington, United States of America.|Institute for Systems Biology, Seattle, Washington, United States of America.|Institute for Systems Biology, Seattle, Washington, United States of America.|Institute for Systems Biology, Seattle, Washington, United States of America.|Institute for Systems Biology, Seattle, Washington, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 8, 'Biomarkers, Tumor|Brain Neoplasms|Computational Biology|Humans|Reproducibility of Results|Transcriptome', 'Journal Article', '10.1371/journal.pcbi.1003148', '23935471', 'We utilized abundant transcriptomic data for the primary classes of brain cancers to study the feasibility of separating all of these diseases simultaneously based on molecular data alone. These signatures were based on a new method reported herein--Identification of Structured Signatures and Classifiers (ISSAC)--that resulted in a brain cancer marker panel of 44 unique genes. Many of these genes have established relevance to the brain cancers examined herein, with others having known roles in cancer biology. Analyses on large-scale data from multiple sources must deal with significant challenges associated with heterogeneity between different published studies, for it was observed that the variation among individual studies often had a larger effect on the transcriptome than did phenotype differences, as is typical. For this reason, we restricted ourselves to studying only cases where we had at least two independent studies performed for each phenotype, and also reprocessed all the raw data from the studies using a unified pre-processing pipeline. We found that learning signatures across multiple datasets greatly enhanced reproducibility and accuracy in predictive performance on truly independent validation sets, even when keeping the size of the training set the same. This was most likely due to the meta-signature encompassing more of the heterogeneity across different sources and conditions, while amplifying signal from the repeated global characteristics of the phenotype. When molecular signatures of brain cancers were constructed from all currently available microarray data, 90% phenotype prediction accuracy, or the accuracy of identifying a particular brain cancer from the background of all phenotypes, was found. Looking forward, we discuss our approach in the context of the eventual development of organ-specific molecular signatures from peripheral fluids such as the blood.'),
(86126, 2013, 'plos', 'A mixture of delta-rules approximation to bayesian inference in change-point problems', 'Wilson, Robert C|Nassar, Matthew R|Gold, Joshua I', 'Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey, United States of America. rcw2@princeton.edu|Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey, United States of America. rcw2@princeton.edu|Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey, United States of America. rcw2@princeton.edu', 'Jersey|Jersey|Jersey', 39, 'Algorithms|Bayes Theorem|Computer Graphics|Computer Simulation', 'Journal Article', '10.1371/journal.pcbi.1003150', '23935472', 'Error-driven learning rules have received considerable attention because of their close relationships to both optimal theory and neurobiological mechanisms. However, basic forms of these rules are effective under only a restricted set of conditions in which the environment is stable. Recent studies have defined optimal solutions to learning problems in more general, potentially unstable, environments, but the relevance of these complex mathematical solutions to how the brain solves these problems remains unclear. Here, we show that one such Bayesian solution can be approximated by a computationally straightforward mixture of simple error-driven Delta rules. This simpler model can make effective inferences in a dynamic environment and matches human performance on a predictive-inference task using a mixture of a small number of Delta rules. This model represents an important conceptual advance in our understanding of how the brain can use relatively simple computations to make nearly optimal inferences in a dynamic world. '),
(86127, 2013, 'plos', 'Evolutionary evidence for alternative structure in RNA sequence co-variation', 'Ritz, Justin|Martin, Joshua S|Laederach, Alain', 'Department of Biology, University of North Carolina, Chapel Hill, North Carolina, United States of America.|Department of Biology, University of North Carolina, Chapel Hill, North Carolina, United States of America.|Department of Biology, University of North Carolina, Chapel Hill, North Carolina, United States of America.', 'United States|United States|United States', 23, 'Evolution, Molecular|Nucleic Acid Conformation|RNA, Bacterial', 'Journal Article', '10.1371/journal.pcbi.1003152', '23935473', 'Sequence conservation and co-variation of base pairs are hallmarks of structured RNAs. For certain RNAs (e.g. riboswitches), a single sequence must adopt at least two alternative secondary structures to effectively regulate the message. If alternative secondary structures are important to the function of an RNA, we expect to observe evolutionary co-variation supporting multiple conformations. We set out to characterize the evolutionary co-variation supporting alternative conformations in riboswitches to determine the extent to which alternative secondary structures are conserved. We found strong co-variation support for the terminator, P1, and anti-terminator stems in the purine riboswitch by extending alignments to include terminator sequences. When we performed Boltzmann suboptimal sampling on purine riboswitch sequences with terminators we found that these sequences appear to have evolved to favor specific alternative conformations. We extended our analysis of co-variation to classic alignments of group I/II introns, tRNA, and other classes of riboswitches. In a majority of these RNAs, we found evolutionary evidence for alternative conformations that are compatible with the Boltzmann suboptimal ensemble. Our analyses suggest that alternative conformations are selected for and thus likely play functional roles in even the most structured of RNAs. '),
(86128, 2013, 'plos', 'Insertion of the Caxc2xb2xe2x81xba-independent phospholipase Axe2x82x82 into a phospholipid bilayer via coarse-grained and atomistic molecular dynamics simulations', 'Bucher, Denis|Hsu, Yuan-Hao|Mouchlis, Varnavas D|Dennis, Edward A|McCammon, J Andrew', 'Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, United States of America. bucher.denis@gmail.com|Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, United States of America. bucher.denis@gmail.com|Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, United States of America. bucher.denis@gmail.com|Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, United States of America. bucher.denis@gmail.com|Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, United States of America. bucher.denis@gmail.com', 'United States|United States|United States|United States|United States', 25, 'Calcium|Lipid Bilayers|Molecular Dynamics Simulation|Phospholipases A2|Phospholipids', 'Journal Article', '10.1371/journal.pcbi.1003156', '23935474', 'Group VI Caxc2xb2xe2x81xba-independent phospholipase Axe2x82x82 (iPLAxe2x82x82) is a water-soluble enzyme that is active when associated with phospholipid membranes. Despite its clear pharmaceutical relevance, no X-ray or NMR structural information is currently available for the iPLAxe2x82x82 or its membrane complex. In this paper, we combine homology modeling with coarse-grained (CG) and all-atom (AA) molecular dynamics (MD) simulations to build structural models of iPLAxe2x82x82 in association with a phospholipid bilayer. CG-MD simulations of the membrane insertion process were employed to provide a starting point for an atomistic description. Six AA-MD simulations were then conducted for 60 ns, starting from different initial CG structures, to refine the membrane complex. The resulting structures are shown to be consistent with each other and with deuterium exchange mass spectrometry (DXMS) experiments, suggesting that our approach is suitable for the modeling of iPLAxe2x82x82 at the membrane surface. The models show that an anchoring region (residues 710-724) forms an amphipathic helix that is stabilized by the membrane. In future studies, the proposed iPLAxe2x82x82 models should provide a structural basis for understanding the mechanisms of lipid extraction and drug-inhibition. In addition, the dual-resolution approach discussed here should provide the means for the future exploration of the impact of lipid diversity and sequence mutations on the activity of iPLAxe2x82x82 and related enzymes.'),
(86129, 2013, 'plos', 'Information and efficiency in the nervous system--a synthesis', 'Sengupta, Biswa|Stemmler, Martin B|Friston, Karl J', 'The Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. b.sengupta@ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. b.sengupta@ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. b.sengupta@ucl.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Action Potentials|Humans|Nervous System Physiological Phenomena|Signal Transduction|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003157', '23935475', 'In systems biology, questions concerning the molecular and cellular makeup of an organism are of utmost importance, especially when trying to understand how unreliable components--like genetic circuits, biochemical cascades, and ion channels, among others--enable reliable and adaptive behaviour. The repertoire and speed of biological computations are limited by thermodynamic or metabolic constraints: an example can be found in neurons, where fluctuations in biophysical states limit the information they can encode--with almost 20-60% of the total energy allocated for the brain used for signalling purposes, either via action potentials or by synaptic transmission. Here, we consider the imperatives for neurons to optimise computational and metabolic efficiency, wherein benefits and costs trade-off against each other in the context of self-organised and adaptive behaviour. In particular, we try to link information theoretic (variational) and thermodynamic (Helmholtz) free-energy formulations of neuronal processing and show how they are related in a fundamental way through a complexity minimisation lemma.'),
(86130, 2013, 'plos', 'Cell-cycle dependence of transcription dominates noise in gene expression', 'Zopf, C J|Quinn, Katie|Zeidman, Joshua|Maheshri, Narendra', 'Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States', 81, 'Cell Cycle|Gene Expression|Protein Biosynthesis|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1003161', '23935476', 'The large variability in mRNA and protein levels found from both static and dynamic measurements in single cells has been largely attributed to random periods of transcription, often occurring in bursts. The cell cycle has a pronounced global role in affecting transcriptional and translational output, but how this influences transcriptional statistics from noisy promoters is unknown and generally ignored by current stochastic models. Here we show that variable transcription from the synthetic tetO promoter in S. cerevisiae is dominated by its dependence on the cell cycle. Real-time measurements of fluorescent protein at high expression levels indicate tetO promoters increase transcription rate xe2x88xbc2-fold in S/G2/M similar to constitutive genes. At low expression levels, where tetO promoters are thought to generate infrequent bursts of transcription, we observe random pulses of expression restricted to S/G2/M, which are correlated between homologous promoters present in the same cell. The analysis of static, single-cell mRNA measurements at different points along the cell cycle corroborates these findings. Our results demonstrate that highly variable mRNA distributions in yeast are not solely the result of randomly switching between periods of active and inactive gene expression, but instead largely driven by differences in transcriptional activity between G1 and S/G2/M. '),
(86131, 2013, 'plos', 'Quantifying cell fate decisions for differentiation and reprogramming of a human stem cell network: landscape and biological paths', 'Li, Chunhe|Wang, Jin', 'Department of Chemistry and Physics, State University of New York at Stony Brook, Stony Brook, New York, United States of America.|Department of Chemistry and Physics, State University of New York at Stony Brook, Stony Brook, New York, United States of America.', 'United States|United States', 0, 'Cell Differentiation|Computational Biology|Gene Regulatory Networks|Genetic Markers|Humans|Kinetics|Models, Biological|Stem Cells', 'Journal Article', '10.1371/journal.pcbi.1003165', '23935477', 'Cellular reprogramming has been recently intensively studied experimentally. We developed a global potential landscape and kinetic path framework to explore a human stem cell developmental network composed of 52 genes. We uncovered the underlying landscape for the stem cell network with two basins of attractions representing stem and differentiated cell states, quantified and exhibited the high dimensional biological paths for the differentiation and reprogramming process, connecting the stem cell state and differentiated cell state. Both the landscape and non-equilibrium curl flux determine the dynamics of cell differentiation jointly. Flux leads the kinetic paths to be deviated from the steepest descent gradient path, and the corresponding differentiation and reprogramming paths are irreversible. Quantification of paths allows us to find out how the differentiation and reprogramming occur and which important states they go through. We show the developmental process proceeds as moving from the stem cell basin of attraction to the differentiation basin of attraction. The landscape topography characterized by the barrier heights and transition rates quantitatively determine the global stability and kinetic speed of cell fate decision process for development. Through the global sensitivity analysis, we provided some specific predictions for the effects of key genes and regulation connections on the cellular differentiation or reprogramming process. Key links from sensitivity analysis and biological paths can be used to guide the differentiation designs or reprogramming tactics. '),
(86132, 2013, 'plos', 'Parameter trajectory analysis to identify treatment effects of pharmacological interventions', 'Tiemann, Christian A|Vanlier, Joep|Oosterveer, Maaike H|Groen, Albert K|Hilbers, Peter A J|van Riel, Natal A W', 'Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands. c.a.tiemann@tue.nl|Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands. c.a.tiemann@tue.nl|Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands. c.a.tiemann@tue.nl|Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands. c.a.tiemann@tue.nl|Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands. c.a.tiemann@tue.nl|Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands. c.a.tiemann@tue.nl', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 0, 'Animals|Cholesterol, HDL|Computational Biology|Drug Therapy|Hydrocarbons, Fluorinated|Lipoproteins, VLDL|Liver|Liver X Receptors|Mice|Mice, Inbred C57BL|Models, Biological|Monte Carlo Method|Orphan Nuclear Receptors|Pharmacological Phenomena|Phenotype|Reproducibility of Results|Sulfonamides|Triglycerides', 'Journal Article', '10.1371/journal.pcbi.1003166', '23935478', 'The field of medical systems biology aims to advance understanding of molecular mechanisms that drive disease progression and to translate this knowledge into therapies to effectively treat diseases. A challenging task is the investigation of long-term effects of a (pharmacological) treatment, to establish its applicability and to identify potential side effects. We present a new modeling approach, called Analysis of Dynamic Adaptations in Parameter Trajectories (ADAPT), to analyze the long-term effects of a pharmacological intervention. A concept of time-dependent evolution of model parameters is introduced to study the dynamics of molecular adaptations. The progression of these adaptations is predicted by identifying necessary dynamic changes in the model parameters to describe the transition between experimental data obtained during different stages of the treatment. The trajectories provide insight in the affected underlying biological systems and identify the molecular events that should be studied in more detail to unravel the mechanistic basis of treatment outcome. Modulating effects caused by interactions with the proteome and transcriptome levels, which are often less well understood, can be captured by the time-dependent descriptions of the parameters. ADAPT was employed to identify metabolic adaptations induced upon pharmacological activation of the liver X receptor (LXR), a potential drug target to treat or prevent atherosclerosis. The trajectories were investigated to study the cascade of adaptations. This provided a counter-intuitive insight concerning the function of scavenger receptor class B1 (SR-B1), a receptor that facilitates the hepatic uptake of cholesterol. Although activation of LXR promotes cholesterol efflux and -excretion, our computational analysis showed that the hepatic capacity to clear cholesterol was reduced upon prolonged treatment. This prediction was confirmed experimentally by immunoblotting measurements of SR-B1 in hepatic membranes. Next to the identification of potential unwanted side effects, we demonstrate how ADAPT can be used to design new target interventions to prevent these. '),
(86133, 2013, 'plos', 'Full design automation of multi-state RNA devices to program gene expression using energy-based optimization', 'Rodrigo, Guillermo|Landrain, Thomas E|Majer, Eszter|Daròs, José-Antonio|Jaramillo, Alfonso', 'Institute of Systems and Synthetic Biology, CNRS UPS 3509-Université dÉvry Val dEssonne-Genopole, Évry, France.|Institute of Systems and Synthetic Biology, CNRS UPS 3509-Université dÉvry Val dEssonne-Genopole, Évry, France.|Institute of Systems and Synthetic Biology, CNRS UPS 3509-Université dÉvry Val dEssonne-Genopole, Évry, France.|Institute of Systems and Synthetic Biology, CNRS UPS 3509-Université dÉvry Val dEssonne-Genopole, Évry, France.|Institute of Systems and Synthetic Biology, CNRS UPS 3509-Université dÉvry Val dEssonne-Genopole, Évry, France.', 'France|France|France|France|France', 20, 'Models, Genetic|Protein Biosynthesis|RNA|Reproducibility of Results|Ribosomes|Synthetic Biology|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003172', '23935479', 'Small RNAs (sRNAs) can operate as regulatory agents to control protein expression by interaction with the 5 untranslated region of the mRNA. We have developed a physicochemical framework, relying on base pair interaction energies, to design multi-state sRNA devices by solving an optimization problem with an objective function accounting for the stability of the transition and final intermolecular states. Contrary to the analysis of the reaction kinetics of an ensemble of sRNAs, we solve the inverse problem of finding sequences satisfying targeted reactions. We show here that our objective function correlates well with measured riboregulatory activity of a set of mutants. This has enabled the application of the methodology for an extended design of RNA devices with specified behavior, assuming different molecular interaction models based on Watson-Crick interaction. We designed several YES, NOT, AND, and OR logic gates, including the design of combinatorial riboregulators. In sum, our de novo approach provides a new paradigm in synthetic biology to design molecular interaction mechanisms facilitating future high-throughput functional sRNA design. '),
(86134, 2013, 'plos', 'Organism-adapted specificity of the allosteric regulation of pyruvate kinase in lactic acid bacteria', 'Veith, Nadine|Feldman-Salit, Anna|Cojocaru, Vlad|Henrich, Stefan|Kummer, Ursula|Wade, Rebecca C', 'Molecular and Cellular Modelling Group, Heidelberg Institute for Theoretical Studies-HITS, Heidelberg, Germany. Nadine.Veith@bioquant.uni-heidelberg.de|Molecular and Cellular Modelling Group, Heidelberg Institute for Theoretical Studies-HITS, Heidelberg, Germany. Nadine.Veith@bioquant.uni-heidelberg.de|Molecular and Cellular Modelling Group, Heidelberg Institute for Theoretical Studies-HITS, Heidelberg, Germany. Nadine.Veith@bioquant.uni-heidelberg.de|Molecular and Cellular Modelling Group, Heidelberg Institute for Theoretical Studies-HITS, Heidelberg, Germany. Nadine.Veith@bioquant.uni-heidelberg.de|Molecular and Cellular Modelling Group, Heidelberg Institute for Theoretical Studies-HITS, Heidelberg, Germany. Nadine.Veith@bioquant.uni-heidelberg.de|Molecular and Cellular Modelling Group, Heidelberg Institute for Theoretical Studies-HITS, Heidelberg, Germany. Nadine.Veith@bioquant.uni-heidelberg.de', 'Germany|Germany|Germany|Germany|Germany|Germany', 11, 'Allosteric Regulation|Amino Acid Sequence|Lactobacillus|Molecular Sequence Data|Pyruvate Kinase|Sequence Homology, Amino Acid', 'Journal Article', '10.1371/journal.pcbi.1003159', '23946717', 'Pyruvate kinase (PYK) is a critical allosterically regulated enzyme that links glycolysis, the primary energy metabolism, to cellular metabolism. Lactic acid bacteria rely almost exclusively on glycolysis for their energy production under anaerobic conditions, which reinforces the key role of PYK in their metabolism. These organisms are closely related, but have adapted to a huge variety of native environments. They include food-fermenting organisms, important symbionts in the human gut, and antibiotic-resistant pathogens. In contrast to the rather conserved inhibition of PYK by inorganic phosphate, the activation of PYK shows high variability in the type of activating compound between different lactic acid bacteria. System-wide comparative studies of the metabolism of lactic acid bacteria are required to understand the reasons for the diversity of these closely related microorganisms. These require knowledge of the identities of the enzyme modifiers. Here, we predict potential allosteric activators of PYKs from three lactic acid bacteria which are adapted to different native environments. We used protein structure-based molecular modeling and enzyme kinetic modeling to predict and validate potential activators of PYK. Specifically, we compared the electrostatic potential and the binding of phosphate moieties at the allosteric binding sites, and predicted potential allosteric activators by docking. We then made a kinetic model of Lactococcus lactis PYK to relate the activator predictions to the intracellular sugar-phosphate conditions in lactic acid bacteria. This strategy enabled us to predict fructose 1,6-bisphosphate as the sole activator of the Enterococcus faecalis PYK, and to predict that the PYKs from Streptococcus pyogenes and Lactobacillus plantarum show weaker specificity for their allosteric activators, while still having fructose 1,6-bisphosphate play the main activator role in vivo. These differences in the specificity of allosteric activation may reflect adaptation to different environments with different concentrations of activating compounds. The combined computational approach employed can readily be applied to other enzymes. '),
(86135, 2013, 'plos', 'Software for computing and annotating genomic ranges', 'Lawrence, Michael|Huber, Wolfgang|Pagès, Hervé|Aboyoun, Patrick|Carlson, Marc|Gentleman, Robert|Morgan, Martin T|Carey, Vincent J', 'Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, California, United States of America. michafla@gene.com|Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, California, United States of America. michafla@gene.com|Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, California, United States of America. michafla@gene.com|Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, California, United States of America. michafla@gene.com|Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, California, United States of America. michafla@gene.com|Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, California, United States of America. michafla@gene.com|Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, California, United States of America. michafla@gene.com|Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, California, United States of America. michafla@gene.com', 'United States|United States|United States|United States|United States|United States|United States|Un', 1001, 'Algorithms|Animals|Databases, Genetic|Genomics|Humans|Mice|Sequence Alignment|Sequence Analysis, DNA|Software', 'Journal Article', '10.1371/journal.pcbi.1003118', '23950696', 'We describe Bioconductor infrastructure for representing and computing on annotated genomic ranges and integrating genomic data with the statistical computing features of R and its extensions. At the core of the infrastructure are three packages: IRanges, GenomicRanges, and GenomicFeatures. These packages provide scalable data structures for representing annotated ranges on the genome, with special support for transcript structures, read alignments and coverage vectors. Computational facilities include efficient algorithms for overlap and nearest neighbor detection, coverage calculation and other range operations. This infrastructure directly supports more than 80 other Bioconductor packages, including those for sequence analysis, differential expression analysis and visualization. '),
(86136, 2013, 'plos', 'Binding polymorphism in the DNA bound state of the Pdx1 homeodomain', 'Babin, Volodymyr|Wang, Dongli|Rose, Robert B|Sagui, Celeste', 'Center for High Performance Simulations-CHiPS and Department of Physics, North Carolina State University, Raleigh, North Carolina, United States of America.|Center for High Performance Simulations-CHiPS and Department of Physics, North Carolina State University, Raleigh, North Carolina, United States of America.|Center for High Performance Simulations-CHiPS and Department of Physics, North Carolina State University, Raleigh, North Carolina, United States of America.|Center for High Performance Simulations-CHiPS and Department of Physics, North Carolina State University, Raleigh, North Carolina, United States of America.', 'United States|United States|United States|United States', 0, 'Computer Simulation|DNA|Homeodomain Proteins|Humans|Molecular Dynamics Simulation|Protein Binding|Protein Conformation|Trans-Activators', 'Journal Article', '10.1371/journal.pcbi.1003160', '23950697', 'The subtle effects of DNA-protein recognition are illustrated in the homeodomain fold. This is one of several small DNA binding motifs that, in spite of limited DNA binding specificity, adopts crucial, specific roles when incorporated in a transcription factor. The homeodomain is composed of a 3-helix domain and a mobile N-terminal arm. Helix 3 (the recognition helix) interacts with the DNA bases through the major groove, while the N-terminal arm becomes ordered upon binding a specific sequence through the minor groove. Although many structural studies have characterized the DNA binding properties of homeodomains, the factors behind the binding specificity are still difficult to elucidate. A crystal structure of the Pdx1 homeodomain bound to DNA (PDB 2H1K) obtained previously in our lab shows two complexes with differences in the conformation of the N-terminal arm, major groove contacts, and backbone contacts, raising new questions about the DNA recognition process by homeodomains. Here, we carry out fully atomistic Molecular Dynamics simulations both in crystal and aqueous environments in order to elucidate the nature of the difference in binding contacts. The crystal simulations reproduce the X-ray experimental structures well. In the absence of crystal packing constraints, the differences between the two complexes increase during the solution simulations. Thus, the conformational differences are not an artifact of crystal packing. In solution, the homeodomain with a disordered N-terminal arm repositions to a partially specific orientation. Both the crystal and aqueous simulations support the existence of different stable binding conformers identified in the original crystallographic data with different degrees of specificity. We propose that protein-protein and protein-DNA interactions favor a subset of the possible conformations. This flexibility in DNA binding may facilitate multiple functions for the same transcription factor. '),
(86137, 2013, 'plos', 'Evolutionary tradeoffs between economy and effectiveness in biological homeostasis systems', 'Szekely, Pablo|Sheftel, Hila|Mayo, Avi|Alon, Uri', 'Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel|Israel|Israel', 33, 'Animals|Biological Evolution|Calcium Signaling|Cattle|Computational Biology|DNA Repair|Feedback, Physiological|Heat-Shock Response|Homeostasis|Mice|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1003163', '23950698', 'Biological regulatory systems face a fundamental tradeoff: they must be effective but at the same time also economical. For example, regulatory systems that are designed to repair damage must be effective in reducing damage, but economical in not making too many repair proteins because making excessive proteins carries a fitness cost to the cell, called protein burden. In order to see how biological systems compromise between the two tasks of effectiveness and economy, we applied an approach from economics and engineering called Pareto optimality. This approach allows calculating the best-compromise systems that optimally combine the two tasks. We used a simple and general model for regulation, known as integral feedback, and showed that best-compromise systems have particular combinations of biochemical parameters that control the response rate and basal level. We find that the optimal systems fall on a curve in parameter space. Due to this feature, even if one is able to measure only a small fraction of the systems parameters, one can infer the rest. We applied this approach to estimate parameters in three biological systems: response to heat shock and response to DNA damage in bacteria, and calcium homeostasis in mammals.'),
(86138, 2013, 'plos', 'Top-down beta rhythms support selective attention via interlaminar interaction: a model', 'Lee, Jung H|Whittington, Miles A|Kopell, Nancy J', 'Department of Mathematics & Statistics, Boston University, Boston, Massachusetts, United States of America. jleeh@bu.edu|Department of Mathematics & Statistics, Boston University, Boston, Massachusetts, United States of America. jleeh@bu.edu|Department of Mathematics & Statistics, Boston University, Boston, Massachusetts, United States of America. jleeh@bu.edu', 'United States|United States|United States', 0, 'Action Potentials|Animals|Beta Rhythm|Computational Biology|Computer Simulation|Macaca|Models, Neurological|Neurons|Pyramidal Cells', 'Journal Article', '10.1371/journal.pcbi.1003164', '23950699', 'Cortical rhythms have been thought to play crucial roles in our cognitive abilities. Rhythmic activity in the beta frequency band, around 20 Hz, has been reported in recent studies that focused on neural correlates of attention, indicating that top-down beta rhythms, generated in higher cognitive areas and delivered to earlier sensory areas, can support attentional gain modulation. To elucidate functional roles of beta rhythms and underlying mechanisms, we built a computational model of sensory cortical areas. Our simulation results show that top-down beta rhythms can activate ascending synaptic projections from L5 to L4 and L2/3, responsible for biased competition in superficial layers. In the simulation, slow-inhibitory interneurons are shown to resonate to the 20 Hz input and modulate the activity in superficial layers in an attention-related manner. The predicted critical roles of these cells in attentional gain provide a potential mechanism by which cholinergic drive can support selective attention. '),
(86139, 2013, 'plos', 'Shape similarity, better than semantic membership, accounts for the structure of visual object representations in a population of monkey inferotemporal neurons', 'Baldassi, Carlo|Alemi-Neissi, Alireza|Pagan, Marino|Dicarlo, James J|Zecchina, Riccardo|Zoccolan, Davide', 'Department of Applied Science and Technology & Center for Computational Sciences, Politecnico di Torino, Torino, Italy.|Department of Applied Science and Technology & Center for Computational Sciences, Politecnico di Torino, Torino, Italy.|Department of Applied Science and Technology & Center for Computational Sciences, Politecnico di Torino, Torino, Italy.|Department of Applied Science and Technology & Center for Computational Sciences, Politecnico di Torino, Torino, Italy.|Department of Applied Science and Technology & Center for Computational Sciences, Politecnico di Torino, Torino, Italy.|Department of Applied Science and Technology & Center for Computational Sciences, Politecnico di Torino, Torino, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy', 56, 'Algorithms|Animals|Cluster Analysis|Computational Biology|Discriminant Analysis|Haplorhini|Models, Neurological|Multivariate Analysis|Neurons|Semantics|Temporal Lobe|Vision, Ocular', 'Journal Article', '10.1371/journal.pcbi.1003167', '23950700', 'The anterior inferotemporal cortex (IT) is the highest stage along the hierarchy of visual areas that, in primates, processes visual objects. Although several lines of evidence suggest that IT primarily represents visual shape information, some recent studies have argued that neuronal ensembles in IT code the semantic membership of visual objects (i.e., represent conceptual classes such as animate and inanimate objects). In this study, we investigated to what extent semantic, rather than purely visual information, is represented in IT by performing a multivariate analysis of IT responses to a set of visual objects. By relying on a variety of machine-learning approaches (including a cutting-edge clustering algorithm that has been recently developed in the domain of statistical physics), we found that, in most instances, IT representation of visual objects is accounted for by their similarity at the level of shape or, more surprisingly, low-level visual properties. Only in a few cases we observed IT representations of semantic classes that were not explainable by the visual similarity of their members. Overall, these findings reassert the primary function of IT as a conveyor of explicit visual shape information, and reveal that low-level visual properties are represented in IT to a greater extent than previously appreciated. In addition, our work demonstrates how combining a variety of state-of-the-art multivariate approaches, and carefully estimating the contribution of shape similarity to the representation of object categories, can substantially advance our understanding of neuronal coding of visual objects in cortex. '),
(86140, 2013, 'plos', 'Ultrasensitivity in phosphorylation-dephosphorylation cycles with little substrate', 'Martins, Bruno M C|Swain, Peter S', 'SynthSys-Synthetic and Systems Biology, The University of Edinburgh, Edinburgh, United Kingdom. bruno.martins@ed.ac.uk|SynthSys-Synthetic and Systems Biology, The University of Edinburgh, Edinburgh, United Kingdom. bruno.martins@ed.ac.uk', 'United Kingdom|United Kingdom', 0, 'Allosteric Regulation|Computational Biology|Computer Simulation|Models, Biological|Phosphoric Monoester Hydrolases|Phosphorylation|Phosphotransferases|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Substrate Specificity', 'Journal Article', '10.1371/journal.pcbi.1003175', '23950701', 'Cellular decision-making is driven by dynamic behaviours, such as the preparations for sunrise enabled by circadian rhythms and the choice of cell fates enabled by positive feedback. Such behaviours are often built upon ultrasensitive responses where a linear change in input generates a sigmoidal change in output. Phosphorylation-dephosphorylation cycles are one means to generate ultrasensitivity. Using bioinformatics, we show that in vivo levels of kinases and phosphatases frequently exceed the levels of their corresponding substrates in budding yeast. This result is in contrast to the conditions often required by zero-order ultrasensitivity, perhaps the most well known means for how such cycles become ultrasensitive. We therefore introduce a mechanism to generate ultrasensitivity when numbers of enzymes are higher than numbers of substrates. Our model combines distributive and non-distributive actions of the enzymes with two-stage binding and concerted allosteric transitions of the substrate. We use analytical and numerical methods to calculate the Hill number of the response. For a substrate with [Formula: see text] phosphosites, we find an upper bound of the Hill number of [Formula: see text], and so even systems with a single phosphosite can be ultrasensitive. Two-stage binding, where an enzyme must first bind to a binding site on the substrate before it can access the substrates phosphosites, allows the enzymes to sequester the substrate. Such sequestration combined with competition for each phosphosite provides an intuitive explanation for the sigmoidal shifts in levels of phosphorylated substrate. Additionally, we find cases for which the response is not monotonic, but shows instead a peak at intermediate levels of input. Given its generality, we expect the mechanism described by our model to often underlay decision-making circuits in eukaryotic cells. '),
(86141, 2013, 'plos', 'Viral proteins originated de novo by overprinting can be identified by codon usage: application to the gene nursery of Deltaretroviruses', 'Pavesi, Angelo|Magiorkinis, Gkikas|Karlin, David G', 'Department of Life Sciences, University of Parma, I-43124 Parma, Italy. angelo.pavesi@unipr.it|Department of Life Sciences, University of Parma, I-43124 Parma, Italy. angelo.pavesi@unipr.it|Department of Life Sciences, University of Parma, I-43124 Parma, Italy. angelo.pavesi@unipr.it', 'Italy|Italy|Italy', 39, 'Codon|Evolution, Molecular|Genome, Viral|Genomics|Human T-lymphotropic virus 1|Models, Genetic|Viral Proteins', 'Journal Article', '10.1371/journal.pcbi.1003162', '23966842', 'A well-known mechanism through which new protein-coding genes originate is by modification of pre-existing genes, e.g. by duplication or horizontal transfer. In contrast, many viruses generate protein-coding genes de novo, via the overprinting of a new reading frame onto an existing (ancestral) frame. This mechanism is thought to play an important role in viral pathogenicity, but has been poorly explored, perhaps because identifying the de novo frames is very challenging. Therefore, a new approach to detect them was needed. We assembled a reference set of overlapping genes for which we could reliably determine the ancestral frames, and found that their codon usage was significantly closer to that of the rest of the viral genome than the codon usage of de novo frames. Based on this observation, we designed a method that allowed the identification of de novo frames based on their codon usage with a very good specificity, but intermediate sensitivity. Using our method, we predicted that the Rex gene of deltaretroviruses has originated de novo by overprinting the Tax gene. Intriguingly, several genes in the same genomic region have also originated de novo and encode proteins that regulate the functions of Tax. Such gene nurseries may be common in viral genomes. Finally, our results confirm that the genomic GC content is not the only determinant of codon usage in viruses and suggest that a constraint linked to translation must influence codon usage. '),
(86142, 2013, 'plos', 'Host mobility drives pathogen competition in spatially structured populations', 'Poletto, Chiara|Meloni, Sandro|Colizza, Vittoria|Moreno, Yamir|Vespignani, Alessandro', 'Computational Epidemiology Laboratory, Institute for Scientific Interchange, Turin, Italy. chiara.poletto@isi.it|Computational Epidemiology Laboratory, Institute for Scientific Interchange, Turin, Italy. chiara.poletto@isi.it|Computational Epidemiology Laboratory, Institute for Scientific Interchange, Turin, Italy. chiara.poletto@isi.it|Computational Epidemiology Laboratory, Institute for Scientific Interchange, Turin, Italy. chiara.poletto@isi.it|Computational Epidemiology Laboratory, Institute for Scientific Interchange, Turin, Italy. chiara.poletto@isi.it', 'Italy|Italy|Italy|Italy|Italy', 0, 'Coinfection|Computational Biology|Host-Pathogen Interactions|Humans|Influenza A virus|Influenza, Human|Microbial Interactions|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1003169', '23966843', 'Interactions among multiple infectious agents are increasingly recognized as a fundamental issue in the understanding of key questions in public health regarding pathogen emergence, maintenance, and evolution. The full description of host-multipathogen systems is, however, challenged by the multiplicity of factors affecting the interaction dynamics and the resulting competition that may occur at different scales, from the within-host scale to the spatial structure and mobility of the host population. Here we study the dynamics of two competing pathogens in a structured host population and assess the impact of the mobility pattern of hosts on the pathogen competition. We model the spatial structure of the host population in terms of a metapopulation network and focus on two strains imported locally in the system and having the same transmission potential but different infectious periods. We find different scenarios leading to competitive success of either one of the strain or to the codominance of both strains in the system. The dominance of the strain characterized by the shorter or longer infectious period depends exclusively on the structure of the population and on the the mobility of hosts across patches. The proposed modeling framework allows the integration of other relevant epidemiological, environmental and demographic factors, opening the path to further mathematical and computational studies of the dynamics of multipathogen systems. ');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86143, 2013, 'plos', 'Characteristic effects of stochastic oscillatory forcing on neural firing: analytical theory and comparison to paddlefish electroreceptor data', 'Bauermeister, Christoph|Schwalger, Tilo|Russell, David F|Neiman, Alexander B|Lindner, Benjamin', 'Max-Planck-Institute for the Physics of Complex Systems, Dresden, Germany.|Max-Planck-Institute for the Physics of Complex Systems, Dresden, Germany.|Max-Planck-Institute for the Physics of Complex Systems, Dresden, Germany.|Max-Planck-Institute for the Physics of Complex Systems, Dresden, Germany.|Max-Planck-Institute for the Physics of Complex Systems, Dresden, Germany.', 'Germany|Germany|Germany|Germany|Germany', 10, 'Action Potentials|Animals|Computational Biology|Computer Simulation|Fishes|Models, Neurological|Models, Statistical|Sensory Receptor Cells', 'Journal Article', '10.1371/journal.pcbi.1003170', '23966844', 'Stochastic signals with pronounced oscillatory components are frequently encountered in neural systems. Input currents to a neuron in the form of stochastic oscillations could be of exogenous origin, e.g. sensory input or synaptic input from a network rhythm. They shape spike firing statistics in a characteristic way, which we explore theoretically in this report. We consider a perfect integrate-and-fire neuron that is stimulated by a constant base current (to drive regular spontaneous firing), along with Gaussian narrow-band noise (a simple example of stochastic oscillations), and a broadband noise. We derive expressions for the nth-order interval distribution, its variance, and the serial correlation coefficients of the interspike intervals (ISIs) and confirm these analytical results by computer simulations. The theory is then applied to experimental data from electroreceptors of paddlefish, which have two distinct types of internal noisy oscillators, one forcing the other. The theory provides an analytical description of their afferent spiking statistics during spontaneous firing, and replicates a pronounced dependence of ISI serial correlation coefficients on the relative frequency of the driving oscillations, and furthermore allows extraction of certain parameters of the intrinsic oscillators embedded in these electroreceptors. '),
(86144, 2013, 'plos', 'Simulating cortical development as a self constructing process: a novel multi-scale approach combining molecular and physical aspects', 'Zubler, Frederic|Hauri, Andreas|Pfister, Sabina|Bauer, Roman|Anderson, John C|Whatley, Adrian M|Douglas, Rodney J', 'Institute of Neuroinformatics, University of Zürich/Swiss Federal Institute of Technology Zürich, Switzerland. fred@ini.phys.ethz.ch|Institute of Neuroinformatics, University of Zürich/Swiss Federal Institute of Technology Zürich, Switzerland. fred@ini.phys.ethz.ch|Institute of Neuroinformatics, University of Zürich/Swiss Federal Institute of Technology Zürich, Switzerland. fred@ini.phys.ethz.ch|Institute of Neuroinformatics, University of Zürich/Swiss Federal Institute of Technology Zürich, Switzerland. fred@ini.phys.ethz.ch|Institute of Neuroinformatics, University of Zürich/Swiss Federal Institute of Technology Zürich, Switzerland. fred@ini.phys.ethz.ch|Institute of Neuroinformatics, University of Zürich/Swiss Federal Institute of Technology Zürich, Switzerland. fred@ini.phys.ethz.ch|Institute of Neuroinformatics, University of Zürich/Swiss Federal Institute of Technology Zürich, Switzerland. fred@ini.phys.ethz.ch', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 17, 'Animals|Axons|Cats|Cell Movement|Cell Shape|Computational Biology|Computer Simulation|Dendrites|Gene Regulatory Networks|Models, Neurological|Neurogenesis|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1003173', '23966845', 'Current models of embryological development focus on intracellular processes such as gene expression and protein networks, rather than on the complex relationship between subcellular processes and the collective cellular organization these processes support. We have explored this collective behavior in the context of neocortical development, by modeling the expansion of a small number of progenitor cells into a laminated cortex with layer and cell type specific projections. The developmental process is steered by a formal language analogous to genomic instructions, and takes place in a physically realistic three-dimensional environment. A common genome inserted into individual cells control their individual behaviors, and thereby gives rise to collective developmental sequences in a biologically plausible manner. The simulation begins with a single progenitor cell containing the artificial genome. This progenitor then gives rise through a lineage of offspring to distinct populations of neuronal precursors that migrate to form the cortical laminae. The precursors differentiate by extending dendrites and axons, which reproduce the experimentally determined branching patterns of a number of different neuronal cell types observed in the cat visual cortex. This result is the first comprehensive demonstration of the principles of self-construction whereby the cortical architecture develops. In addition, our model makes several testable predictions concerning cell migration and branching mechanisms. '),
(86145, 2013, 'plos', 'Priors engaged in long-latency responses to mechanical perturbations suggest a rapid update in state estimation', 'Crevecoeur, Frxc3xa9dxc3xa9ric|Scott, Stephen H', 'Centre for Neuroscience Studies, Queens University, Kingston, Canada.|Centre for Neuroscience Studies, Queens University, Kingston, Canada.', 'Canada|Canada', 0, 'Algorithms|Biomechanical Phenomena|Computer Simulation|Elbow|Electromyography|Feedback, Sensory|Humans|Models, Biological|Muscle, Skeletal|Psychomotor Performance|Torque|Upper Extremity', 'Journal Article', '10.1371/journal.pcbi.1003177', '23966846', 'In every motor task, our brain must handle external forces acting on the body. For example, riding a bike on cobblestones or skating on irregular surface requires us to appropriately respond to external perturbations. In these situations, motor predictions cannot help anticipate the motion of the body induced by external factors, and direct use of delayed sensory feedback will tend to generate instability. Here, we show that to solve this problem the motor system uses a rapid sensory prediction to correct the estimated state of the limb. We used a postural task with mechanical perturbations to address whether sensory predictions were engaged in upper-limb corrective movements. Subjects altered their initial motor response in xe2x88xbc60 ms, depending on the expected perturbation profile, suggesting the use of an internal model, or prior, in this corrective process. Further, we found trial-to-trial changes in corrective responses indicating a rapid update of these perturbation priors. We used a computational model based on Kalman filtering to show that the response modulation was compatible with a rapid correction of the estimated state engaged in the feedback response. Such a process may allow us to handle external disturbances encountered in virtually every physical activity, which is likely an important feature of skilled motor behaviour. '),
(86146, 2013, 'plos', 'Sensory information and encounter rates of interacting species', 'Hein, Andrew M|McKinley, Scott A', 'Department of Biology, University of Florida, Gainesville, Florida, United States of America. amhein@ufl.edu|Department of Biology, University of Florida, Gainesville, Florida, United States of America. amhein@ufl.edu', 'United States|United States', 0, 'Animals|Computational Biology|Computer Simulation|Models, Biological|Predatory Behavior|Sensation', 'Journal Article', '10.1371/journal.pcbi.1003178', '23966847', 'Most motile organisms use sensory cues when searching for resources, mates, or prey. The searcher measures sensory data and adjusts its search behavior based on those data. Yet, classical models of species encounter rates assume that searchers move independently of their targets. This assumption leads to the familiar mass action-like encounter rate kinetics typically used in modeling species interactions. Here we show that this common approach can mischaracterize encounter rate kinetics if searchers use sensory information to search actively for targets. We use the example of predator-prey interactions to illustrate that predators capable of long-distance directional sensing can encounter prey at a rate proportional to prey density to the [Formula: see text] power (where [Formula: see text] is the dimension of the environment) when prey density is low. Similar anomalous encounter rate functions emerge even when predators pursue prey using only noisy, directionless signals. Thus, in both the high-information extreme of long-distance directional sensing, and the low-information extreme of noisy non-directional sensing, encounter rate kinetics differ qualitatively from those derived by classic theory of species interactions. Using a standard model of predator-prey population dynamics, we show that the new encounter rate kinetics derived here can change the outcome of species interactions. Our results demonstrate how the use of sensory information can alter the rates and outcomes of physical interactions in biological systems. '),
(86147, 2013, 'plos', 'Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine', 'Graupner, Michael|Maex, Reinoud|Gutkin, Boris', 'Group for Neural Theory, Laboratoire de Neurosciences Cognitives, INSERM Unitxc3xa9 969, Dxc3xa9partment dEtudes Cognitives, xc3x89cole Normale Supxc3xa9rieure, Paris, France. michael.graupner@nyu.edu|Group for Neural Theory, Laboratoire de Neurosciences Cognitives, INSERM Unitxc3xa9 969, Dxc3xa9partment dEtudes Cognitives, xc3x89cole Normale Supxc3xa9rieure, Paris, France. michael.graupner@nyu.edu|Group for Neural Theory, Laboratoire de Neurosciences Cognitives, INSERM Unitxc3xa9 969, Dxc3xa9partment dEtudes Cognitives, xc3x89cole Normale Supxc3xa9rieure, Paris, France. michael.graupner@nyu.edu', 'France|France|France', 17, 'Acetylcholine|Acetylcholinesterase|Animals|Computer Simulation|Dopamine|Dopaminergic Neurons|Mice|Models, Neurological|Nicotine|Receptors, Nicotinic|Ventral Tegmental Area', 'Journal Article', '10.1371/journal.pcbi.1003183', '23966848', 'Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the xcexb14xcexb22-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement. '),
(86148, 2013, 'plos', 'Biochemical competition makes fatty-acid xcexb2-oxidation vulnerable to substrate overload', 'van Eunen, Karen|Simons, Sereh M J|Gerding, Albert|Bleeker, Aycha|den Besten, Gijs|Touw, Catharina M L|Houten, Sander M|Groen, Bert K|Krab, Klaas|Reijngoud, Dirk-Jan|Bakker, Barbara M', 'Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Neth', 0, 'Animals|Carnitine|Fatty Acids|Female|Kinetics|Liver|Metabolic Networks and Pathways|Mitochondria|Models, Biological|NAD|Obesity|Oxidation-Reduction|Palmitoyl Coenzyme A|Palmitoylcarnitine|Rats|Rats, Wistar|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1003186', '23966849', 'Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid xcexb2-oxidation, we constructed a detailed computational model of the pathway and subjected it to a fat overload condition. The model contains reversible and saturable enzyme-kinetic equations and experimentally determined parameters for rat-liver enzymes. It was validated by adding palmitoyl CoA or palmitoyl carnitine to isolated rat-liver mitochondria: without refitting of measured parameters, the model correctly predicted the xcexb2-oxidation flux as well as the time profiles of most acyl-carnitine concentrations. Subsequently, we simulated the condition of obesity by increasing the palmitoyl-CoA concentration. At a high concentration of palmitoyl CoA the xcexb2-oxidation became overloaded: the flux dropped and metabolites accumulated. This behavior originated from the competition between acyl CoAs of different chain lengths for a set of acyl-CoA dehydrogenases with overlapping substrate specificity. This effectively induced competitive feedforward inhibition and thereby led to accumulation of CoA-ester intermediates and depletion of free CoA (CoASH). The mitochondrial [NADxe2x81xba]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of xcexb2-oxidation and mitochondrial respiration.'),
(86149, 2013, 'plos', 'Spike triggered hormone secretion in vasopressin cells, a model investigation of mechanism and heterogeneous population function', 'MacGregor, Duncan J|Leng, Gareth', 'Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom. duncan.macgregor@ed.ac.uk|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom. duncan.macgregor@ed.ac.uk', 'United Kingdom|United Kingdom', 13, 'Action Potentials|Animals|Calcium|Cytoplasmic Vesicles|Models, Neurological|Neurons|Rats|Signal Transduction|Supraoptic Nucleus|Vasopressins', 'Journal Article', '10.1371/journal.pcbi.1003187', '23966850', 'Vasopressin neurons generate distinctive phasic patterned spike activity in response to elevated extracellular osmotic pressure. These spikes are generated in the cell body and are conducted down the axon to the axonal terminals where they trigger Caxc2xb2xe2x81xba entry and subsequent exocytosis of hormone-containing vesicles and secretion of vasopressin. This mechanism is highly non-linear, subject to both frequency facilitation and fatigue, such that the rate of secretion depends on both the rate and patterning of the spike activity. Here we used computational modelling to investigate this relationship and how it shapes the overall response of the neuronal population. We generated a concise single compartment model of the secretion mechanism, fitted to experimentally observed profiles of facilitation and fatigue, and based on representations of the hypothesised underlying mechanisms. These mechanisms include spike broadening, Caxc2xb2xe2x81xba channel inactivation, a Caxc2xb2xe2x81xba sensitive Kxe2x81xba current, and releasable and reserve pools of vesicles. We coupled the secretion model to an existing integrate-and-fire based spiking model in order to study the secretion response to increasing synaptic input, and compared phasic and non-phasic spiking models to assess the functional value of the phasic spiking pattern. The secretory response of individual phasic cells is very non-linear, but the response of a heterogeneous population of phasic cells shows a much more linear response to increasing input, matching the linear response we observe experimentally, though in this respect, phasic cells have no apparent advantage over non-phasic cells. Another challenge for the cells is maintaining this linear response during chronic stimulation, and we show that the activity-dependent fatigue mechanism has a potentially useful function in helping to maintain secretion despite depletion of stores. Without this mechanism, secretion in response to a steady stimulus declines as the stored content declines.'),
(86150, 2013, 'plos', 'From principal component to direct coupling analysis of coevolution in proteins: low-eigenvalue modes are needed for structure prediction', 'Cocco, Simona|Monasson, Remi|Weigt, Martin', 'Laboratoire de Physique Statistique de lEcole Normale Supérieure - UMR 8550, associé au CNRS et à lUniversité Pierre et Marie Curie, Paris, France.|Laboratoire de Physique Statistique de lEcole Normale Supérieure - UMR 8550, associé au CNRS et à lUniversité Pierre et Marie Curie, Paris, France.|Laboratoire de Physique Statistique de lEcole Normale Supérieure - UMR 8550, associé au CNRS et à lUniversité Pierre et Marie Curie, Paris, France.', 'France|France|France', 0, 'Algorithms|Entropy|Models, Molecular|Principal Component Analysis|Protein Conformation|Proteins|Sequence Alignment|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1003176', '23990764', 'Various approaches have explored the covariation of residues in multiple-sequence alignments of homologous proteins to extract functional and structural information. Among those are principal component analysis (PCA), which identifies the most correlated groups of residues, and direct coupling analysis (DCA), a global inference method based on the maximum entropy principle, which aims at predicting residue-residue contacts. In this paper, inspired by the statistical physics of disordered systems, we introduce the Hopfield-Potts model to naturally interpolate between these two approaches. The Hopfield-Potts model allows us to identify relevant patterns of residues from the knowledge of the eigenmodes and eigenvalues of the residue-residue correlation matrix. We show how the computation of such statistical patterns makes it possible to accurately predict residue-residue contacts with a much smaller number of parameters than DCA. This dimensional reduction allows us to avoid overfitting and to extract contact information from multiple-sequence alignments of reduced size. In addition, we show that low-eigenvalue correlation modes, discarded by PCA, are important to recover structural information: the corresponding patterns are highly localized, that is, they are concentrated in few sites, which we find to be in close contact in the three-dimensional protein fold. '),
(86151, 2013, 'plos', 'Stochasticity, bistability and the wisdom of crowds: a model for associative learning in genetic regulatory networks', 'Sorek, Matan|Balaban, Nathalie Q|Loewenstein, Yonatan', 'Edmond and Lily Safra Center for Brain Sciences and the Interdisciplinary Center for Neural Computation, The Hebrew University of Jerusalem, Jerusalem, Israel. matan.sorek@mail.huji.ac.il|Edmond and Lily Safra Center for Brain Sciences and the Interdisciplinary Center for Neural Computation, The Hebrew University of Jerusalem, Jerusalem, Israel. matan.sorek@mail.huji.ac.il|Edmond and Lily Safra Center for Brain Sciences and the Interdisciplinary Center for Neural Computation, The Hebrew University of Jerusalem, Jerusalem, Israel. matan.sorek@mail.huji.ac.il', 'Israel|Israel|Israel', 0, 'Bacteria|Computer Simulation|Gene Regulatory Networks|Learning|Markov Chains|Models, Genetic|Models, Neurological|Neural Networks (Computer)', 'Journal Article', '10.1371/journal.pcbi.1003179', '23990765', 'It is generally believed that associative memory in the brain depends on multistable synaptic dynamics, which enable the synapses to maintain their value for extended periods of time. However, multistable dynamics are not restricted to synapses. In particular, the dynamics of some genetic regulatory networks are multistable, raising the possibility that even single cells, in the absence of a nervous system, are capable of learning associations. Here we study a standard genetic regulatory network model with bistable elements and stochastic dynamics. We demonstrate that such a genetic regulatory network model is capable of learning multiple, general, overlapping associations. The capacity of the network, defined as the number of associations that can be simultaneously stored and retrieved, is proportional to the square root of the number of bistable elements in the genetic regulatory network. Moreover, we compute the capacity of a clonal population of cells, such as in a colony of bacteria or a tissue, to store associations. We show that even if the cells do not interact, the capacity of the population to store associations substantially exceeds that of a single cell and is proportional to the number of bistable elements. Thus, we show that even single cells are endowed with the computational power to learn associations, a power that is substantially enhanced when these cells form a population. '),
(86152, 2013, 'plos', 'Nucleosome free regions in yeast promoters result from competitive binding of transcription factors that interact with chromatin modifiers', 'Ozonov, Evgeniy A|van Nimwegen, Erik', 'Biozentrum, University of Basel, and Swiss Institute of Bioinformatics, Basel, Switzerland.|Biozentrum, University of Basel, and Swiss Institute of Bioinformatics, Basel, Switzerland.', 'Switzerland|Switzerland', 16, 'Binding, Competitive|Chromatin|DNA, Fungal|Genes, Fungal|Models, Genetic|Models, Statistical|Nucleosomes|Promoter Regions, Genetic|Protein Binding|Reproducibility of Results|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1003181', '23990766', 'Because DNA packaging in nucleosomes modulates its accessibility to transcription factors (TFs), unraveling the causal determinants of nucleosome positioning is of great importance to understanding gene regulation. Although there is evidence that intrinsic sequence specificity contributes to nucleosome positioning, the extent to which other factors contribute to nucleosome positioning is currently highly debated. Here we obtained both in vivo and in vitro reference maps of positions that are either consistently covered or free of nucleosomes across multiple experimental data-sets in Saccharomyces cerevisiae. We then systematically quantified the contribution of TF binding to nucleosome positioning using a rigorous statistical mechanics model in which TFs compete with nucleosomes for binding DNA. Our results reconcile previous seemingly conflicting results on the determinants of nucleosome positioning and provide a quantitative explanation for the difference between in vivo and in vitro positioning. On a genome-wide scale, nucleosome positioning is dominated by the phasing of nucleosome arrays over gene bodies, and their positioning is mainly determined by the intrinsic sequence preferences of nucleosomes. In contrast, larger nucleosome free regions in promoters, which likely have a much more significant impact on gene expression, are determined mainly by TF binding. Interestingly, of the 158 yeast TFs included in our modeling, we find that only 10-20 significantly contribute to inducing nucleosome-free regions, and these TFs are highly enriched for having direct interactions with chromatin remodelers. Together our results imply that nucleosome free regions in yeast promoters results from the binding of a specific class of TFs that recruit chromatin remodelers.'),
(86153, 2013, 'plos', 'A self-directed method for cell-type identification and separation of gene expression microarrays', 'Zuckerman, Neta S|Noam, Yair|Goldsmith, Andrea J|Lee, Peter P', 'Department of Cancer Immunotherapeutics and Tumor Immunology, City of Hope and Beckman Research Institute, Duarte, California, United States of America.|Department of Cancer Immunotherapeutics and Tumor Immunology, City of Hope and Beckman Research Institute, Duarte, California, United States of America.|Department of Cancer Immunotherapeutics and Tumor Immunology, City of Hope and Beckman Research Institute, Duarte, California, United States of America.|Department of Cancer Immunotherapeutics and Tumor Immunology, City of Hope and Beckman Research Institute, Duarte, California, United States of America.', 'United States|United States|United States|United States', 0, 'Algorithms|Animals|Brain|Cluster Analysis|Computational Biology|Databases, Genetic|Gene Expression Profiling|Humans|Liver|Monocytes|Myocardium|Oligonucleotide Array Sequence Analysis|Organ Specificity|Rats', 'Journal Article', '10.1371/journal.pcbi.1003189', '23990767', 'Gene expression analysis is generally performed on heterogeneous tissue samples consisting of multiple cell types. Current methods developed to separate heterogeneous gene expression rely on prior knowledge of the cell-type composition and/or signatures--these are not available in most public datasets. We present a novel method to identify the cell-type composition, signatures and proportions per sample without need for a-priori information. The method was successfully tested on controlled and semi-controlled datasets and performed as accurately as current methods that do require additional information. As such, this method enables the analysis of cell-type specific gene expression using existing large pools of publically available microarray datasets.'),
(86154, 2013, 'plos', 'On the importance of polar interactions for complexes containing intrinsically disordered proteins', 'Wong, Eric T C|Na, Dokyun|Gsponer, Jörg', 'Centre for High-Throughput Biology, University of British Columbia, East Mall, Vancouver, Canada.|Centre for High-Throughput Biology, University of British Columbia, East Mall, Vancouver, Canada.|Centre for High-Throughput Biology, University of British Columbia, East Mall, Vancouver, Canada.', 'Canada|Canada|Canada', 43, 'Amino Acids|Computational Biology|Databases, Protein|Hydrogen Bonding|Hydrophobic and Hydrophilic Interactions|Intrinsically Disordered Proteins|Models, Chemical|Models, Molecular|Protein Binding|Reproducibility of Results|Sequence Alignment|Static Electricity|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003192', '23990768', 'There is a growing recognition for the importance of proteins with large intrinsically disordered (ID) segments in cell signaling and regulation. ID segments in these proteins often harbor regions that mediate molecular recognition. Coupled folding and binding of the recognition regions has been proposed to confer high specificity to interactions involving ID segments. However, researchers recently questioned the origin of the interaction specificity of ID proteins because of the overrepresentation of hydrophobic residues in their interaction interfaces. Here, we focused on the role of polar and charged residues in interactions mediated by ID segments. Making use of the extended nature of most ID segments when in complex with globular proteins, we first identified large numbers of complexes between globular proteins and ID segments by using radius-of-gyration-based selection criteria. Consistent with previous studies, we found the interfaces of these complexes to be enriched in hydrophobic residues, and that these residues contribute significantly to the stability of the interaction interface. However, our analyses also show that polar interactions play a larger role in these complexes than in structured protein complexes. Computational alanine scanning and salt-bridge analysis indicate that interfaces in ID complexes are highly complementary with respect to electrostatics, more so than interfaces of globular proteins. Follow-up calculations of the electrostatic contributions to the free energy of binding uncovered significantly stronger Coulombic interactions in complexes harbouring ID segments than in structured protein complexes. However, they are counter-balanced by even higher polar-desolvation penalties. We propose that polar interactions are a key contributing factor to the observed high specificity of ID segment-mediated interactions. '),
(86155, 2013, 'plos', 'Gauses principle and the effect of resource partitioning on the dynamical coexistence of replicating templates', 'Szilágyi, András|Zachar, István|Szathmáry, Eörs', 'Department of Plant Systematics, Institute of Biology, Eötvös University, Budapest, Hungary.|Department of Plant Systematics, Institute of Biology, Eötvös University, Budapest, Hungary.|Department of Plant Systematics, Institute of Biology, Eötvös University, Budapest, Hungary.', 'Hungary|Hungary|Hungary', 0, 'Cluster Analysis|Computational Biology|Computer Simulation|GATA2 Transcription Factor|Gene Expression Regulation|Granulocyte Colony-Stimulating Factor|Interleukin-3|Models, Genetic|Models, Statistical|Monte Carlo Method|RNA, Messenger|Recombinant Fusion Proteins|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1003193', '23990769', 'Models of competitive template replication, although basic for replicator dynamics and primordial evolution, have not yet taken different sequences explicitly into account, neither have they analyzed the effect of resource partitioning (feeding on different resources) on coexistence. Here we show by analytical and numerical calculations that Gauses principle of competitive exclusion holds for template replicators if resources (nucleotides) affect growth linearly and coexistence is at fixed point attractors. Cases of complementary or homologous pairing between building blocks with parallel or antiparallel strands show no deviation from the rule that the nucleotide compositions of stably coexisting species must be different and there cannot be more coexisting replicator species than nucleotide types. Besides this overlooked mechanism of template coexistence we show also that interesting sequence effects prevail as parts of sequences that are copied earlier affect coexistence more strongly due to the higher concentration of the corresponding replication intermediates. Template and copy always count as one species due their constraint of strict stoichiometric coupling. Stability of fixed-point coexistence tends to decrease with the length of sequences, although this effect is unlikely to be detrimental for sequences below 100 nucleotides. In sum, resource partitioning (niche differentiation) is the default form of competitive coexistence for replicating templates feeding on a cocktail of different nucleotides, as it may have been the case in the RNA world. Our analysis of different pairing and strand orientation schemes is relevant for artificial and potentially astrobiological genetics. '),
(86156, 2013, 'plos', 'Causes and consequences of hyperexcitation in central clock neurons', 'Diekman, Casey O|Belle, Mino D C|Irwin, Robert P|Allen, Charles N|Piggins, Hugh D|Forger, Daniel B', 'Department of Mathematical Sciences, New Jersey Institute of Technology, Newark, New Jersey, United States of America.|Department of Mathematical Sciences, New Jersey Institute of Technology, Newark, New Jersey, United States of America.|Department of Mathematical Sciences, New Jersey Institute of Technology, Newark, New Jersey, United States of America.|Department of Mathematical Sciences, New Jersey Institute of Technology, Newark, New Jersey, United States of America.|Department of Mathematical Sciences, New Jersey Institute of Technology, Newark, New Jersey, United States of America.|Department of Mathematical Sciences, New Jersey Institute of Technology, Newark, New Jersey, United States of America.', 'Jersey|Jersey|Jersey|Jersey|Jersey|Jersey', 26, 'Animals|CLOCK Proteins|Calcium|Calcium Channels, L-Type|Circadian Rhythm|Computer Simulation|Feedback, Physiological|Female|Intracellular Space|Male|Mice|Models, Neurological|Neurons|Patch-Clamp Techniques|Reproducibility of Results|Suprachiasmatic Nucleus|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1003196', '23990770', 'Hyperexcited states, including depolarization block and depolarized low amplitude membrane oscillations (DLAMOs), have been observed in neurons of the suprachiasmatic nuclei (SCN), the site of the central mammalian circadian (~24-hour) clock. The causes and consequences of this hyperexcitation have not yet been determined. Here, we explore how individual ionic currents contribute to these hyperexcited states, and how hyperexcitation can then influence molecular circadian timekeeping within SCN neurons. We developed a mathematical model of the electrical activity of SCN neurons, and experimentally verified its prediction that DLAMOs depend on post-synaptic L-type calcium current. The model predicts that hyperexcited states cause high intracellular calcium concentrations, which could trigger transcription of clock genes. The model also predicts that circadian control of certain ionic currents can induce hyperexcited states. Putting it all together into an integrative model, we show how membrane potential and calcium concentration provide a fast feedback that can enhance rhythmicity of the intracellular circadian clock. This work puts forward a novel role for electrical activity in circadian timekeeping, and suggests that hyperexcited states provide a general mechanism for linking membrane electrical dynamics to transcription activation in the nucleus.'),
(86157, 2013, 'plos', 'Transcriptional regulation of lineage commitment--a stochastic model of cell fate decisions', 'Teles, Jose|Pina, Cristina|Edén, Patrik|Ohlsson, Mattias|Enver, Tariq|Peterson, Carsten', 'Computational Biology & Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden.|Computational Biology & Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden.|Computational Biology & Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden.|Computational Biology & Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden.|Computational Biology & Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden.|Computational Biology & Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden.', 'Sweden|Sweden|Sweden|Sweden|Sweden|Sweden', 35, 'Cell Differentiation|Cluster Analysis|Computational Biology|Computer Simulation|GATA2 Transcription Factor|Gene Expression Regulation|Granulocyte Colony-Stimulating Factor|Interleukin-3|Models, Biological|Models, Statistical|Monte Carlo Method|RNA, Messenger|Recombinant Fusion Proteins|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1003197', '23990771', 'Molecular mechanisms employed by individual multipotent cells at the point of lineage commitment remain largely uncharacterized. Current paradigms span from instructive to noise-driven mechanisms. Of considerable interest is also whether commitment involves a limited set of genes or the entire transcriptional program, and to what extent gene expression configures multiple trajectories into commitment. Importantly, the transient nature of the commitment transition confounds the experimental capture of committing cells. We develop a computational framework that simulates stochastic commitment events, and affords mechanistic exploration of the fate transition. We use a combined modeling approach guided by gene expression classifier methods that infers a time-series of stochastic commitment events from experimental growth characteristics and gene expression profiling of individual hematopoietic cells captured immediately before and after commitment. We define putative regulators of commitment and probabilistic rules of transition through machine learning methods, and employ clustering and correlation analyses to interrogate gene regulatory interactions in multipotent cells. Against this background, we develop a Monte Carlo time-series stochastic model of transcription where the parameters governing promoter status, mRNA production and mRNA decay in multipotent cells are fitted to experimental static gene expression distributions. Monte Carlo time is converted to physical time using cell culture kinetic data. Probability of commitment in time is a function of gene expression as defined by a logistic regression model obtained from experimental single-cell expression data. Our approach should be applicable to similar differentiating systems where single cell data is available. Within our system, we identify robust model solutions for the multipotent population within physiologically reasonable values and explore model predictions with regard to molecular scenarios of entry into commitment. The model suggests distinct dependencies of different commitment-associated genes on mRNA dynamics and promoter activity, which globally influence the probability of lineage commitment. '),
(86158, 2013, 'plos', 'International Society for Computational Biology welcomes its newest class of fellows', 'Fogg, Christiana N|Kovats, Diane E', 'International Society for Computational Biology, La Jolla, California, United States of America.|International Society for Computational Biology, La Jolla, California, United States of America.', 'United States|United States', 0, 'Computational Biology|Humans|Societies, Scientific', 'Journal Article', '10.1371/journal.pcbi.1003199', '23990772', '-'),
(86159, 2013, 'plos', 'Predicting disease risk using bootstrap ranking and classification algorithms', 'Manor, Ohad|Segal, Eran', 'Dept of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel. eran@weizmann.ac.il|Dept of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel. eran@weizmann.ac.il', 'Israel|Israel', 15, 'Algorithms|Area Under Curve|Cluster Analysis|Computational Biology|Disease|Genetic Predisposition to Disease|Genotype|Humans|Models, Genetic|Polymorphism, Single Nucleotide|Reproducibility of Results|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1003200', '23990773', 'Genome-wide association studies (GWAS) are widely used to search for genetic loci that underlie human disease. Another goal is to predict disease risk for different individuals given their genetic sequence. Such predictions could either be used as a black box in order to promote changes in life-style and screening for early diagnosis, or as a model that can be studied to better understand the mechanism of the disease. Current methods for risk prediction typically rank single nucleotide polymorphisms (SNPs) by the p-value of their association with the disease, and use the top-associated SNPs as input to a classification algorithm. However, the predictive power of such methods is relatively poor. To improve the predictive power, we devised BootRank, which uses bootstrapping in order to obtain a robust prioritization of SNPs for use in predictive models. We show that BootRank improves the ability to predict disease risk of unseen individuals in the Wellcome Trust Case Control Consortium (WTCCC) data and results in a more robust set of SNPs and a larger number of enriched pathways being associated with the different diseases. Finally, we show that combining BootRank with seven different classification algorithms improves performance compared to previous studies that used the WTCCC data. Notably, diseases for which BootRank results in the largest improvements were recently shown to have more heritability than previously thought, likely due to contributions from variants with low minimum allele frequency (MAF), suggesting that BootRank can be beneficial in cases where SNPs affecting the disease are poorly tagged or have low MAF. Overall, our results show that improving disease risk prediction from genotypic information may be a tangible goal, with potential implications for personalized disease screening and treatment. '),
(86160, 2013, 'plos', 'Model-based analysis of HER activation in cells co-expressing EGFR, HER2 and HER3', 'Shankaran, Harish|Zhang, Yi|Tan, Yunbing|Resat, Haluk', 'Computational Biology and Bioinformatics Group, Pacific Northwest National Laboratory, Richland, Washington, United States of America.|Computational Biology and Bioinformatics Group, Pacific Northwest National Laboratory, Richland, Washington, United States of America.|Computational Biology and Bioinformatics Group, Pacific Northwest National Laboratory, Richland, Washington, United States of America.|Computational Biology and Bioinformatics Group, Pacific Northwest National Laboratory, Richland, Washington, United States of America.', 'United States|United States|United States|United States', 0, 'Antibodies, Monoclonal|Cell Line|Computer Simulation|Epithelial Cells|ErbB Receptors|Humans|MAP Kinase Signaling System|Mammary Glands, Human|Mitogen-Activated Protein Kinases|Models, Biological|Phosphorylation|Proto-Oncogene Proteins c-akt|Receptor, ErbB-2|Receptor, ErbB-3|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1003201', '23990774', 'The HER/ErbB family of receptor tyrosine kinases drives critical responses in normal physiology and cancer, and the expression levels of the various HER receptors are critical determinants of clinical outcomes. HER activation is driven by the formation of various dimer complexes between members of this receptor family. The HER dimer types can have differential effects on downstream signaling and phenotypic outcomes. We constructed an integrated mathematical model of HER activation, and trafficking to quantitatively link receptor expression levels to dimerization and activation. We parameterized the model with a comprehensive set of HER phosphorylation and abundance data collected in a panel of human mammary epithelial cells expressing varying levels of EGFR/HER1, HER2 and HER3. Although parameter estimation yielded multiple solutions, predictions for dimer phosphorylation were in agreement with each other. We validated the model using experiments where pertuzumab was used to block HER2 dimerization. We used the model to predict HER dimerization and activation patterns in a panel of human mammary epithelial cells lines with known HER expression levels in response to stimulations with ligands EGF and HRG. Simulations over the range of expression levels seen in various cell lines indicate that: i) EGFR phosphorylation is driven by HER1-HER1 and HER1-HER2 dimers, and not HER1-HER3 dimers, ii) HER1-HER2 and HER2-HER3 dimers both contribute significantly to HER2 activation with the EGFR expression level determining the relative importance of these species, and iii) the HER2-HER3 dimer is largely responsible for HER3 activation. The model can be used to predict phosphorylated dimer levels for any given HER expression profile. This information in turn can be used to quantify the potencies of the various HER dimers, and can potentially inform personalized therapeutic approaches. '),
(86161, 2013, 'plos', 'Determinants of beat-to-beat variability of repolarization duration in the canine ventricular myocyte: a computational analysis', 'Heijman, Jordi|Zaza, Antonio|Johnson, Daniel M|Rudy, Yoram|Peeters, Ralf L M|Volders, Paul G A|Westra, Ronald L', 'Department of Knowledge Engineering, Maastricht University, Maastricht, The Netherlands.|Department of Knowledge Engineering, Maastricht University, Maastricht, The Netherlands.|Department of Knowledge Engineering, Maastricht University, Maastricht, The Netherlands.|Department of Knowledge Engineering, Maastricht University, Maastricht, The Netherlands.|Department of Knowledge Engineering, Maastricht University, Maastricht, The Netherlands.|Department of Knowledge Engineering, Maastricht University, Maastricht, The Netherlands.|Department of Knowledge Engineering, Maastricht University, Maastricht, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 59, 'Action Potentials|Animals|Computational Biology|Computer Simulation|Dogs|Heart Conduction System|Heart Rate|Heart Ventricles|Ion Channels|Linear Models|Models, Cardiovascular|Myocytes, Cardiac', 'Journal Article', '10.1371/journal.pcbi.1003202', '23990775', 'Beat-to-beat variability of repolarization duration (BVR) is an intrinsic characteristic of cardiac function and a better marker of proarrhythmia than repolarization prolongation alone. The ionic mechanisms underlying baseline BVR in physiological conditions, its rate dependence, and the factors contributing to increased BVR in pathologies remain incompletely understood. Here, we employed computer modeling to provide novel insights into the subcellular mechanisms of BVR under physiological conditions and during simulated drug-induced repolarization prolongation, mimicking long-QT syndromes type 1, 2, and 3. We developed stochastic implementations of 13 major ionic currents and fluxes in a model of canine ventricular-myocyte electrophysiology. Combined stochastic gating of these components resulted in short- and long-term variability, consistent with experimental data from isolated canine ventricular myocytes. The model indicated that the magnitude of stochastic fluctuations is rate dependent due to the rate dependence of action-potential (AP) duration (APD). This process (the active component) and the intrinsic nonlinear relationship between membrane current and APD (intrinsic component) contribute to the rate dependence of BVR. We identified a major role in physiological BVR for stochastic gating of the persistent Na(+) current (INa) and rapidly activating delayed-rectifier K(+) current (IKr). Inhibition of IKr or augmentation of INa significantly increased BVR, whereas subsequent xcexb2-adrenergic receptor stimulation reduced it, similar to experimental findings in isolated myocytes. In contrast, xcexb2-adrenergic stimulation increased BVR in simulated long-QT syndrome type 1. In addition to stochastic channel gating, AP morphology, APD, and beat-to-beat variations in Ca(2+) were found to modulate single-cell BVR. Cell-to-cell coupling decreased BVR and this was more pronounced when a model cell with increased BVR was coupled to a model cell with normal BVR. In conclusion, our results provide new insights into the ionic mechanisms underlying BVR and suggest that BVR reflects multiple potentially proarrhythmic parameters, including increased ion-channel stochasticity, prolonged APD, and abnormal Ca(2+) handling.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86162, 2013, 'plos', 'Conditional cooperativity of toxin - antitoxin regulation can mediate bistability between growth and dormancy', 'Cataudella, Ilaria|Sneppen, Kim|Gerdes, Kenn|Mitarai, Namiko', 'Niels Bohr Institute/CMOL, University of Copenhagen, Copenhagen, Denmark.|Niels Bohr Institute/CMOL, University of Copenhagen, Copenhagen, Denmark.|Niels Bohr Institute/CMOL, University of Copenhagen, Copenhagen, Denmark.|Niels Bohr Institute/CMOL, University of Copenhagen, Copenhagen, Denmark.', 'Denmark|Denmark|Denmark|Denmark', 41, 'Bacterial Physiological Phenomena|Bacterial Toxins|Computational Biology|Drug Resistance, Bacterial|Escherichia coli|Escherichia coli Proteins|Feedback, Physiological|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1003174', '24009488', 'Many toxin-antitoxin operons are regulated by the toxin/antitoxin ratio by mechanisms collectively coined conditional cooperativity. Toxin and antitoxin form heteromers with different stoichiometric ratios, and the complex with the intermediate ratio works best as a transcription repressor. This allows transcription at low toxin level, strong repression at intermediate toxin level, and then again transcription at high toxin level. Such regulation has two interesting features, firstly, it provides a non-monotonous response to the concentration of one of the proteins, and secondly, it opens for ultra-sensitivity mediated by the sequestration of the functioning heteromers. We explore possible functions of conditional regulation in simple feedback motifs, and show that it can provide bistability for a wide range of parameters. We then demonstrate that the conditional cooperativity in toxin-antitoxin systems combined with the growth-inhibition activity of free toxin can mediate bistability between a growing state and a dormant state. '),
(86163, 2013, 'plos', 'Sparse coding models can exhibit decreasing sparseness while learning sparse codes for natural images', 'Zylberberg, Joel|DeWeese, Michael Robert', 'Department of Physics, University of California, Berkeley, Berkeley, California, United States of America.|Department of Physics, University of California, Berkeley, Berkeley, California, United States of America.', 'United States|United States', 11, 'Animals|Computational Biology|Computer Simulation|Ferrets|Macaca|Models, Neurological|Neurons|Statistics, Nonparametric|Visual Cortex|Visual Fields', 'Journal Article', '10.1371/journal.pcbi.1003182', '24009489', 'The sparse coding hypothesis has enjoyed much success in predicting response properties of simple cells in primary visual cortex (V1) based solely on the statistics of natural scenes. In typical sparse coding models, model neuron activities and receptive fields are optimized to accurately represent input stimuli using the least amount of neural activity. As these networks develop to represent a given class of stimulus, the receptive fields are refined so that they capture the most important stimulus features. Intuitively, this is expected to result in sparser network activity over time. Recent experiments, however, show that stimulus-evoked activity in ferret V1 becomes less sparse during development, presenting an apparent challenge to the sparse coding hypothesis. Here we demonstrate that some sparse coding models, such as those employing homeostatic mechanisms on neural firing rates, can exhibit decreasing sparseness during learning, while still achieving good agreement with mature V1 receptive field shapes and a reasonably sparse mature network state. We conclude that observed developmental trends do not rule out sparseness as a principle of neural coding per se: a mature network can perform sparse coding even if sparseness decreases somewhat during development. To make comparisons between model and physiological receptive fields, we introduce a new nonparametric method for comparing receptive field shapes using image registration techniques. '),
(86164, 2013, 'plos', 'A general model for toxin-antitoxin module dynamics can explain persister cell formation in E coli', 'Gelens, Lendert|Hill, Lydia|Vandervelde, Alexandra|Danckaert, Jan|Loris, Remy', 'Applied Physics Research Group APHY, Vrije Universiteit Brussel, Brussels, Belgium. lendert.gelens@vub.ac.be|Applied Physics Research Group APHY, Vrije Universiteit Brussel, Brussels, Belgium. lendert.gelens@vub.ac.be|Applied Physics Research Group APHY, Vrije Universiteit Brussel, Brussels, Belgium. lendert.gelens@vub.ac.be|Applied Physics Research Group APHY, Vrije Universiteit Brussel, Brussels, Belgium. lendert.gelens@vub.ac.be|Applied Physics Research Group APHY, Vrije Universiteit Brussel, Brussels, Belgium. lendert.gelens@vub.ac.be', 'Belgium|Belgium|Belgium|Belgium|Belgium', 45, 'Bacterial Toxins|Binding Sites|Computer Simulation|Escherichia coli|Escherichia coli Proteins|Models, Biological|Operator Regions, Genetic|Protein Biosynthesis|RNA, Bacterial|RNA, Messenger|Repressor Proteins', 'Journal Article', '10.1371/journal.pcbi.1003190', '24009490', 'Toxin-Antitoxin modules are small operons involved in stress response and persister cell formation that encode a toxin and its corresponding neutralizing antitoxin. Regulation of these modules involves a complex mechanism known as conditional cooperativity, which is supposed to prevent unwanted toxin activation. Here we develop mathematical models for their regulation, based on published molecular and structural data, and parameterized using experimental data for F-plasmid ccdAB, bacteriophage P1 phd/doc and E. coli relBE. We show that the level of free toxin in the cell is mainly controlled through toxin sequestration in toxin-antitoxin complexes of various stoichiometry rather than by gene regulation. If the toxin translation rate exceeds twice the antitoxin translation rate, toxins accumulate in all cells. Conditional cooperativity and increasing the number of binding sites on the operator serves to reduce the metabolic burden of the cell by reducing the total amounts of proteins produced. Combining conditional cooperativity and bridging of antitoxins by toxins when bound to their operator sites allows creation of persister cells through rare, extreme stochastic spikes in the free toxin level. The amplitude of these spikes determines the duration of the persister state. Finally, increases in the antitoxin degradation rate and decreases in the bacterial growth rate cause a rise in the amount of persisters during nutritional stress. '),
(86165, 2013, 'plos', 'Visual nonclassical receptive field effects emerge from sparse coding in a dynamical system', 'Zhu, Mengchen|Rozell, Christopher J', 'Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.|Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.', 'Georgia|Georgia', 0, 'Action Potentials|Animals|Computational Biology|Computer Simulation|Ferrets|Models, Neurological|Neurons|Visual Cortex|Visual Fields', 'Journal Article', '10.1371/journal.pcbi.1003191', '24009491', 'Extensive electrophysiology studies have shown that many V1 simple cells have nonlinear response properties to stimuli within their classical receptive field (CRF) and receive contextual influence from stimuli outside the CRF modulating the cells response. Models seeking to explain these non-classical receptive field (nCRF) effects in terms of circuit mechanisms, input-output descriptions, or individual visual tasks provide limited insight into the functional significance of these response properties, because they do not connect the full range of nCRF effects to optimal sensory coding strategies. The (population) sparse coding hypothesis conjectures an optimal sensory coding approach where a neural population uses as few active units as possible to represent a stimulus. We demonstrate that a wide variety of nCRF effects are emergent properties of a single sparse coding model implemented in a neurally plausible network structure (requiring no parameter tuning to produce different effects). Specifically, we replicate a wide variety of nCRF electrophysiology experiments (e.g., end-stopping, surround suppression, contrast invariance of orientation tuning, cross-orientation suppression, etc.) on a dynamical system implementing sparse coding, showing that this model produces individual units that reproduce the canonical nCRF effects. Furthermore, when the population diversity of an nCRF effect has also been reported in the literature, we show that this model produces many of the same population characteristics. These results show that the sparse coding hypothesis, when coupled with a biophysically plausible implementation, can provide a unified high-level functional interpretation to many response properties that have generally been viewed through distinct mechanistic or phenomenological models. '),
(86166, 2013, 'plos', 'Flux imbalance analysis and the sensitivity of cellular growth to changes in metabolite pools', 'Reznik, Ed|Mehta, Pankaj|Segrè, Daniel', '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', 41, 'Algorithms|Escherichia coli|Gene Expression Profiling|Intracellular Space|Metabolic Networks and Pathways|Metabolomics|Models, Biological|Statistics, Nonparametric|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1003195', '24009492', 'Stoichiometric models of metabolism, such as flux balance analysis (FBA), are classically applied to predicting steady state rates - or fluxes - of metabolic reactions in genome-scale metabolic networks. Here we revisit the central assumption of FBA, i.e. that intracellular metabolites are at steady state, and show that deviations from flux balance (i.e. flux imbalances) are informative of some features of in vivo metabolite concentrations. Mathematically, the sensitivity of FBA to these flux imbalances is captured by a native feature of linear optimization, the dual problem, and its corresponding variables, known as shadow prices. First, using recently published data on chemostat growth of Saccharomyces cerevisae under different nutrient limitations, we show that shadow prices anticorrelate with experimentally measured degrees of growth limitation of intracellular metabolites. We next hypothesize that metabolites which are limiting for growth (and thus have very negative shadow price) cannot vary dramatically in an uncontrolled way, and must respond rapidly to perturbations. Using a collection of published datasets monitoring the time-dependent metabolomic response of Escherichia coli to carbon and nitrogen perturbations, we test this hypothesis and find that metabolites with negative shadow price indeed show lower temporal variation following a perturbation than metabolites with zero shadow price. Finally, we illustrate the broader applicability of flux imbalance analysis to other constraint-based methods. In particular, we explore the biological significance of shadow prices in a constraint-based method for integrating gene expression data with a stoichiometric model. In this case, shadow prices point to metabolites that should rise or drop in concentration in order to increase consistency between flux predictions and gene expression data. In general, these results suggest that the sensitivity of metabolic optima to violations of the steady state constraints carries biologically significant information on the processes that control intracellular metabolites in the cell. '),
(86167, 2013, 'plos', 'The individualized genetic barrier predicts treatment response in a large cohort of HIV-1 infected patients', 'Beerenwinkel, Niko|Montazeri, Hesam|Schuhmacher, Heike|Knupfer, Patrick|von Wyl, Viktor|Furrer, Hansjakob|Battegay, Manuel|Hirschel, Bernard|Cavassini, Matthias|Vernazza, Pietro|Bernasconi, Enos|Yerly, Sabine|Böni, Jürg|Klimkait, Thomas|Cellerai, Cristina|Günthard, Huldrych F|Swiss HIV Cohort Study', 'Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. niko.beerenwinkel@bsse.ethz.ch', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Swit', 0, 'Adult|Anti-HIV Agents|Bayes Theorem|Cohort Studies|Drug Resistance, Viral|Female|HIV Infections|HIV-1|Humans|Logistic Models|Male|Middle Aged|Models, Biological|Models, Genetic|Models, Statistical|Odds Ratio|ROC Curve|Treatment Outcome', 'Journal Article', '10.1371/journal.pcbi.1003203', '24009493', 'The success of combination antiretroviral therapy is limited by the evolutionary escape dynamics of HIV-1. We used Isotonic Conjunctive Bayesian Networks (I-CBNs), a class of probabilistic graphical models, to describe this process. We employed partial order constraints among viral resistance mutations, which give rise to a limited set of mutational pathways, and we modeled phenotypic drug resistance as monotonically increasing along any escape pathway. Using this model, the individualized genetic barrier (IGB) to each drug is derived as the probability of the virus not acquiring additional mutations that confer resistance. Drug-specific IGBs were combined to obtain the IGB to an entire regimen, which quantifies the virus genetic potential for developing drug resistance under combination therapy. The IGB was tested as a predictor of therapeutic outcome using between 2,185 and 2,631 treatment change episodes of subtype B infected patients from the Swiss HIV Cohort Study Database, a large observational cohort. Using logistic regression, significant univariate predictors included most of the 18 drugs and single-drug IGBs, the IGB to the entire regimen, the expert rules-based genotypic susceptibility score (GSS), several individual mutations, and the peak viral load before treatment change. In the multivariate analysis, the only genotype-derived variables that remained significantly associated with virological success were GSS and, with 10-fold stronger association, IGB to regimen. When predicting suppression of viral load below 400 cps/ml, IGB outperformed GSS and also improved GSS-containing predictors significantly, but the difference was not significant for suppression below 50 cps/ml. Thus, the IGB to regimen is a novel data-derived predictor of treatment outcome that has potential to improve the interpretation of genotypic drug resistance tests. '),
(86168, 2013, 'plos', 'Network and atomistic simulations unveil the structural determinants of mutations linked to retinal diseases', 'Mariani, Simona|DellOrco, Daniele|Felline, Angelo|Raimondi, Francesco|Fanelli, Francesca', 'Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.|Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.|Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.|Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.|Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.', 'Italy|Italy|Italy|Italy|Italy', 19, 'Amino Acid Sequence|Animals|Binding Sites|Cyclic Nucleotide Phosphodiesterases, Type 6|Eye Diseases, Hereditary|GTP-Binding Protein alpha Subunits|Guanosine Triphosphate|Mice|Mice, Transgenic|Models, Biological|Molecular Dynamics Simulation|Molecular Sequence Data|Mutation|Night Blindness|RGS Proteins|Retinal Diseases|Sequence Alignment|Vision, Ocular', 'Journal Article', '10.1371/journal.pcbi.1003207', '24009494', 'A number of incurable retinal diseases causing vision impairments derive from alterations in visual phototransduction. Unraveling the structural determinants of even monogenic retinal diseases would require network-centered approaches combined with atomistic simulations. The transducin G38D mutant associated with the Nougaret Congenital Night Blindness (NCNB) was thoroughly investigated by both mathematical modeling of visual phototransduction and atomistic simulations on the major targets of the mutational effect. Mathematical modeling, in line with electrophysiological recordings, indicates reduction of phosphodiesterase 6 (PDE) recognition and activation as the main determinants of the pathological phenotype. Sub-microsecond molecular dynamics (MD) simulations coupled with Functional Mode Analysis improve the resolution of information, showing that such impairment is likely due to disruption of the PDExcexb3 binding cavity in transducin. Protein Structure Network analyses additionally suggest that the observed slight reduction of theRGS9-catalyzed GTPase activity of transducin depends on perturbed communication between RGS9 and GTP binding site. These findings provide insights into the structural fundamentals of abnormal functioning of visual phototransduction caused by a missense mutation in one component of the signaling network. This combination of network-centered modeling with atomistic simulations represents a paradigm for future studies aimed at thoroughly deciphering the structural determinants of genetic retinal diseases. Analogous approaches are suitable to unveil the mechanism of information transfer in any signaling network either in physiological or pathological conditions. '),
(86169, 2013, 'plos', 'Effective harmonic potentials: insights into the internal cooperativity and sequence-specificity of protein dynamics', 'Dehouck, Yves|Mikhailov, Alexander S', 'Department of Physical Chemistry, Fritz-Haber-Institut der Max-Planck-Gesellschaft, Berlin, Germany. ydehouck@ulb.ac.be|Department of Physical Chemistry, Fritz-Haber-Institut der Max-Planck-Gesellschaft, Berlin, Germany. ydehouck@ulb.ac.be', 'Germany|Germany', 0, 'Amino Acids|Computational Biology|Databases, Protein|Molecular Dynamics Simulation|Nuclear Magnetic Resonance, Biomolecular|Protein Conformation|Proteins|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1003209', '24009495', 'The proper biological functioning of proteins often relies on the occurrence of coordinated fluctuations around their native structure, or on their ability to perform wider and sometimes highly elaborated motions. Hence, there is considerable interest in the definition of accurate coarse-grained descriptions of protein dynamics, as an alternative to more computationally expensive approaches. In particular, the elastic network model, in which residue motions are subjected to pairwise harmonic potentials, is known to capture essential aspects of conformational dynamics in proteins, but has so far remained mostly phenomenological, and unable to account for the chemical specificities of amino acids. We propose, for the first time, a method to derive residue- and distance-specific effective harmonic potentials from the statistical analysis of an extensive dataset of NMR conformational ensembles. These potentials constitute dynamical counterparts to the mean-force statistical potentials commonly used for static analyses of protein structures. In the context of the elastic network model, they yield a strongly improved description of the cooperative aspects of residue motions, and give the opportunity to systematically explore the influence of sequence details on protein dynamics. '),
(86170, 2013, 'plos', 'How microRNA and transcription factor co-regulatory networks affect osteosarcoma cell proliferation', 'Poos, Kathrin|Smida, Jan|Nathrath, Michaela|Maugg, Doris|Baumhoer, Daniel|Korsching, Eberhard', 'Institute of Bioinformatics, University of Münster, Münster, Germany.|Institute of Bioinformatics, University of Münster, Münster, Germany.|Institute of Bioinformatics, University of Münster, Münster, Germany.|Institute of Bioinformatics, University of Münster, Münster, Germany.|Institute of Bioinformatics, University of Münster, Münster, Germany.|Institute of Bioinformatics, University of Münster, Münster, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany', 0, 'Bone Neoplasms|Cell Growth Processes|Cell Line, Tumor|Cell Movement|Cluster Analysis|Computational Biology|Disease Progression|Fuzzy Logic|Humans|MicroRNAs|Osteosarcoma|Protein Interaction Maps|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1003210', '24009496', 'Osteosarcomas (OS) are complex bone tumors with various genomic alterations. These alterations affect the expression and function of several genes due to drastic changes in the underlying gene regulatory network. However, we know little about critical gene regulators and their functional consequences on the pathogenesis of OS. Therefore, we aimed to determine microRNA and transcription factor (TF) co-regulatory networks in OS cell proliferation. Cell proliferation is an essential part in the pathogenesis of OS and deeper understanding of its regulation might help to identify potential therapeutic targets. Based on expression data of OS cell lines divided according to their proliferative activity, we obtained 12 proliferation-related microRNAs and corresponding target genes. Therewith, microRNA and TF co-regulatory networks were generated and analyzed regarding their structure and functional influence. We identified key co-regulators comprising the microRNAs miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC in the derived networks. These regulators are implicated in NFKB- and RB1-signaling and focal adhesion processes based on their common or interacting target genes (e.g., CDK6, CTNNB1, E2F4, HES1, ITGA6, NFKB1, NOTCH1, and SIN3A). Thus, we proposed a model of OS cell proliferation which is primarily co-regulated through the interactions of the mentioned microRNA and TF combinations. This study illustrates the benefit of systems biological approaches in the analysis of complex diseases. We integrated experimental data with publicly available information to unravel the coordinated (post)-transcriptional control of microRNAs and TFs to identify potential therapeutic targets in OS. The resulting microRNA and TF co-regulatory networks are publicly available for further exploration to generate or evaluate own hypotheses of the pathogenesis of OS (http://www.complex-systems.uni-muenster.de/co_networks.html). '),
(86171, 2013, 'plos', 'Structural similarities and differences between amyloidogenic and non-amyloidogenic islet amyloid polypeptide (IAPP) sequences and implications for the dual physiological and pathological activities of these peptides', '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', 57, 'Amino Acid Sequence|Animals|Cats|Humans|Islet Amyloid Polypeptide|Molecular Dynamics Simulation|Molecular Sequence Data|Protein Conformation|Protein Folding|Rats|Sequence Alignment|Swine', 'Comparative Study', '10.1371/journal.pcbi.1003211', '24009497', 'IAPP, a 37 amino-acid peptide hormone belonging to the calcitonin family, is an intrinsically disordered protein that is coexpressed and cosecreted along with insulin by pancreatic islet xcexb2-cells in response to meals. IAPP plays a physiological role in glucose regulation, however, in certain species, IAPP can aggregate and this process is linked to xcexb2-cell death and Type II Diabetes. Using replica exchange molecular dynamics with extensive sampling (16 replicas per sequence and 600 ns per replica), we investigate the structure of the monomeric state of two species of aggregating peptides (human and cat IAPP) and two species of non-aggregating peptides (pig and rat IAPP). Our simulations reveal that the pig and rat conformations are very similar, and consist of helix-coil and helix-hairpin conformations. The aggregating sequences, on the other hand, populate the same helix-coil and helix-hairpin conformations as the non-aggregating sequence, but, in addition, populate a hairpin structure. Our exhaustive simulations, coupled with available peptide-activity data, leads us to a structure-activity relationship (SAR) in which we propose that the functional role of IAPP is carried out by the helix-coil conformation, a structure common to both aggregating and non-aggregating species. The pathological role of this peptide may have multiple origins, including the interaction of the helical elements with membranes. Nonetheless, our simulations suggest that the hairpin structure, only observed in the aggregating species, might be linked to the pathological role of this peptide, either as a direct precursor to amyloid fibrils, or as part of a cylindrin type of toxic oligomer. We further propose that the helix-hairpin fold is also a possible aggregation prone conformation that would lead normally non-aggregating variants of IAPP to form fibrils under conditions where an external perturbation is applied. The SAR relationship is used to suggest the rational design of therapeutics for treating diabetes. '),
(86172, 2013, 'plos', 'Finding associations among histone modifications using sparse partial correlation networks', 'Lasserre, Julia|Chung, Ho-Ryun|Vingron, Martin', 'Computational Molecular Biology, MPI for Molecular Genetics, Berlin, Germany.|Computational Molecular Biology, MPI for Molecular Genetics, Berlin, Germany.|Computational Molecular Biology, MPI for Molecular Genetics, Berlin, Germany.', 'Germany|Germany|Germany', 0, 'Algorithms|CD4-Positive T-Lymphocytes|Gene Regulatory Networks|Histones|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1003168', '24039558', 'Histone modifications are known to play an important role in the regulation of transcription. While individual modifications have received much attention in genome-wide analyses, little is known about their relationships. Some authors have built Bayesian networks of modifications, however most often they have used discretized data, and relied on unrealistic assumptions such as the absence of feedback mechanisms or hidden confounding factors. Here, we propose to infer undirected networks based on partial correlations between histone modifications. Within the partial correlation framework, correlations among two variables are controlled for associations induced by the other variables. Partial correlation networks thus focus on direct associations of histone modifications. We apply this methodology to data in CD4+ cells. The resulting network is well supported by common knowledge. When pairs of modifications show a large difference between their correlation and their partial correlation, a potential confounding factor is identified and provided as explanation. Data from different cell types (IMR90, H1) is also exploited in the analysis to assess the stability of the networks. The results are remarkably similar across cell types. Based on this observation, the networks from the three cell types are integrated into a consensus network to increase robustness. The data and the results discussed in the manuscript can be found, together with code, on http://spcn.molgen.mpg.de/index.html. '),
(86173, 2013, 'plos', 'Distal loop flexibility of a regulatory domain modulates dynamics and activity of C-terminal SRC kinase (csk)', 'Barkho, Sulyman|Pierce, Levi C T|McGlone, Maria L|Li, Sheng|Woods, Virgil L|Walker, Ross C|Adams, Joseph A|Jennings, Patricia A', 'Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California, United States of America.|Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California, United States of America.|Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California, United States of America.|Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California, United States of America.|Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California, United States of America.|Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California, United States of America.|Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California, United States of America.|Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 10, 'Amino Acid Sequence|Biocatalysis|Mass Spectrometry|Models, Molecular|Molecular Sequence Data|Nuclear Magnetic Resonance, Biomolecular|Sequence Homology, Amino Acid|src Homology Domains|src-Family Kinases', 'Journal Article', '10.1371/journal.pcbi.1003188', '24039559', 'The Src family of tyrosine kinases (SFKs) regulate numerous aspects of cell growth and differentiation and are under the principal control of the C-terminal Src Kinase (Csk). Csk and SFKs share a modular design with the kinase domain downstream of the N-terminal SH2 and SH3 domains that regulate catalytic function and membrane localization. While the function of interfacial segments in these multidomain kinases are well-investigated, little is known about how surface sites and long-range, allosteric coupling control protein dynamics and catalytic function. The SH2 domain of Csk is an essential component for the down-regulation of all SFKs. A unique feature of the SH2 domain of Csk is the tight turn in place of the canonical CD loop in a surface site far removed from kinase domain interactions. In this study, we used a combination of experimental and computational methods to probe the importance of this difference by constructing a Csk variant with a longer SH2 CD loop to mimic the flexibility found in homologous kinase SH2 domains. Our results indicate that while the fold and function of the isolated domain and the full-length kinase are not affected by loop elongation, native protein dynamics that are essential for efficient catalysis are perturbed. We also identify key motifs and routes through which the distal SH2 site might influence catalysis at the active site. This study underscores the sensitivity of intramolecular signaling and catalysis to native protein dynamics that arise from modest changes in allosteric regions while providing a potential strategy to alter intrinsic activity and signaling modulation. '),
(86174, 2013, 'plos', 'Genome-wide signatures of transcription factor activity: connecting transcription factors, disease, and small molecules', 'Chen, Jing|Hu, Zhen|Phatak, Mukta|Reichard, John|Freudenberg, Johannes M|Sivaganesan, Siva|Medvedovic, Mario', 'Laboratory for Statistical Genomics and Systems Biology, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.|Laboratory for Statistical Genomics and Systems Biology, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.|Laboratory for Statistical Genomics and Systems Biology, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.|Laboratory for Statistical Genomics and Systems Biology, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.|Laboratory for Statistical Genomics and Systems Biology, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.|Laboratory for Statistical Genomics and Systems Biology, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.|Laboratory for Statistical Genomics and Systems Biology, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 0, 'Chromatin Immunoprecipitation|Disease|Gene Expression Profiling|Genome-Wide Association Study|Humans|Probability|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1003198', '24039560', 'Identifying transcription factors (TF) involved in producing a genome-wide transcriptional profile is an essential step in building mechanistic model that can explain observed gene expression data. We developed a statistical framework for constructing genome-wide signatures of TF activity, and for using such signatures in the analysis of gene expression data produced by complex transcriptional regulatory programs. Our framework integrates ChIP-seq data and appropriately matched gene expression profiles to identify True REGulatory (TREG) TF-gene interactions. It provides genome-wide quantification of the likelihood of regulatory TF-gene interaction that can be used to either identify regulated genes, or as genome-wide signature of TF activity. To effectively use ChIP-seq data, we introduce a novel statistical model that integrates information from all binding peaks within 2 Mb window around a genes transcription start site (TSS), and provides gene-level binding scores and probabilities of regulatory interaction. In the second step we integrate these binding scores and regulatory probabilities with gene expression data to assess the likelihood of True REGulatory (TREG) TF-gene interactions. We demonstrate the advantages of TREG framework in identifying genes regulated by two TFs with widely different distribution of functional binding events (ERxcexb1 and E2f1). We also show that TREG signatures of TF activity vastly improve our ability to detect involvement of ERxcexb1 in producing complex diseases-related transcriptional profiles. Through a large study of disease-related transcriptional signatures and transcriptional signatures of drug activity, we demonstrate that increase in statistical power associated with the use of TREG signatures makes the crucial difference in identifying key targets for treatment, and drugs to use for treatment. All methods are implemented in an open-source R package treg. The package also contains all data used in the analysis including 494 TREG binding profiles based on ENCODE ChIP-seq data. The treg package can be downloaded at http://GenomicsPortals.org. '),
(86175, 2013, 'plos', 'Detecting and removing inconsistencies between experimental data and signaling network topologies using integer linear programming on interaction graphs', 'Melas, Ioannis N|Samaga, Regina|Alexopoulos, Leonidas G|Klamt, Steffen', 'National Technical University of Athens, Athens, Greece.|National Technical University of Athens, Athens, Greece.|National Technical University of Athens, Athens, Greece.|National Technical University of Athens, Athens, Greece.', 'Greece|Greece|Greece|Greece', 28, 'Computer Graphics|Models, Biological|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1003204', '24039561', 'Cross-referencing experimental data with our current knowledge of signaling network topologies is one central goal of mathematical modeling of cellular signal transduction networks. We present a new methodology for data-driven interrogation and training of signaling networks. While most published methods for signaling network inference operate on Bayesian, Boolean, or ODE models, our approach uses integer linear programming (ILP) on interaction graphs to encode constraints on the qualitative behavior of the nodes. These constraints are posed by the network topology and their formulation as ILP allows us to predict the possible qualitative changes (up, down, no effect) of the activation levels of the nodes for a given stimulus. We provide four basic operations to detect and remove inconsistencies between measurements and predicted behavior: (i) find a topology-consistent explanation for responses of signaling nodes measured in a stimulus-response experiment (if none exists, find the closest explanation), (ii) determine a minimal set of nodes that need to be corrected to make an inconsistent scenario consistent, (iii) determine the optimal subgraph of the given network topology which can best reflect measurements from a set of experimental scenarios, (iv) find possibly missing edges that would improve the consistency of the graph with respect to a set of experimental scenarios the most. We demonstrate the applicability of the proposed approach by interrogating a manually curated interaction graph model of EGFR/ErbB signaling against a library of high-throughput phosphoproteomic data measured in primary hepatocytes. Our methods detect interactions that are likely to be inactive in hepatocytes and provide suggestions for new interactions that, if included, would significantly improve the goodness of fit. Our framework is highly flexible and the underlying model requires only easily accessible biological knowledge. All related algorithms were implemented in a freely available toolbox SigNetTrainer making it an appealing approach for various applications. '),
(86176, 2013, 'plos', 'Motility enhancement through surface modification is sufficient for cyanobacterial community organization during phototaxis', 'Ursell, Tristan|Chau, Rosanna Man Wah|Wisen, Susanne|Bhaya, Devaki|Huang, Kerwyn Casey', 'Department of Bioengineering, Stanford University, Stanford, California, United States of America.|Department of Bioengineering, Stanford University, Stanford, California, United States of America.|Department of Bioengineering, Stanford University, Stanford, California, United States of America.|Department of Bioengineering, Stanford University, Stanford, California, United States of America.|Department of Bioengineering, Stanford University, Stanford, California, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Biophysics|Surface Properties|Synechocystis', 'Journal Article', '10.1371/journal.pcbi.1003205', '24039562', 'The emergent behaviors of communities of genotypically identical cells cannot be easily predicted from the behaviors of individual cells. In many cases, it is thought that direct cell-cell communication plays a critical role in the transition from individual to community behaviors. In the unicellular photosynthetic cyanobacterium Synechocystis sp. PCC 6803, individual cells exhibit light-directed motility (phototaxis) over surfaces, resulting in the emergence of dynamic spatial organization of multicellular communities. To probe this striking community behavior, we carried out time-lapse video microscopy coupled with quantitative analysis of single-cell dynamics under varying light conditions. These analyses suggest that cells secrete an extracellular substance that modifies the physical properties of the substrate, leading to enhanced motility and the ability for groups of cells to passively guide one another. We developed a biophysical model that demonstrates that this form of indirect, surface-based communication is sufficient to create distinct motile groups whose shape, velocity, and dynamics qualitatively match our experimental observations, even in the absence of direct cellular interactions or changes in single-cell behavior. Our computational analysis of the predicted community behavior, across a matrix of cellular concentrations and light biases, demonstrates that spatial patterning follows robust scaling laws and provides a useful resource for the generation of testable hypotheses regarding phototactic behavior. In addition, we predict that degradation of the surface modification may account for the secondary patterns occasionally observed after the initial formation of a community structure. Taken together, our modeling and experiments provide a framework to show that the emergent spatial organization of phototactic communities requires modification of the substrate, and this form of surface-based communication could provide insight into the behavior of a wide array of biological communities. '),
(86177, 2013, 'plos', 'Spike triggered covariance in strongly correlated gaussian stimuli', 'Aljadeff, Johnatan|Segev, Ronen|Berry, Michael J|Sharpee, Tatyana O', 'Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America , Center for Theoretical Biological Physics and Department of Physics, University of California, San Diego, La Jolla, California, United States of America.|Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America , Center for Theoretical Biological Physics and Department of Physics, University of California, San Diego, La Jolla, California, United States of America.|Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America , Center for Theoretical Biological Physics and Department of Physics, University of California, San Diego, La Jolla, California, United States of America.|Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America , Center for Theoretical Biological Physics and Department of Physics, University of California, San Diego, La Jolla, California, United States of America.', 'United States|United States|United States|United States', 7, 'Action Potentials|Models, Biological|Neurons', 'Journal Article', '10.1371/journal.pcbi.1003206', '24039563', 'Many biological systems perform computations on inputs that have very large dimensionality. Determining the relevant input combinations for a particular computation is often key to understanding its function. A common way to find the relevant input dimensions is to examine the difference in variance between the input distribution and the distribution of inputs associated with certain outputs. In systems neuroscience, the corresponding method is known as spike-triggered covariance (STC). This method has been highly successful in characterizing relevant input dimensions for neurons in a variety of sensory systems. So far, most studies used the STC method with weakly correlated Gaussian inputs. However, it is also important to use this method with inputs that have long range correlations typical of the natural sensory environment. In such cases, the stimulus covariance matrix has one (or more) outstanding eigenvalues that cannot be easily equalized because of sampling variability. Such outstanding modes interfere with analyses of statistical significance of candidate input dimensions that modulate neuronal outputs. In many cases, these modes obscure the significant dimensions. We show that the sensitivity of the STC method in the regime of strongly correlated inputs can be improved by an order of magnitude or more. This can be done by evaluating the significance of dimensions in the subspace orthogonal to the outstanding mode(s). Analyzing the responses of retinal ganglion cells probed with [Formula: see text] Gaussian noise, we find that taking into account outstanding modes is crucial for recovering relevant input dimensions for these neurons. '),
(86178, 2013, 'plos', 'Semi-automated curation of metabolic models via flux balance analysis: a case study with Mycoplasma gallisepticum', 'Bautista, Eddy J|Zinski, Joseph|Szczepanek, Steven M|Johnson, Erik L|Tulman, Edan R|Ching, Wei-Mei|Geary, Steven J|Srivastava, Ranjan', 'Department of Chemical & Biomolecular Engineering, University of Connecticut, Storrs, Connecticut, United States of America.|Department of Chemical & Biomolecular Engineering, University of Connecticut, Storrs, Connecticut, United States of America.|Department of Chemical & Biomolecular Engineering, University of Connecticut, Storrs, Connecticut, United States of America.|Department of Chemical & Biomolecular Engineering, University of Connecticut, Storrs, Connecticut, United States of America.|Department of Chemical & Biomolecular Engineering, University of Connecticut, Storrs, Connecticut, United States of America.|Department of Chemical & Biomolecular Engineering, University of Connecticut, Storrs, Connecticut, United States of America.|Department of Chemical & Biomolecular Engineering, University of Connecticut, Storrs, Connecticut, United States of America.|Department of Chemical & Biomolecular Engineering, University of Connecticut, Storrs, Connecticut, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Algorithms|Automation|Models, Biological|Mycoplasma gallisepticum', 'Journal Article', '10.1371/journal.pcbi.1003208', '24039564', 'Primarily used for metabolic engineering and synthetic biology, genome-scale metabolic modeling shows tremendous potential as a tool for fundamental research and curation of metabolism. Through a novel integration of flux balance analysis and genetic algorithms, a strategy to curate metabolic networks and facilitate identification of metabolic pathways that may not be directly inferable solely from genome annotation was developed. Specifically, metabolites involved in unknown reactions can be determined, and potentially erroneous pathways can be identified. The procedure developed allows for new fundamental insight into metabolism, as well as acting as a semi-automated curation methodology for genome-scale metabolic modeling. To validate the methodology, a genome-scale metabolic model for the bacterium Mycoplasma gallisepticum was created. Several reactions not predicted by the genome annotation were postulated and validated via the literature. The model predicted an average growth rate of 0.358±0.12[Formula: see text], closely matching the experimentally determined growth rate of M. gallisepticum of 0.244±0.03[Formula: see text]. This work presents a powerful algorithm for facilitating the identification and curation of previously known and new metabolic pathways, as well as presenting the first genome-scale reconstruction of M. gallisepticum. ');
