INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86823, 2014, 'plos', 'Beyond muscles stiffness: importance of state-estimation to account for very fast motor corrections', 'Crevecoeur, Frxc3xa9dxc3xa9ric|Scott, Stephen H', 'Centre for Neuroscience Studies, Queens University, Kingston, Canada.|Centre for Neuroscience Studies, Queens University, Kingston, Canada, Department of Biomedical and Molecular Sciences, Queens University, Kingston, Canada.', 'Canada|Canada', 24, 'Adult|Arm|Biomechanical Phenomena|Electromyography|Feedback, Physiological|Female|Humans|Male|Models, Biological|Muscle Contraction|Muscle, Skeletal|Task Performance and Analysis|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1003869', '25299461', 'Feedback delays are a major challenge for any controlled process, and yet we are able to easily control limb movements with speed and grace. A popular hypothesis suggests that the brain largely mitigates the impact of feedback delays (xe2x88xbc50 ms) by regulating the limb intrinsic visco-elastic properties (or impedance) with muscle co-contraction, which generates forces proportional to changes in joint angle and velocity with zero delay. Although attractive, this hypothesis is often based on estimates of limb impedance that include neural feedback, and therefore describe the entire motor system. In addition, this approach does not systematically take into account that muscles exhibit high intrinsic impedance only for small perturbations (short-range impedance). As a consequence, it remains unclear how the nervous system handles large perturbations, as well as disturbances encountered during movement when short-range impedance cannot contribute. We address this issue by comparing feedback responses to load pulses applied to the elbow of human subjects with theoretical simulations. After validating the model parameters, we show that the ability of humans to generate fast and accurate corrective movements is compatible with a control strategy based on state estimation. We also highlight the merits of delay-uncompensated robust control, which can mitigate the impact of internal model errors, but at the cost of slowing feedback corrections. We speculate that the puzzling observation of presynaptic inhibition of peripheral afferents in the spinal cord at movement onset helps to counter the destabilizing transition from high muscle impedance during posture to low muscle impedance during movement. '),
(86824, 2014, 'plos', 'Hydrophobic compounds reshape membrane domains', 'Barnoud, Jonathan|Rossi, Giulia|Marrink, Siewert J|Monticelli, Luca', 'IBCP, CNRS UMR 5086, Lyon, France, Université Claude Bernard Lyon I, Lyon, France.|Dept of Physics, University of Genoa, Genoa, Italy.|Groningen Biomolecular Sciences and Biotechnology Institute and Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands.|IBCP, CNRS UMR 5086, Lyon, France, Université Claude Bernard Lyon I, Lyon, France.', 'France|Italy|Netherlands|France', 36, 'Computational Biology|Computer Simulation|Hydrophobic and Hydrophilic Interactions|Lipids|Membrane Microdomains|Molecular Dynamics Simulation|Organic Chemicals', 'Journal Article', '10.1371/journal.pcbi.1003873', '25299598', 'Cell membranes have a complex lateral organization featuring domains with distinct composition, also known as rafts, which play an essential role in cellular processes such as signal transduction and protein trafficking. In vivo, perturbations of membrane domains (e.g., by drugs or lipophilic compounds) have major effects on the activity of raft-associated proteins and on signaling pathways, but they are difficult to characterize because of the small size of the domains, typically below optical resolution. Model membranes, instead, can show macroscopic phase separation between liquid-ordered and liquid-disordered domains, and they are often used to investigate the driving forces of membrane lateral organization. Studies in model membranes have shown that some lipophilic compounds perturb membrane domains, but it is not clear which chemical and physical properties determine domain perturbation. The mechanisms of domain stabilization and destabilization are also unknown. Here we describe the effect of six simple hydrophobic compounds on the lateral organization of phase-separated model membranes consisting of saturated and unsaturated phospholipids and cholesterol. Using molecular simulations, we identify two groups of molecules with distinct behavior: aliphatic compounds promote lipid mixing by distributing at the interface between liquid-ordered and liquid-disordered domains, aromatic compounds, instead, stabilize phase separation by partitioning into liquid-disordered domains and excluding cholesterol from the disordered domains. We predict that relatively small concentrations of hydrophobic species can have a broad impact on domain stability in model systems, which suggests possible mechanisms of action for hydrophobic compounds in vivo. '),
(86825, 2014, 'plos', 'Predicting the functions and specificity of triterpenoid synthases: a mechanism-based multi-intermediate docking approach', 'Tian, Bo-Xue|Wallrapp, Frank H|Holiday, Gemma L|Chow, Jeng-Yeong|Babbitt, Patricia C|Poulter, C Dale|Jacobson, Matthew P', 'Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, San Francisco, California, United States of America, California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, California, United States of America.|Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, San Francisco, California, United States of America, California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, California, United States of America.|California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, California, United States of America, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America.|Department of Chemistry, University of Utah, Salt Lake City, Utah, United States of America.|California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, California, United States of America, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America.|Department of Chemistry, University of Utah, Salt Lake City, Utah, United States of America.|Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, San Francisco, California, United States of America, California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, California, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 19, 'Alkyl and Aryl Transferases|Computational Biology|Intramolecular Lyases|Intramolecular Transferases|Molecular Docking Simulation|Protein Engineering|Terpenes', 'Journal Article', '10.1371/journal.pcbi.1003874', '25299649', 'Terpenoid synthases construct the carbon skeletons of tens of thousands of natural products. To predict functions and specificity of triterpenoid synthases, a mechanism-based, multi-intermediate docking approach is proposed. In addition to enzyme function prediction, other potential applications of the current approach, such as enzyme mechanistic studies and enzyme redesign by mutagenesis, are discussed. '),
(86826, 2014, 'plos', 'Depletion of the chromatin looping proteins CTCF and cohesin causes chromatin compaction: insight into chromatin folding by polymer modelling', 'Tark-Dame, Mariliis|Jerabek, Hansjoerg|Manders, Erik M M|van der Wateren, Ingrid M|Heermann, Dieter W|van Driel, Roel', 'Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.|Institute for Theoretical Physics, Heidelberg University, Heidelberg, Germany.|Van Leeuwenhoek Centre for Advanced Microscopy, University of Amsterdam, Amsterdam, The Netherlands, Department for Molecular Biotechnology, University of Gent, Gent, Belgium.|Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.|Institute for Theoretical Physics, Heidelberg University, Heidelberg, Germany.|Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.', 'Netherlands|Germany|Belgium|Netherlands|Germany|Netherlands', 42, 'Apoptosis|CCCTC-Binding Factor|Cell Cycle Proteins|Cells, Cultured|Chromatin|Chromosomal Proteins, Non-Histone|Computational Biology|Computer Simulation|Gene Knockdown Techniques|Humans|Models, Molecular|Nuclear Proteins|Phosphoproteins|Polymers|Repressor Proteins', 'Journal Article', '10.1371/journal.pcbi.1003877', '25299688', 'Folding of the chromosomal fibre in interphase nuclei is an important element in the regulation of gene expression. For instance, physical contacts between promoters and enhancers are a key element in cell-type-specific transcription. We know remarkably little about the principles that control chromosome folding. Here we explore the view that intrachromosomal interactions, forming a complex pattern of loops, are a key element in chromosome folding. CTCF and cohesin are two abundant looping proteins of interphase chromosomes of higher eukaryotes. To investigate the role of looping in large-scale (supra Mb) folding of human chromosomes, we knocked down the gene that codes for CTCF and the one coding for Rad21, an essential subunit of cohesin. We measured the effect on chromosome folding using systematic 3D fluorescent in situ hybridization (FISH). Results show that chromatin becomes more compact after reducing the concentration of these two looping proteins. The molecular basis for this counter-intuitive behaviour is explored by polymer modelling usingy the Dynamic Loop model (Bohn M, Heermann DW (2010) Diffusion-driven looping provides a consistent framework for chromatin organization. PLoS ONE 5: e12218.). We show that compaction can be explained by selectively decreasing the number of short-range loops, leaving long-range looping unchanged. In support of this model prediction it has recently been shown by others that CTCF and cohesin indeed are responsible primarily for short-range looping. Our results suggest that the local and the overall changes in of chromosome structure are controlled by a delicate balance between short-range and long-range loops, allowing easy switching between, for instance, open and more compact chromatin states. '),
(86827, 2014, 'plos', 'In vivo volume and hemoglobin dynamics of human red blood cells', 'Malka, Roy|Delgado, Francisco Feijxc3xb3|Manalis, Scott R|Higgins, John M', 'Center for Systems Biology and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, United States of America, Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America.|Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Center for Systems Biology and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, United States of America, Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America.', 'United States|United States|United States|United States', 12, 'Computational Biology|Cytoplasmic Vesicles|Erythrocyte Volume|Erythrocytes|Hemoglobins|Humans', 'Journal Article', '10.1371/journal.pcbi.1003839', '25299941', 'Human red blood cells (RBCs) lose xe2x88xbc30% of their volume and xe2x88xbc20% of their hemoglobin (Hb) content during their xe2x88xbc100-day lifespan in the bloodstream. These observations are well-documented, but the mechanisms for these volume and hemoglobin loss events are not clear. RBCs shed hemoglobin-containing vesicles during their life in the circulation, and this process is thought to dominate the changes in the RBC physical characteristics occurring during maturation. We combine theory with single-cell measurements to investigate the impact of vesiculation on the reduction in volume, Hb mass, and membrane. We show that vesicle shedding alone is sufficient to explain membrane losses but not volume or Hb losses. We use dry mass measurements of human RBCs to validate the models and to propose that additional unknown mechanisms control volume and Hb reduction and are responsible for xe2x88xbc90% of the observed reduction. RBC population characteristics are used in the clinic to monitor and diagnose a wide range of conditions including malnutrition, inflammation, and cancer. Quantitative characterization of cellular maturation processes may help in the early detection of clinical conditions where maturation patterns are altered. '),
(86828, 2014, 'plos', 'Canonical correlation analysis for gene-based pleiotropy discovery', 'Seoane, Jose A|Campbell, Colin|Day, Ian N M|Casas, Juan P|Gaunt, Tom R', 'School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.|Intelligent Systems Laboratory, University of Bristol, Bristol, United Kingdom.|School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.|Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom.|School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom, MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 17, 'Aged|Blood Coagulation Factors|Cluster Analysis|Databases, Genetic|Female|Genome-Wide Association Study|Genomics|Humans|Hypertrophy, Left Ventricular|Middle Aged|Models, Genetic|Phenotype|Polymorphism, Single Nucleotide', 'Journal Article', '10.1371/journal.pcbi.1003876', '25329069', 'Genome-wide association studies have identified a wealth of genetic variants involved in complex traits and multifactorial diseases. There is now considerable interest in testing variants for association with multiple phenotypes (pleiotropy) and for testing multiple variants for association with a single phenotype (gene-based association tests). Such approaches can increase statistical power by combining evidence for association over multiple phenotypes or genetic variants respectively. Canonical Correlation Analysis (CCA) measures the correlation between two sets of multidimensional variables, and thus offers the potential to combine these two approaches. To apply CCA, we must restrict the number of attributes relative to the number of samples. Hence we consider modules of genetic variation that can comprise a gene, a pathway or another biologically relevant grouping, and/or a set of phenotypes. In order to do this, we use an attribute selection strategy based on a binary genetic algorithm. Applied to a UK-based prospective cohort study of 4286 women (the British Womens Heart and Health Study), we find improved statistical power in the detection of previously reported genetic associations, and identify a number of novel pleiotropic associations between genetic variants and phenotypes. New discoveries include gene-based association of NSF with triglyceride levels and several genes (ACSM3, ERI2, IL18RAP, IL23RAP and NRG1) with left ventricular hypertrophy phenotypes. In multiple-phenotype analyses we find association of NRG1 with left ventricular hypertrophy phenotypes, fibrinogen and urea and pleiotropic relationships of F7 and F10 with Factor VII, Factor IX and cholesterol levels. '),
(86829, 2014, 'plos', 'Likelihood-based gene annotations for gap filling and quality assessment in genome-scale metabolic models', 'Benedict, Matthew N|Mundy, Michael B|Henry, Christopher S|Chia, Nicholas|Price, Nathan D', 'Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.|Mathematics and Computer Science Division, Argonne National Laboratory, Lemont, Illinois, United States of America.|Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America, Department of Surgery, Mayo Clinic, Rochester, Minnesota, United States of America, Department of Physiology and Bioengineering, Mayo Clinic, Rochester, Minnesota, United States of America.|Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, Institute for Systems Biology, Seattle, Washington, United States of America.', 'United States|United States|United States|United States|United States', 39, 'Algorithms|Genomics|Metabolomics|Models, Genetic|Models, Statistical|Molecular Sequence Annotation|Phenotype|Sensitivity and Specificity', 'Journal Article', '10.1371/journal.pcbi.1003882', '25329157', 'Genome-scale metabolic models provide a powerful means to harness information from genomes to deepen biological insights. With exponentially increasing sequencing capacity, there is an enormous need for automated reconstruction techniques that can provide more accurate models in a short time frame. Current methods for automated metabolic network reconstruction rely on gene and reaction annotations to build draft metabolic networks and algorithms to fill gaps in these networks. However, automated reconstruction is hampered by database inconsistencies, incorrect annotations, and gap filling largely without considering genomic information. Here we develop an approach for applying genomic information to predict alternative functions for genes and estimate their likelihoods from sequence homology. We show that computed likelihood values were significantly higher for annotations found in manually curated metabolic networks than those that were not. We then apply these alternative functional predictions to estimate reaction likelihoods, which are used in a new gap filling approach called likelihood-based gap filling to predict more genomically consistent solutions. To validate the likelihood-based gap filling approach, we applied it to models where essential pathways were removed, finding that likelihood-based gap filling identified more biologically relevant solutions than parsimony-based gap filling approaches. We also demonstrate that models gap filled using likelihood-based gap filling provide greater coverage and genomic consistency with metabolic gene functions compared to parsimony-based approaches. Interestingly, despite these findings, we found that likelihoods did not significantly affect consistency of gap filled models with Biolog and knockout lethality data. This indicates that the phenotype data alone cannot necessarily be used to discriminate between alternative solutions for gap filling and therefore, that the use of other information is necessary to obtain a more accurate network. All described workflows are implemented as part of the DOE Systems Biology Knowledgebase (KBase) and are publicly available via API or command-line web interface. '),
(86830, 2014, 'plos', 'Glycolysis is governed by growth regime and simple enzyme regulation in adherent MDCK cells', 'Rehberg, Markus|Ritter, Joachim B|Reichl, Udo', 'Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.|Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.|Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany, Otto von Guericke University Magdeburg, Chair of Bioprocess Engineering, Magdeburg, Germany.', 'Germany|Germany|Germany', 4, 'Animals|Cell Culture Techniques|Computer Simulation|Culture Media|Dogs|Enzymes|Glycolysis|Madin Darby Canine Kidney Cells|Metabolic Networks and Pathways|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1003885', '25329309', 'Due to its vital importance in the supply of cellular pathways with energy and precursors, glycolysis has been studied for several decades regarding its capacity and regulation. For a systems-level understanding of the Madin-Darby canine kidney (MDCK) cell metabolism, we couple a segregated cell growth model published earlier with a structured model of glycolysis, which is based on relatively simple kinetics for enzymatic reactions of glycolysis, to explain the pathway dynamics under various cultivation conditions. The structured model takes into account in vitro enzyme activities, and links glycolysis with pentose phosphate pathway and glycogenesis. Using a single parameterization, metabolite pool dynamics during cell cultivation, glucose limitation and glucose pulse experiments can be consistently reproduced by considering the cultivation history of the cells. Growth phase-dependent glucose uptake together with cell-specific volume changes generate high intracellular metabolite pools and flux rates to satisfy the cellular demand during growth. Under glucose limitation, the coordinated control of glycolytic enzymes re-adjusts the glycolytic flux to prevent the depletion of glycolytic intermediates. Finally, the models predictive power supports the design of more efficient bioprocesses. '),
(86831, 2014, 'plos', 'Spectral signatures of reorganised brain networks in disorders of consciousness', 'Chennu, Srivas|Finoia, Paola|Kamau, Evelyn|Allanson, Judith|Williams, Guy B|Monti, Martin M|Noreika, Valdas|Arnatkeviciute, Aurina|Canales-Johnson, Andrés|Olivares, Francisco|Cabezas-Soto, Daniela|Menon, David K|Pickard, John D|Owen, Adrian M|Bekinschtein, Tristan A', 'Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom, Medical Research Council, Cognition and Brain Sciences Unit, Cambridge, United Kingdom.|Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom, Medical Research Council, Cognition and Brain Sciences Unit, Cambridge, United Kingdom.|Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.|Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.|Wolfson Brain Imaging Centre, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.|Department of Psychology, University of California at Los Angeles, Los Angeles, California, United States of America.|Medical Research Council, Cognition and Brain Sciences Unit, Cambridge, United Kingdom.|Medical Research Council, Cognition and Brain Sciences Unit, Cambridge, United Kingdom.|Medical Research Council, Cognition and Brain Sciences Unit, Cambridge, United Kingdom, Laboratory of Cognitive and Social Neuroscience, Universidad Diego Portales, Santiago, Chile.|Laboratory of Cognitive and Social Neuroscience, Universidad Diego Portales, Santiago, Chile.|Laboratory of Cognitive and Social Neuroscience, Universidad Diego Portales, Santiago, Chile.|Division of Anaesthesia, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.|Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.|The Brain and Mind Institute, Natural Sciences Centre, The University of Western Ontario, London, Ontario, Canada.|Medical Research Council, Cognition and Brain Sciences Unit, Cambridge, United Kingdom, Department of Psychology, University of Cambridge, Cambridge, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United States|United King', 81, 'Adult|Brain|Cluster Analysis|Consciousness|Electroencephalography|Female|Humans|Image Processing, Computer-Assisted|Male|Nerve Net|Persistent Vegetative State|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1003887', '25329398', 'Theoretical advances in the science of consciousness have proposed that it is concomitant with balanced cortical integration and differentiation, enabled by efficient networks of information transfer across multiple scales. Here, we apply graph theory to compare key signatures of such networks in high-density electroencephalographic data from 32 patients with chronic disorders of consciousness, against normative data from healthy controls. Based on connectivity within canonical frequency bands, we found that patient networks had reduced local and global efficiency, and fewer hubs in the alpha band. We devised a novel topographical metric, termed modular span, which showed that the alpha network modules in patients were also spatially circumscribed, lacking the structured long-distance interactions commonly observed in the healthy controls. Importantly however, these differences between graph-theoretic metrics were partially reversed in delta and theta band networks, which were also significantly more similar to each other in patients than controls. Going further, we found that metrics of alpha network efficiency also correlated with the degree of behavioural awareness. Intriguingly, some patients in behaviourally unresponsive vegetative states who demonstrated evidence of covert awareness with functional neuroimaging stood out from this trend: they had alpha networks that were remarkably well preserved and similar to those observed in the controls. Taken together, our findings inform current understanding of disorders of consciousness by highlighting the distinctive brain networks that characterise them. In the significant minority of vegetative patients who follow commands in neuroimaging tests, they point to putative network mechanisms that could support cognitive function and consciousness despite profound behavioural impairment. '),
(86832, 2014, 'plos', 'Linking myometrial physiology to intrauterine pressure, how tissue-level contractions create uterine contractions of labor', 'Young, Roger C|Barendse, Peter', 'Department of Obstetrics and Gynecology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.|Wolfram Research, Somerville, Massachusetts, United States of America.', 'United States|United States', 18, 'Action Potentials|Computational Biology|Computer Simulation|Female|Humans|Models, Biological|Pregnancy|Uterine Contraction', 'Journal Article', '10.1371/journal.pcbi.1003850', '25330227', 'The mechanisms used to coordinate uterine contractions are not known. We develop a new model based on the proposal that there is a maximum distance to which action potentials can propagate in the uterine wall. This establishes regions, where one action potential burst can rapidly recruit all the tissue. Regions are recruited into an organ-level contraction via a stretch-initiated contraction mechanism (myometrial myogenic response). Each uterine contraction begins with a regional contraction, which slightly increases intrauterine pressure. Higher pressure raises tension throughout the uterine wall, which initiates contractions of more regions and further increases pressure. The positive feedback synchronizes regional contractions into an organ-level contraction. Cellular automaton (CA) simulations are performed with Mathematica. Each cell is a region that is assigned an action potential threshold. An anatomy sensitivity factor converts intrauterine pressure to regional tension through the Law of Laplace. A regional contraction occurs when regional tension exceeds regional threshold. Other input variables are: starting and minimum pressure, burst and refractory period durations, enhanced contractile activity during an electrical burst, and reduced activity during the refractory period. Complex patterns of pressure development are seen that mimic the contraction patterns observed in laboring women. Emergent behavior is observed, including global synchronization, multiple pace making regions, and system memory of prior conditions. The complex effects of nifedipine and oxytocin exposure are simulated. The force produced can vary as a nonlinear function of the number of regions. The simulation directly links tissue-level physiology to human labor. The concept of a uterine pacemaker is re-evaluated because pace making activity may occur well before expression of a contraction. We propose a new classification system for biological CAs that parallels the 4-class system of Wolfram. However, instead of classifying the rules, biological CAs should classify the set of input values for the rules that describe the relevant biology. '),
(86833, 2014, 'plos', 'Reactive searching and infotaxis in odor source localization', 'Voges, Nicole|Chaffiol, Antoine|Lucas, Philippe|Martinez, Dominique', 'CNRS, LORIA, UMR 7503, Vandoeuvre-les-Nancy, France.|Inserm, UMR S968, Institut de la Vision, Paris, France.|INRA, UMR 1392, Institute of Ecology and Environmental Sciences of Paris, Versailles, France.|CNRS, LORIA, UMR 7503, Vandoeuvre-les-Nancy, France.', 'France|France|France|France', 0, 'Algorithms|Animals|Appetitive Behavior|Artificial Intelligence|Computational Biology|Female|Flight, Animal|Male|Models, Biological|Moths|Odorants|Pheromones|Robotics', 'Journal Article', '10.1371/journal.pcbi.1003861', '25330317', 'Male moths aiming to locate pheromone-releasing females rely on stimulus-adapted search maneuvers complicated by a discontinuous distribution of pheromone patches. They alternate sequences of upwind surge when perceiving the pheromone and cross- or downwind casting when the odor is lost. We compare four search strategies: three reactive versus one cognitive. The former consist of pre-programmed movement sequences triggered by pheromone detections while the latter uses Bayesian inference to build spatial probability maps. Based on the analysis of triphasic responses of antennal lobe neurons (On, inhibition, Off), we propose three reactive strategies. One combines upwind surge (representing the On response to a pheromone detection) and spiral casting, only. The other two additionally include crosswind (zigzag) casting representing the Off phase. As cognitive strategy we use the infotaxis algorithm which was developed for searching in a turbulent medium. Detection events in the electroantennogram of a moth attached to a robot indirectly control this cyborg, depending on the strategy in use. The recorded trajectories are analyzed with regard to success rates, efficiency, and other features. In addition, we qualitatively compare our robotic trajectories to behavioral search paths. Reactive searching is more efficient (yielding shorter trajectories) for higher pheromone doses whereas cognitive searching works better for lower doses. With respect to our experimental conditions (2 m from starting position to pheromone source), reactive searching with crosswind zigzag yields the shortest trajectories (for comparable success rates). Assuming that the neuronal Off response represents a short-term memory, zigzagging is an efficient movement to relocate a recently lost pheromone plume. Accordingly, such reactive strategies offer an interesting alternative to complex cognitive searching. '),
(86834, 2014, 'plos', 'Modeling dynamics of cell-to-cell variability in TRAIL-induced apoptosis explains fractional killing and predicts reversible resistance', 'Bertaux, François|Stoma, Szymon|Drasdo, Dirk|Batt, Gregory', 'INRIA Paris-Rocquencourt, Le Chesnay, France.|INRIA Paris-Rocquencourt, Le Chesnay, France.|INRIA Paris-Rocquencourt, Le Chesnay, France, Laboratoire Jacques-Louis Lions (LJLL), University of Paris 6 (UPMC) - CNRS (UMR7598), Paris, France.|INRIA Paris-Rocquencourt, Le Chesnay, France.', 'France|France|France|France', 33, 'Apoptosis|HeLa Cells|Humans|Models, Biological|Signal Transduction|Stochastic Processes|TNF-Related Apoptosis-Inducing Ligand', 'Journal Article', '10.1371/journal.pcbi.1003893', '25340343', 'Isogenic cells sensing identical external signals can take markedly different decisions. Such decisions often correlate with pre-existing cell-to-cell differences in protein levels. When not neglected in signal transduction models, these differences are accounted for in a static manner, by assuming randomly distributed initial protein levels. However, this approach ignores the a priori non-trivial interplay between signal transduction and the source of this cell-to-cell variability: temporal fluctuations of protein levels in individual cells, driven by noisy synthesis and degradation. Thus, modeling protein fluctuations, rather than their consequences on the initial population heterogeneity, would set the quantitative analysis of signal transduction on firmer grounds. Adopting this dynamical view on cell-to-cell differences amounts to recast extrinsic variability into intrinsic noise. Here, we propose a generic approach to merge, in a systematic and principled manner, signal transduction models with stochastic protein turnover models. When applied to an established kinetic model of TRAIL-induced apoptosis, our approach markedly increased model prediction capabilities. One obtains a mechanistic explanation of yet-unexplained observations on fractional killing and non-trivial robust predictions of the temporal evolution of cell resistance to TRAIL in HeLa cells. Our results provide an alternative explanation to survival via induction of survival pathways since no TRAIL-induced regulations are needed and suggest that short-lived anti-apoptotic protein Mcl1 exhibit large and rare fluctuations. More generally, our results highlight the importance of accounting for stochastic protein turnover to quantitatively understand signal transduction over extended durations, and imply that fluctuations of short-lived proteins deserve particular attention. '),
(86835, 2014, 'plos', 'Investigating the structure and dynamics of the PIK3CA wild-type and H1047R oncogenic mutant', 'Gkeka, Paraskevi|Evangelidis, Thomas|Pavlaki, Maria|Lazani, Vasiliki|Christoforidis, Savvas|Agianian, Bogos|Cournia, Zoe', 'Biomedical Research Foundation, Academy of Athens, Athens, Greece.|Biomedical Research Foundation, Academy of Athens, Athens, Greece.|Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.|Department of Biomedical Research, Institute of Molecular Biology and Biotechnology-Foundation for Research and Technology (IMBB-BR/FORTH), Ioannina, Greece.|Department of Biomedical Research, Institute of Molecular Biology and Biotechnology-Foundation for Research and Technology (IMBB-BR/FORTH), Ioannina, Greece, Department of Medicine, University of Ioannina, Ioannina, Greece.|Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.|Biomedical Research Foundation, Academy of Athens, Athens, Greece.', 'Greece|Greece|Greece|Greece|Greece|Greece|Greece', 42, 'Class I Phosphatidylinositol 3-Kinases|Cluster Analysis|Humans|Models, Biological|Molecular Dynamics Simulation|Mutation|Neoplasm Proteins|Neoplasms|Phosphatidylinositol 3-Kinases|Protein Binding|Surface Plasmon Resonance', 'Journal Article', '10.1371/journal.pcbi.1003895', '25340423', 'The PIK3CA gene is one of the most frequently mutated oncogenes in human cancers. It encodes p110xcexb1, the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3Kxcexb1), which activates signaling cascades leading to cell proliferation, survival, and cell growth. The most frequent mutation in PIK3CA is H1047R, which results in enzymatic overactivation. Understanding how the H1047R mutation causes the enhanced activity of the protein in atomic detail is central to developing mutant-specific therapeutics for cancer. To this end, Surface Plasmon Resonance (SPR) experiments and Molecular Dynamics (MD) simulations were carried out for both wild-type (WT) and H1047R mutant proteins. An expanded positive charge distribution on the membrane binding regions of the mutant with respect to the WT protein is observed through MD simulations, which justifies the increased ability of the mutated protein variant to bind to membranes rich in anionic lipids in our SPR experiments. Our results further support an auto-inhibitory role of the C-terminal tail in the WT protein, which is abolished in the mutant protein due to loss of crucial intermolecular interactions. Moreover, Functional Mode Analysis reveals that the H1047R mutation alters the twisting motion of the N-lobe of the kinase domain with respect to the C-lobe and shifts the position of the conserved P-loop residues in the vicinity of the active site. These findings demonstrate the dynamical and structural differences of the two proteins in atomic detail and propose a mechanism of overactivation for the mutant protein. The results may be further utilized for the design of mutant-specific PI3Kxcexb1 inhibitors that exploit the altered mutant conformation. '),
(86836, 2014, 'plos', 'A taxonomy of bacterial microcompartment loci constructed by a novel scoring method', 'Axen, Seth D|Erbilgin, Onur|Kerfeld, Cheryl A', 'DOE Joint Genome Institute, Walnut Creek, California, United States of America.|Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, California, United States of America.|Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, California, United States of America, DOE Plant Research Laboratory, Michigan State University, East Lansing, Michigan, United States of America, Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America, Berkeley Synthetic Biology Institute, Berkeley, California, United States of America.', 'United States|United States|United States', 0, 'Aldehyde Dehydrogenase|Algorithms|Bacteria|Bacterial Proteins|Bioengineering|Computational Biology|Gene Regulatory Networks|Organelles|Phylogeny', 'Journal Article', '10.1371/journal.pcbi.1003898', '25340524', 'Bacterial microcompartments (BMCs) are proteinaceous organelles involved in both autotrophic and heterotrophic metabolism. All BMCs share homologous shell proteins but differ in their complement of enzymes, these are typically encoded adjacent to shell protein genes in genetic loci, or operons. To enable the identification and prediction of functional (sub)types of BMCs, we developed LoClass, an algorithm that finds putative BMC loci and inventories, weights, and compares their constituent pfam domains to construct a locus similarity network and predict locus (sub)types. In addition to using LoClass to analyze sequences in the Non-redundant Protein Database, we compared predicted BMC loci found in seven candidate bacterial phyla (six from single-cell genomic studies) to the LoClass taxonomy. Together, these analyses resulted in the identification of 23 different types of BMCs encoded in 30 distinct locus (sub)types found in 23 bacterial phyla. These include the two carboxysome types and a divergent set of metabolosomes, BMCs that share a common catalytic core and process distinct substrates via specific signature enzymes. Furthermore, many Candidate BMCs were found that lack one or more core metabolosome components, including one that is predicted to represent an entirely new paradigm for BMC-associated metabolism, joining the carboxysome and metabolosome. By placing these results in a phylogenetic context, we provide a framework for understanding the horizontal transfer of these loci, a starting point for studies aimed at understanding the evolution of BMCs. This comprehensive taxonomy of BMC loci, based on their constituent protein domains, foregrounds the functional diversity of BMCs and provides a reference for interpreting the role of BMC gene clusters encoded in isolate, single cell, and metagenomic data. Many loci encode ancillary functions such as transporters or genes for cofactor assembly, this expanded vocabulary of BMC-related functions should be useful for design of genetic modules for introducing BMCs in bioengineering applications. '),
(86837, 2014, 'plos', 'Rhythmic manipulation of objects with complex dynamics: predictability over chaos', 'Nasseroleslami, Bahman|Hasson, Christopher J|Sternad, Dagmar', 'Department of Biology, Northeastern University, Boston, Massachusetts, United States of America.|Department of Physical Therapy, Movement and Rehabilitation Sciences, Northeastern University, Boston, Massachusetts, United States of America.|Department of Biology, Northeastern University, Boston, Massachusetts, United States of America, Department of Electrical and Computer Engineering, Northeastern University, Boston, Massachusetts, United States of America, Department of Physics, Northeastern University, Boston, Massachusetts, United States of America, Center for the Interdisciplinary Research on Complex Systems, Northeastern University, Boston, Massachusetts, United States of America.', 'United States|United States|United States', 0, 'Adult|Biomechanical Phenomena|Female|Hand|Humans|Male|Middle Aged|Models, Theoretical|Movement|Robotics|Task Performance and Analysis|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1003900', '25340581', 'The study of object manipulation has been largely confined to discrete tasks, where accuracy, mechanical effort, or smoothness were examined to explain subjects preferred movements. This study investigated a rhythmic manipulation task, which involved continuous interaction with a nonlinear object that led to unpredictable object behavior. Using a simplified virtual version of the task of carrying a cup of coffee, we studied how this unpredictable object behavior affected the selected strategies. The experiment was conducted in a virtual set-up, where subjects moved a cup with a ball inside, modeled by cart-and-pendulum dynamics. Inverse dynamics calculations of the system showed that performing the task with different amplitudes and relative phases required different force profiles and rendered the objects dynamics with different degrees of predictability (quantified by Mutual Information between the applied force and the cup kinematics and its sensitivity). Subjects (nxe2x80x8a=xe2x80x8a8) oscillated the virtual cup between two targets via a robotic manipulandum, paced by a metronome at 1 Hz for 50 trials, each lasting 45 s. They were free to choose their movement amplitude and relative phase between the ball and cup. Experimental results showed that subjects increased their movement amplitudes, which rendered the interactions with the object more predictable and with lower sensitivity to the execution variables. These solutions were associated with higher average exerted force and lower object smoothness, contradicting common expectations from studies on discrete object manipulation and unrestrained movements. Instead, the findings showed that humans selected strategies with higher predictability of interaction dynamics. This finding expressed that humans seek movement strategies where force and kinematics synchronize to repeatable patterns that may require less sensorimotor information processing. '),
(86838, 2014, 'plos', 'Ten simple rules for writing a PLOS ten simple rules article', 'Dashnow, Harriet|Lonsdale, Andrew|Bourne, Philip E', 'Bioinformatics, Murdoch Childrens Research Institute, Parkville, Victoria, Australia, Life Science Computation Centre, Victorian Life Sciences Computation Initiative, Carlton, Victoria, Australia, The University of Melbourne, Parkville, Victoria, Australia.|The Australian Research Council Centre of Excellence in Plant Cell Walls, School of Botany, University of Melbourne, Parkville, Victoria, Australia.|Office of the Director, National Institutes of Health, Bethesda, Maryland United States of America.', 'Australia|Australia|United States', 0, 'Computational Biology|Cooperative Behavior|Humans|Periodicals as Topic|Research|Wit and Humor as Topic|Writing', 'Editorial', '10.1371/journal.pcbi.1003858', '25340653', '-'),
(86839, 2014, 'plos', 'Energy landscape of all-atom protein-protein interactions revealed by multiscale enhanced sampling', 'Moritsugu, Kei|Terada, Tohru|Kidera, Akinori', 'Computational Science Research Program, RIKEN, Hirosawa, Wako, Saitama, Japan, Graduate School of Medical Life Science, Yokohama City University, Suehiro-cho, Tsurumi-ku, Yokohama, Japan.|Computational Science Research Program, RIKEN, Hirosawa, Wako, Saitama, Japan, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan.|Computational Science Research Program, RIKEN, Hirosawa, Wako, Saitama, Japan, Graduate School of Medical Life Science, Yokohama City University, Suehiro-cho, Tsurumi-ku, Yokohama, Japan.', 'Japan|Japan|Japan', 12, 'Computational Biology|Molecular Dynamics Simulation|Protein Binding|Protein Conformation|Proteins|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003901', '25340714', 'Protein-protein interactions are regulated by a subtle balance of complicated atomic interactions and solvation at the interface. To understand such an elusive phenomenon, it is necessary to thoroughly survey the large configurational space from the stable complex structure to the dissociated states using the all-atom model in explicit solvent and to delineate the energy landscape of protein-protein interactions. In this study, we carried out a multiscale enhanced sampling (MSES) simulation of the formation of a barnase-barstar complex, which is a protein complex characterized by an extraordinary tight and fast binding, to determine the energy landscape of atomistic protein-protein interactions. The MSES adopts a multicopy and multiscale scheme to enable for the enhanced sampling of the all-atom model of large proteins including explicit solvent. During the 100-ns MSES simulation of the barnase-barstar system, we observed the association-dissociation processes of the atomistic protein complex in solution several times, which contained not only the native complex structure but also fully non-native configurations. The sampled distributions suggest that a large variety of non-native states went downhill to the stable complex structure, like a fast folding on a funnel-like potential. This funnel landscape is attributed to dominant configurations in the early stage of the association process characterized by near-native orientations, which will accelerate the native inter-molecular interactions. These configurations are guided mostly by the shape complementarity between barnase and barstar, and lead to the fast formation of the final complex structure along the downhill energy landscape. '),
(86840, 2014, 'plos', 'Ensembles of spiking neurons with noise support optimal probabilistic inference in a dynamically changing environment', 'Legenstein, Robert|Maass, Wolfgang', 'Institute for Theoretical Computer Science, Graz University of Technology, Graz, Austria.|Institute for Theoretical Computer Science, Graz University of Technology, Graz, Austria.', 'Austria|Austria', 25, 'Action Potentials|Animals|Computational Biology|Markov Chains|Models, Neurological|Models, Statistical|Monte Carlo Method|Motor Cortex|Neurons|Rats', 'Journal Article', '10.1371/journal.pcbi.1003859', '25340749', 'It has recently been shown that networks of spiking neurons with noise can emulate simple forms of probabilistic inference through neural sampling, i.e., by treating spikes as samples from a probability distribution of network states that is encoded in the network. Deficiencies of the existing model are its reliance on single neurons for sampling from each random variable, and the resulting limitation in representing quickly varying probabilistic information. We show that both deficiencies can be overcome by moving to a biologically more realistic encoding of each salient random variable through the stochastic firing activity of an ensemble of neurons. The resulting model demonstrates that networks of spiking neurons with noise can easily track and carry out basic computational operations on rapidly varying probability distributions, such as the odds of getting rewarded for a specific behavior. We demonstrate the viability of this new approach towards neural coding and computation, which makes use of the inherent parallelism of generic neural circuits, by showing that this model can explain experimentally observed firing activity of cortical neurons for a variety of tasks that require rapid temporal integration of sensory information. ');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86841, 2014, 'plos', 'Chromatin loops as allosteric modulators of enhancer-promoter interactions', 'Doyle, Boryana|Fudenberg, Geoffrey|Imakaev, Maxim|Mirny, Leonid A', 'Program for Research in Mathematics, Engineering and Science for High School Students, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, Undergraduate Research Opportunities Program, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Graduate Program in Biophysics, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, Graduate Program in Biophysics, Harvard University, Cambridge, Massachusetts, United States of America, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States', 0, 'Chromatin|Computational Biology|Enhancer Elements, Genetic|Gene Expression Regulation|Models, Genetic|Promoter Regions, Genetic|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1003867', '25340767', 'The classic model of eukaryotic gene expression requires direct spatial contact between a distal enhancer and a proximal promoter. Recent Chromosome Conformation Capture (3C) studies show that enhancers and promoters are embedded in a complex network of looping interactions. Here we use a polymer model of chromatin fiber to investigate whether, and to what extent, looping interactions between elements in the vicinity of an enhancer-promoter pair can influence their contact frequency. Our equilibrium polymer simulations show that a chromatin loop, formed by elements flanking either an enhancer or a promoter, suppresses enhancer-promoter interactions, working as an insulator. A loop formed by elements located in the region between an enhancer and a promoter, on the contrary, facilitates their interactions. We find that different mechanisms underlie insulation and facilitation, insulation occurs due to steric exclusion by the loop, and is a global effect, while facilitation occurs due to an effective shortening of the enhancer-promoter genomic distance, and is a local effect. Consistently, we find that these effects manifest quite differently for in silico 3C and microscopy. Our results show that looping interactions that do not directly involve an enhancer-promoter pair can nevertheless significantly modulate their interactions. This phenomenon is analogous to allosteric regulation in proteins, where a conformational change triggered by binding of a regulatory molecule to one site affects the state of another site. '),
(86842, 2014, 'plos', 'Regression analysis of combined gene expression regulation in acute myeloid leukemia', 'Li, Yue|Liang, Minggao|Zhang, Zhaolei', 'Department of Computer Science, University of Toronto, Toronto, Canada, The Donnelly Centre, University of Toronto, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.|Department of Computer Science, University of Toronto, Toronto, Canada, The Donnelly Centre, University of Toronto, Toronto, Canada, Department of Molecular Genetics, University of Toronto, Toronto, Canada, Banting and Best Department of Medical Research, University of Toronto, Toronto, Canada.', 'Canada|Canada|Canada', 0, 'Adult|Computational Biology|Gene Expression Profiling|Gene Expression Regulation, Neoplastic|Gene Regulatory Networks|Humans|Kaplan-Meier Estimate|Leukemia, Myeloid, Acute|Male|MicroRNAs|Regression Analysis', 'Journal Article', '10.1371/journal.pcbi.1003908', '25340776', 'Gene expression is a combinatorial function of genetic/epigenetic factors such as copy number variation (CNV), DNA methylation (DM), transcription factors (TF) occupancy, and microRNA (miRNA) post-transcriptional regulation. At the maturity of microarray/sequencing technologies, large amounts of data measuring the genome-wide signals of those factors became available from Encyclopedia of DNA Elements (ENCODE) and The Cancer Genome Atlas (TCGA). However, there is a lack of an integrative model to take full advantage of these rich yet heterogeneous data. To this end, we developed RACER (Regression Analysis of Combined Expression Regulation), which fits the mRNA expression as response using as explanatory variables, the TF data from ENCODE, and CNV, DM, miRNA expression signals from TCGA. Briefly, RACER first infers the sample-specific regulatory activities by TFs and miRNAs, which are then used as inputs to infer specific TF/miRNA-gene interactions. Such a two-stage regression framework circumvents a common difficulty in integrating ENCODE data measured in generic cell-line with the sample-specific TCGA measurements. As a case study, we integrated Acute Myeloid Leukemia (AML) data from TCGA and the related TF binding data measured in K562 from ENCODE. As a proof-of-concept, we first verified our model formalism by 10-fold cross-validation on predicting gene expression. We next evaluated RACER on recovering known regulatory interactions, and demonstrated its superior statistical power over existing methods in detecting known miRNA/TF targets. Additionally, we developed a feature selection procedure, which identified 18 regulators, whose activities clustered consistently with cytogenetic risk groups. One of the selected regulators is miR-548p, whose inferred targets were significantly enriched for leukemia-related pathway, implicating its novel role in AML pathogenesis. Moreover, survival analysis using the inferred activities identified C-Fos as a potential AML prognostic marker. Together, we provided a novel framework that successfully integrated the TCGA and ENCODE data in revealing AML-specific regulatory program at global level. '),
(86843, 2014, 'plos', 'Predicting chemical environments of bacteria from receptor signaling', 'Clausznitzer, Diana|Micali, Gabriele|Neumann, Silke|Sourjik, Victor|Endres, Robert G', 'Department of Life Sciences, Imperial College, London, United Kingdom, Centre for Integrative Systems Biology and Bioinformatics, Imperial College, London, United Kingdom, BioQuant, Heidelberg University, Heidelberg, Germany, Institute for Medical Informatics and Biometry, Technische Universität Dresden, Dresden, Germany.|Department of Life Sciences, Imperial College, London, United Kingdom, Centre for Integrative Systems Biology and Bioinformatics, Imperial College, London, United Kingdom.|Centre of Molecular Biology, Heidelberg University, DKFZ-ZMBH Alliance, Heidelberg, Germany.|Centre of Molecular Biology, Heidelberg University, DKFZ-ZMBH Alliance, Heidelberg, Germany, Max Planck Institute for Terrestrial Microbiology, Marburg, Germany.|Department of Life Sciences, Imperial College, London, United Kingdom, Centre for Integrative Systems Biology and Bioinformatics, Imperial College, London, United Kingdom.', 'Germany|United Kingdom|Germany|Germany|United Kingdom', 0, 'Cellular Microenvironment|Chemotaxis|Computational Biology|Computer Simulation|Escherichia coli|Information Theory|Models, Biological|Models, Chemical', 'Journal Article', '10.1371/journal.pcbi.1003870', '25340783', 'Sensory systems have evolved to respond to input stimuli of certain statistical properties, and to reliably transmit this information through biochemical pathways. Hence, for an experimentally well-characterized sensory system, one ought to be able to extract valuable information about the statistics of the stimuli. Based on dose-response curves from in vivo fluorescence resonance energy transfer (FRET) experiments of the bacterial chemotaxis sensory system, we predict the chemical gradients chemotactic Escherichia coli cells typically encounter in their natural environment. To predict average gradients cells experience, we revaluate the phenomenological Webers law and its generalizations to the Weber-Fechner law and fold-change detection. To obtain full distributions of gradients we use information theory and simulations, considering limitations of information transmission from both cell-external and internal noise. We identify broad distributions of exponential gradients, which lead to log-normal stimuli and maximal drift velocity. Our results thus provide a first step towards deciphering the chemical nature of complex, experimentally inaccessible cellular microenvironments, such as the human intestine. '),
(86844, 2014, 'plos', 'Lipid clustering correlates with membrane curvature as revealed by molecular simulations of complex lipid bilayers', 'Koldsxc3xb8, Heidi|Shorthouse, David|Hxc3xa9lie, Jean|Sansom, Mark S P', 'Department of Biochemistry, University of Oxford, Oxford, United Kingdom.|Department of Biochemistry, University of Oxford, Oxford, United Kingdom.|Department of Biochemistry, University of Oxford, Oxford, United Kingdom.|Department of Biochemistry, University of Oxford, Oxford, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Amino Acid Sequence|Computational Biology|Lipid Bilayers|Membrane Microdomains|Membrane Proteins|Molecular Dynamics Simulation|Molecular Sequence Data', 'Journal Article', '10.1371/journal.pcbi.1003911', '25340788', 'Cell membranes are complex multicomponent systems, which are highly heterogeneous in the lipid distribution and composition. To date, most molecular simulations have focussed on relatively simple lipid compositions, helping to inform our understanding of in vitro experimental studies. Here we describe on simulations of complex asymmetric plasma membrane model, which contains seven different lipids species including the glycolipid GM3 in the outer leaflet and the anionic lipid, phosphatidylinositol 4,5-bisphophate (PIP2), in the inner leaflet. Plasma membrane models consisting of 1500 lipids and resembling the in vivo composition were constructed and simulations were run for 5 xc2xb5s. In these simulations the most striking feature was the formation of nano-clusters of GM3 within the outer leaflet. In simulations of protein interactions within a plasma membrane model, GM3, PIP2, and cholesterol all formed favorable interactions with the model xcexb1-helical protein. A larger scale simulation of a model plasma membrane containing 6000 lipid molecules revealed correlations between curvature of the bilayer surface and clustering of lipid molecules. In particular, the concave (when viewed from the extracellular side) regions of the bilayer surface were locally enriched in GM3. In summary, these simulations explore the nanoscale dynamics of model bilayers which mimic the in vivo lipid composition of mammalian plasma membranes, revealing emergent nanoscale membrane organization which may be coupled both to fluctuations in local membrane geometry and to interactions with proteins. '),
(86845, 2014, 'plos', 'Quantifying the turnover of transcriptional subclasses of HIV-1-infected cells', 'Althaus, Christian L|Joos, Beda|Perelson, Alan S|Günthard, Huldrych F', 'Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland.|Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland.|Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland.', 'Switzerland|Switzerland|Mexico|Switzerland', 0, 'Anti-Retroviral Agents|Computational Biology|Drug Therapy, Combination|HIV Infections|HIV-1|Humans|Leukocytes, Mononuclear|Models, Genetic|RNA, Viral', 'Journal Article', '10.1371/journal.pcbi.1003871', '25340797', 'HIV-1-infected cells in peripheral blood can be grouped into different transcriptional subclasses. Quantifying the turnover of these cellular subclasses can provide important insights into the viral life cycle and the generation and maintenance of latently infected cells. We used previously published data from five patients chronically infected with HIV-1 that initiated combination antiretroviral therapy (cART). Patient-matched PCR for unspliced and multiply spliced viral RNAs combined with limiting dilution analysis provided measurements of transcriptional profiles at the single cell level. Furthermore, measurement of intracellular transcripts and extracellular virion-enclosed HIV-1 RNA allowed us to distinguish productive from non-productive cells. We developed a mathematical model describing the dynamics of plasma virus and the transcriptional subclasses of HIV-1-infected cells. Fitting the model to the data allowed us to better understand the phenotype of different transcriptional subclasses and their contribution to the overall turnover of HIV-1 before and during cART. The average number of virus-producing cells in peripheral blood is small during chronic infection. We find that a substantial fraction of cells can become defectively infected. Assuming that the infection is homogenous throughout the body, we estimate an average in vivo viral burst size on the order of 104 virions per cell. Our study provides novel quantitative insights into the turnover and development of different subclasses of HIV-1-infected cells, and indicates that cells containing solely unspliced viral RNA are a good marker for viral latency. The model illustrates how the pool of latently infected cells becomes rapidly established during the first months of acute infection and continues to increase slowly during the first years of chronic infection. Having a detailed understanding of this process will be useful for the evaluation of viral eradication strategies that aim to deplete the latent reservoir of HIV-1. '),
(86846, 2014, 'plos', 'Linking macroscopic with microscopic neuroanatomy using synthetic neuronal populations', 'Schneider, Calvin J|Cuntz, Hermann|Soltesz, Ivan', 'Department of Anatomy and Neurobiology, University of California Irvine, Irvine, California, United States of America.|Ernst Strüngmann Institute (ESI) for Neuroscience in Cooperation with Max Planck Society, Frankfurt/Main, Germany, Institute of Clinical Neuroanatomy, Goethe University, Frankfurt/Main, Germany, Frankfurt Institute for Advanced Studies, Frankfurt/Main, Germany.|Department of Anatomy and Neurobiology, University of California Irvine, Irvine, California, United States of America.', 'United States|Germany|United States', 16, 'Animals|Computational Biology|Computer Simulation|Dendrites|Dentate Gyrus|Models, Neurological|Neuroanatomy|Neurons|Rats', 'Journal Article', '10.1371/journal.pcbi.1003921', '25340814', 'Dendritic morphology has been shown to have a dramatic impact on neuronal function. However, population features such as the inherent variability in dendritic morphology between cells belonging to the same neuronal type are often overlooked when studying computation in neural networks. While detailed models for morphology and electrophysiology exist for many types of single neurons, the role of detailed single cell morphology in the population has not been studied quantitatively or computationally. Here we use the structural context of the neural tissue in which dendritic trees exist to drive their generation in silico. We synthesize the entire population of dentate gyrus granule cells, the most numerous cell type in the hippocampus, by growing their dendritic trees within their characteristic dendritic fields bounded by the realistic structural context of (1) the granule cell layer that contains all somata and (2) the molecular layer that contains the dendritic forest. This process enables branching statistics to be linked to larger scale neuroanatomical features. We find large differences in dendritic total length and individual path length measures as a function of location in the dentate gyrus and of somatic depth in the granule cell layer. We also predict the number of unique granule cell dendrites invading a given volume in the molecular layer. This work enables the complete population-level study of morphological properties and provides a framework to develop complex and realistic neural network models. '),
(86847, 2014, 'plos', 'Bistable forespore engulfment in Bacillus subtilis by a zipper mechanism in absence of the cell wall', 'Ojkic, Nikola|López-Garrido, Javier|Pogliano, Kit|Endres, Robert G', 'Department of Life Sciences, Imperial College, London, United Kingdom, Centre for Integrative Systems Biology and Bioinformatics, Imperial College, London, United Kingdom.|Division of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America.|Division of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America.|Department of Life Sciences, Imperial College, London, United Kingdom, Centre for Integrative Systems Biology and Bioinformatics, Imperial College, London, United Kingdom.', 'United Kingdom|United States|United States|United Kingdom', 11, 'Bacillus subtilis|Biophysical Phenomena|Cell Shape|Cell Wall|Computational Biology|Models, Biological|Spores, Bacterial', 'Journal Article', '10.1371/journal.pcbi.1003912', '25356555', 'To survive starvation, the bacterium Bacillus subtilis forms durable spores. The initial step of sporulation is asymmetric cell division, leading to a large mother-cell and a small forespore compartment. After division is completed and the dividing septum is thinned, the mother cell engulfs the forespore in a slow process based on cell-wall degradation and synthesis. However, recently a new cell-wall independent mechanism was shown to significantly contribute, which can even lead to fast engulfment in [Formula: see text] 60 [Formula: see text] of the cases when the cell wall is completely removed. In this backup mechanism, strong ligand-receptor binding between mother-cell protein SpoIIIAH and forespore-protein SpoIIQ leads to zipper-like engulfment, but quantitative understanding is missing. In our work, we combined fluorescence image analysis and stochastic Langevin simulations of the fluctuating membrane to investigate the origin of fast bistable engulfment in absence of the cell wall. Our cell morphologies compare favorably with experimental time-lapse microscopy, with engulfment sensitive to the number of SpoIIQ-SpoIIIAH bonds in a threshold-like manner. By systematic exploration of model parameters, we predict regions of osmotic pressure and membrane-surface tension that produce successful engulfment. Indeed, decreasing the medium osmolarity in experiments prevents engulfment in line with our predictions. Forespore engulfment may thus not only be an ideal model system to study decision-making in single cells, but its biophysical principles are likely applicable to engulfment in other cell types, e.g. during phagocytosis in eukaryotes. '),
(86848, 2014, 'plos', 'Establishing and managing a global student network', 'Shanmugam, Avinash|Macintyre, Geoff', 'Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America.|The Centre for Neural Engineering, University of Melbourne, Parkville, Victoria, Australia.', 'United States|Australia', 1, 'Communication|Computational Biology|Humans|Internet|Social Networking|Societies, Scientific|Students', 'Journal Article', '10.1371/journal.pcbi.1003920', '25356597', '-'),
(86849, 2014, 'plos', 'Estimating location without external cues', 'Cheung, Allen', 'The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia.', 'Australia', 0, 'Animals|Attention|Computational Biology|Cues|Models, Biological|Rats|Spatial Navigation', 'Journal Article', '10.1371/journal.pcbi.1003927', '25356642', 'The ability to determine ones location is fundamental to spatial navigation. Here, it is shown that localization is theoretically possible without the use of external cues, and without knowledge of initial position or orientation. With only error-prone self-motion estimates as input, a fully disoriented agent can, in principle, determine its location in familiar spaces with 1-fold rotational symmetry. Surprisingly, localization does not require the sensing of any external cue, including the boundary. The combination of self-motion estimates and an internal map of the arena provide enough information for localization. This stands in conflict with the supposition that 2D arenas are analogous to open fields. Using a rodent error model, it is shown that the localization performance which can be achieved is enough to initiate and maintain stable firing patterns like those of grid cells, starting from full disorientation. Successful localization was achieved when the rotational asymmetry was due to the external boundary, an interior barrier or a void space within an arena. Optimal localization performance was found to depend on arena shape, arena size, local and global rotational asymmetry, and the structure of the path taken during localization. Since allothetic cues including visual and boundary contact cues were not present, localization necessarily relied on the fusion of idiothetic self-motion cues and memory of the boundary. Implications for spatial navigation mechanisms are discussed, including possible relationships with place field overdispersion and hippocampal reverse replay. Based on these results, experiments are suggested to identify if and where information fusion occurs in the mammalian spatial memory system. '),
(86850, 2014, 'plos', 'dcGOR: an R package for analysing ontologies and protein domain annotations', 'Fang, Hai', 'Computational Genomics Group, Department of Computer Science, University of Bristol, Bristol, United Kingdom.', 'United Kingdom', 7, 'Animals|Biological Ontologies|Cluster Analysis|Computational Biology|Humans|Molecular Sequence Annotation|Proteins|Software', 'Journal Article', '10.1371/journal.pcbi.1003929', '25356683', 'I introduce an open-source R package dcGOR to provide the bioinformatics community with the ease to analyse ontologies and protein domain annotations, particularly those in the dcGO database. The dcGO is a comprehensive resource for protein domain annotations using a panel of ontologies including Gene Ontology. Although increasing in popularity, this database needs statistical and graphical support to meet its full potential. Moreover, there are no bioinformatics tools specifically designed for domain ontology analysis. As an add-on package built in the R software environment, dcGOR offers a basic infrastructure with great flexibility and functionality. It implements new data structure to represent domains, ontologies, annotations, and all analytical outputs as well. For each ontology, it provides various mining facilities, including: (i) domain-based enrichment analysis and visualisation, (ii) construction of a domain (semantic similarity) network according to ontology annotations, and (iii) significance analysis for estimating a contact (statistical significance) network. To reduce runtime, most analyses support high-performance parallel computing. Taking as inputs a list of protein domains of interest, the package is able to easily carry out in-depth analyses in terms of functional, phenotypic and diseased relevance, and network-level understanding. More importantly, dcGOR is designed to allow users to import and analyse their own ontologies and annotations on domains (taken from SCOP, Pfam and InterPro) and RNAs (from Rfam) as well. The package is freely available at CRAN for easy installation, and also at GitHub for version control. The dedicated website with reproducible demos can be found at http://supfam.org/dcGOR. '),
(86851, 2014, 'plos', 'Multiscale approach to the determination of the photoactive yellow protein signaling state ensemble', 'A Rohrdanz, Mary|Zheng, Wenwei|Lambeth, Bradley|Vreede, Jocelyne|Clementi, Cecilia', 'Center for Theoretical Biological Physics, Rice University, Houston, Texas, United States of America, Chemistry Department, Rice University, Houston, Texas, United States of America.|Center for Theoretical Biological Physics, Rice University, Houston, Texas, United States of America, Chemistry Department, Rice University, Houston, Texas, United States of America.|Center for Theoretical Biological Physics, Rice University, Houston, Texas, United States of America.|vant Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands.|Center for Theoretical Biological Physics, Rice University, Houston, Texas, United States of America, Chemistry Department, Rice University, Houston, Texas, United States of America.', 'United States|United States|United States|Netherlands|United States', 5, 'Algorithms|Bacterial Proteins|Computational Biology|Computer Simulation|Diffusion|Models, Molecular|Photoreceptors, Microbial|Signal Transduction|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003797', '25356903', 'The nature of the optical cycle of photoactive yellow protein (PYP) makes its elucidation challenging for both experiment and theory. The long transition times render conventional simulation methods ineffective, and yet the short signaling-state lifetime makes experimental data difficult to obtain and interpret. Here, through an innovative combination of computational methods, a prediction and analysis of the biological signaling state of PYP is presented. Coarse-grained modeling and locally scaled diffusion map are first used to obtain a rough birds-eye view of the free energy landscape of photo-activated PYP. Then all-atom reconstruction, followed by an enhanced sampling scheme, diffusion map-directed-molecular dynamics are used to focus in on the signaling-state region of configuration space and obtain an ensemble of signaling state structures. To the best of our knowledge, this is the first time an all-atom reconstruction from a coarse grained model has been performed in a relatively unexplored region of molecular configuration space. We compare our signaling state prediction with previous computational and more recent experimental results, and the comparison is favorable, which validates the method presented. This approach provides additional insight to understand the PYP photo cycle, and can be applied to other systems for which more direct methods are impractical. '),
(86852, 2014, 'plos', 'The route of HIV escape from immune response targeting multiple sites is determined by the cost-benefit tradeoff of escape mutations', 'Batorsky, Rebecca|Sergeev, Rinat A|Rouzine, Igor M', 'Department of Physics and Astronomy, Tufts University, Medford, Massachusetts, United States of America, Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, United States of America.|Department of Microbiology, Tufts University, Boston, Massachusetts, United States of America.|Department of Microbiology, Tufts University, Boston, Massachusetts, United States of America.', 'United States|United States|United States', 13, 'Computational Biology|Genetic Fitness|HIV Infections|HIV-1|Humans|Mutation|T-Lymphocytes, Cytotoxic', 'Journal Article', '10.1371/journal.pcbi.1003878', '25356981', 'Cytotoxic T lymphocytes (CTL) are a major factor in the control of HIV replication. CTL arise in acute infection, causing escape mutations to spread rapidly through the population of infected cells. As a result, the virus develops partial resistance to the immune response. The factors controlling the order of mutating epitope sites are currently unknown and would provide a valuable tool for predicting conserved epitopes. In this work, we adapt a well-established mathematical model of HIV evolution under dynamical selection pressure from multiple CTL clones to include partial impairment of CTL recognition, [Formula: see text], as well as cost to viral replication, [Formula: see text]. The process of escape is described in terms of the cost-benefit tradeoff of escape mutations and predicts a trajectory in the cost-benefit plane connecting sequentially escaped sites, which moves from high recognition loss/low fitness cost to low recognition loss/high fitness cost and has a larger slope for early escapes than for late escapes. The slope of the trajectory offers an interpretation of positive correlation between fitness costs and HLA binding impairment to HLA-A molecules and a protective subset of HLA-B molecules that was observed for clinically relevant escape mutations in the Pol gene. We estimate the value of [Formula: see text] from published experimental studies to be in the range (0.01-0.86) and show that the assumption of complete recognition loss ([Formula: see text]) leads to an overestimate of mutation cost. Our analysis offers a consistent interpretation of the commonly observed pattern of escape, in which several escape mutations are observed transiently in an epitope. This non-nested pattern is a combined effect of temporal changes in selection pressure and partial recognition loss. We conclude that partial recognition loss is as important as fitness loss for predicting the order of escapes and, ultimately, for predicting conserved epitopes that can be targeted by vaccines. '),
(86853, 2014, 'plos', 'FamSeq: a variant calling program for family-based sequencing data using graphics processing units', 'Peng, Gang|Fan, Yu|Wang, Wenyi', 'Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.', 'United States|United States|United States', 7, 'Algorithms|Computational Biology|Computer Graphics|Family|Genetic Variation|High-Throughput Nucleotide Sequencing|Humans|Image Processing, Computer-Assisted|Models, Genetic|Pedigree|Sequence Analysis, DNA|Software', 'Journal Article', '10.1371/journal.pcbi.1003880', '25357123', 'Various algorithms have been developed for variant calling using next-generation sequencing data, and various methods have been applied to reduce the associated false positive and false negative rates. Few variant calling programs, however, utilize the pedigree information when the family-based sequencing data are available. Here, we present a program, FamSeq, which reduces both false positive and false negative rates by incorporating the pedigree information from the Mendelian genetic model into variant calling. To accommodate variations in data complexity, FamSeq consists of four distinct implementations of the Mendelian genetic model: the Bayesian network algorithm, a graphics processing unit version of the Bayesian network algorithm, the Elston-Stewart algorithm and the Markov chain Monte Carlo algorithm. To make the software efficient and applicable to large families, we parallelized the Bayesian network algorithm that copes with pedigrees with inbreeding loops without losing calculation precision on an NVIDIA graphics processing unit. In order to compare the difference in the four methods, we applied FamSeq to pedigree sequencing data with family sizes that varied from 7 to 12. When there is no inbreeding loop in the pedigree, the Elston-Stewart algorithm gives analytical results in a short time. If there are inbreeding loops in the pedigree, we recommend the Bayesian network method, which provides exact answers. To improve the computing speed of the Bayesian network method, we parallelized the computation on a graphics processing unit. This allowed the Bayesian network method to process the whole genome sequencing data of a family of 12 individuals within two days, which was a 10-fold time reduction compared to the time required for this computation on a central processing unit. '),
(86854, 2014, 'plos', 'Phosphate sink containing two-component signaling systems as tunable threshold devices', 'Amin, Munia|Kothamachu, Varun B|Feliu, Elisenda|Scharf, Birgit E|Porter, Steven L|Soyer, Orkun S', 'Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom, Systems Biology Program, College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, United Kingdom.|Systems Biology Program, College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, United Kingdom.|Department of Mathematical Sciences, University of Copenhagen, Copenhagen, Denmark.|Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, United States of America.|Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom.|School of Life Sciences, University of Warwick, Coventry, United Kingdom.', 'United Kingdom|United Kingdom|Denmark|United States|United Kingdom|United Kingdom', 17, 'Chemotaxis|Models, Biological|Phosphates|Reproducibility of Results|Signal Transduction|Sinorhizobium meliloti|Synthetic Biology', 'Journal Article', '10.1371/journal.pcbi.1003890', '25357192', 'Synthetic biology aims to design de novo biological systems and reengineer existing ones. These efforts have mostly focused on transcriptional circuits, with reengineering of signaling circuits hampered by limited understanding of their systems dynamics and experimental challenges. Bacterial two-component signaling systems offer a rich diversity of sensory systems that are built around a core phosphotransfer reaction between histidine kinases and their output response regulator proteins, and thus are a good target for reengineering through synthetic biology. Here, we explore the signal-response relationship arising from a specific motif found in two-component signaling. In this motif, a single histidine kinase (HK) phosphotransfers reversibly to two separate output response regulator (RR) proteins. We show that, under the experimentally observed parameters from bacteria and yeast, this motif not only allows rapid signal termination, whereby one of the RRs acts as a phosphate sink towards the other RR (i.e. the output RR), but also implements a sigmoidal signal-response relationship. We identify two mathematical conditions on system parameters that are necessary for sigmoidal signal-response relationships and define key parameters that control threshold levels and sensitivity of the signal-response curve. We confirm these findings experimentally, by in vitro reconstitution of the one HK-two RR motif found in the Sinorhizobium meliloti chemotaxis pathway and measuring the resulting signal-response curve. We find that the level of sigmoidality in this system can be experimentally controlled by the presence of the sink RR, and also through an auxiliary protein that is shown to bind to the HK (yielding Hill coefficients of above 7). These findings show that the one HK-two RR motif allows bacteria and yeast to implement tunable switch-like signal processing and provides an ideal basis for developing threshold devices for synthetic biology applications. '),
(86855, 2014, 'plos', 'Robust identification of noncoding RNA from transcriptomes requires phylogenetically-informed sampling', 'Lindgreen, Stinus|Umu, Sinan Uxc4x9fur|Lai, Alicia Sook-Wei|Eldai, Hisham|Liu, Wenting|McGimpsey, Stephanie|Wheeler, Nicole E|Biggs, Patrick J|Thomson, Nick R|Barquist, Lars|Poole, Anthony M|Gardner, Paul P', 'Department of Biology, University of Copenhagen, Copenhagen, Denmark, School of Biological Sciences, University of Canterbury, Christchurch, New Zealand.|School of Biological Sciences, University of Canterbury, Christchurch, New Zealand, Biomolecular Interaction Centre, University of Canterbury, Christchurch, New Zealand.|School of Biological Sciences, University of Canterbury, Christchurch, New Zealand.|School of Biological Sciences, University of Canterbury, Christchurch, New Zealand.|School of Biological Sciences, University of Canterbury, Christchurch, New Zealand.|School of Biological Sciences, University of Canterbury, Christchurch, New Zealand.|School of Biological Sciences, University of Canterbury, Christchurch, New Zealand.|Institute of Veterinary, Animal & Biomedical Sciences, Massey University, Palmerston North, New Zealand, Allan Wilson Centre for Molecular Ecology & Evolution, Massey University, Palmerston North, New Zealand.|Pathogen Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.|Pathogen Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom, Institute for Molecular Infection Biology, University of Wuerzburg, Wuerzburg, Germany.|School of Biological Sciences, University of Canterbury, Christchurch, New Zealand, Biomolecular Interaction Centre, University of Canterbury, Christchurch, New Zealand, Allan Wilson Centre for Molecular Ecology & Evolution, Massey University, Palmerston North, New Zealand.|School of Biological Sciences, University of Canterbury, Christchurch, New Zealand, Biomolecular Interaction Centre, University of Canterbury, Christchurch, New Zealand.', 'Denmark|New Zealand|New Zealand|New Zealand|New Zealand|New Zealand|New Zealand|New Zealand|United K', 26, 'Archaea|Bacteria|Cluster Analysis|Computational Biology|Databases, Genetic|Gene Expression Profiling|Phylogeny|RNA, Archaeal|RNA, Bacterial|RNA, Untranslated|Transcriptome', 'Journal Article', '10.1371/journal.pcbi.1003907', '25357249', 'Noncoding RNAs are integral to a wide range of biological processes, including translation, gene regulation, host-pathogen interactions and environmental sensing. While genomics is now a mature field, our capacity to identify noncoding RNA elements in bacterial and archaeal genomes is hampered by the difficulty of de novo identification. The emergence of new technologies for characterizing transcriptome outputs, notably RNA-seq, are improving noncoding RNA identification and expression quantification. However, a major challenge is to robustly distinguish functional outputs from transcriptional noise. To establish whether annotation of existing transcriptome data has effectively captured all functional outputs, we analysed over 400 publicly available RNA-seq datasets spanning 37 different Archaea and Bacteria. Using comparative tools, we identify close to a thousand highly-expressed candidate noncoding RNAs. However, our analyses reveal that capacity to identify noncoding RNA outputs is strongly dependent on phylogenetic sampling. Surprisingly, and in stark contrast to protein-coding genes, the phylogenetic window for effective use of comparative methods is perversely narrow: aggregating public datasets only produced one phylogenetic cluster where these tools could be used to robustly separate unannotated noncoding RNAs from a null hypothesis of transcriptional noise. Our results show that for the full potential of transcriptomics data to be realized, a change in experimental design is paramount: effective transcriptomics requires phylogeny-aware sampling. '),
(86856, 2014, 'plos', 'Deducing the kinetics of protein synthesis in vivo from the transition rates measured in vitro', 'Rudorf, Sophia|Thommen, Michael|Rodnina, Marina V|Lipowsky, Reinhard', 'Theory and Bio-Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.|Physical Biochemistry, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.|Physical Biochemistry, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.|Theory and Bio-Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.', 'Germany|Germany|Germany|Germany', 23, 'Codon|Computational Biology|Kinetics|Models, Biological|Protein Biosynthesis|Proteins|Ribosomes|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003909', '25358034', 'The molecular machinery of life relies on complex multistep processes that involve numerous individual transitions, such as molecular association and dissociation steps, chemical reactions, and mechanical movements. The corresponding transition rates can be typically measured in vitro but not in vivo. Here, we develop a general method to deduce the in-vivo rates from their in-vitro values. The method has two basic components. First, we introduce the kinetic distance, a new concept by which we can quantitatively compare the kinetics of a multistep process in different environments. The kinetic distance depends logarithmically on the transition rates and can be interpreted in terms of the underlying free energy barriers. Second, we minimize the kinetic distance between the in-vitro and the in-vivo process, imposing the constraint that the deduced rates reproduce a known global property such as the overall in-vivo speed. In order to demonstrate the predictive power of our method, we apply it to protein synthesis by ribosomes, a key process of gene expression. We describe the latter process by a codon-specific Markov model with three reaction pathways, corresponding to the initial binding of cognate, near-cognate, and non-cognate tRNA, for which we determine all individual transition rates in vitro. We then predict the in-vivo rates by the constrained minimization procedure and validate these rates by three independent sets of in-vivo data, obtained for codon-dependent translation speeds, codon-specific translation dynamics, and missense error frequencies. In all cases, we find good agreement between theory and experiment without adjusting any fit parameter. The deduced in-vivo rates lead to smaller error frequencies than the known in-vitro rates, primarily by an improved initial selection of tRNA. The method introduced here is relatively simple from a computational point of view and can be applied to any biomolecular process, for which we have detailed information about the in-vitro kinetics. '),
(86857, 2014, 'plos', 'Putting theory to the test: which regulatory mechanisms can drive realistic growth of a root?', 'De Vos, Dirk|Vissenberg, Kris|Broeckhove, Jan|Beemster, Gerrit T S', 'Molecular Plant Physiology and Biotechnology, Department of Biology, University of Antwerp, Antwerp, Belgium.|Plant Growth and Development, Department of Biology, University of Antwerp, Antwerp, Belgium.|Computational Modelling and Programming, Department of Mathematics and Informatics, University of Antwerp, Antwerp, Belgium.|Molecular Plant Physiology and Biotechnology, Department of Biology, University of Antwerp, Antwerp, Belgium.', 'Belgium|Belgium|Belgium|Belgium', 20, 'Arabidopsis|Biomechanical Phenomena|Computational Biology|Cytokinins|Indoleacetic Acids|Models, Biological|Plant Roots', 'Journal Article', '10.1371/journal.pcbi.1003910', '25358093', 'In recent years there has been a strong development of computational approaches to mechanistically understand organ growth regulation in plants. In this study, simulation methods were used to explore which regulatory mechanisms can lead to realistic output at the cell and whole organ scale and which other possibilities must be discarded as they result in cellular patterns and kinematic characteristics that are not consistent with experimental observations for the Arabidopsis thaliana primary root. To aid in this analysis, a Uniform Longitudinal Strain Rule (ULSR) was formulated as a necessary condition for stable, unidirectional, symplastic growth. Our simulations indicate that symplastic structures are robust to differences in longitudinal strain rates along the growth axis only if these differences are small and short-lived. Whereas simple cell-autonomous regulatory rules based on counters and timers can produce stable growth, it was found that steady developmental zones and smooth transitions in cell lengths are not feasible. By introducing spatial cues into growth regulation, those inadequacies could be avoided and experimental data could be faithfully reproduced. Nevertheless, a root growth model based on previous polar auxin-transport mechanisms violates the proposed ULSR due to the presence of lateral gradients. Models with layer-specific regulation or layer-driven growth offer potential solutions. Alternatively, a model representing the known cross-talk between auxin, as the cell proliferation promoting factor, and cytokinin, as the cell differentiation promoting factor, predicts the effect of hormone-perturbations on meristem size. By down-regulating PIN-mediated transport through the transcription factor SHY2, cytokinin effectively flattens the lateral auxin gradient, at the basal boundary of the division zone, (thereby imposing the ULSR) to signal the exit of proliferation and start of elongation. This model exploration underlines the value of generating virtual root growth kinematics to dissect and understand the mechanisms controlling this biological system. '),
(86858, 2014, 'plos', 'Inference of epidemiological dynamics based on simulated phylogenies using birth-death and coalescent models', 'Boskova, Veronika|Bonhoeffer, Sebastian|Stadler, Tanja', 'Department of Biosystems Science & Engineering (D-BSSE), Eidgenössische Technische Hochschule (ETH) Zürich, Basel, Switzerland.|Institute of Integrative Biology, Eidgenössische Technische Hochschule (ETH) Zürich, Zürich, Switzerland.|Department of Biosystems Science & Engineering (D-BSSE), Eidgenössische Technische Hochschule (ETH) Zürich, Basel, Switzerland.', 'Switzerland|Switzerland|Switzerland', 17, 'Birth Rate|Computational Biology|Computer Simulation|Epidemiologic Methods|Humans|Models, Biological|Mortality|Phylogeny|Population Dynamics', 'Journal Article', '10.1371/journal.pcbi.1003913', '25375100', 'Quantifying epidemiological dynamics is crucial for understanding and forecasting the spread of an epidemic. The coalescent and the birth-death model are used interchangeably to infer epidemiological parameters from the genealogical relationships of the pathogen population under study, which in turn are inferred from the pathogen genetic sequencing data. To compare the performance of these widely applied models, we performed a simulation study. We simulated phylogenetic trees under the constant rate birth-death model and the coalescent model with a deterministic exponentially growing infected population. For each tree, we re-estimated the epidemiological parameters using both a birth-death and a coalescent based method, implemented as an MCMC procedure in BEAST v2.0. In our analyses that estimate the growth rate of an epidemic based on simulated birth-death trees, the point estimates such as the maximum a posteriori/maximum likelihood estimates are not very different. However, the estimates of uncertainty are very different. The birth-death model had a higher coverage than the coalescent model, i.e. contained the true value in the highest posterior density (HPD) interval more often (2-13% vs. 31-75% error). The coverage of the coalescent decreases with decreasing basic reproductive ratio and increasing sampling probability of infecteds. We hypothesize that the biases in the coalescent are due to the assumption of deterministic rather than stochastic population size changes. Both methods performed reasonably well when analyzing trees simulated under the coalescent. The methods can also identify other key epidemiological parameters as long as one of the parameters is fixed to its true value. In summary, when using genetic data to estimate epidemic dynamics, our results suggest that the birth-death method will be less sensitive to population fluctuations of early outbreaks than the coalescent method that assumes a deterministic exponentially growing infected population. ');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86859, 2014, 'plos', 'Mouse hair cycle expression dynamics modeled as coupled mesenchymal and epithelial oscillators', 'Tasseff, Ryan|Bheda-Malge, Anjali|DiColandrea, Teresa|Bascom, Charles C|Isfort, Robert J|Gelinas, Richard', 'Institute for Systems Biology, Seattle, Washington, United States of America.|Institute for Systems Biology, Seattle, Washington, United States of America.|Procter and Gamble, Mason, Ohio, United States of America.|Procter and Gamble, Mason, Ohio, United States of America.|Procter and Gamble, Mason, Ohio, 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', 7, 'Animals|Circadian Rhythm|Computational Biology|Epithelial Cells|Gene Expression Regulation|Hair|Hair Follicle|Male|Mice|Mice, Inbred C57BL|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1003914', '25375120', 'The hair cycle is a dynamic process where follicles repeatedly move through phases of growth, retraction, and relative quiescence. This process is an example of temporal and spatial biological complexity. Understanding of the hair cycle and its regulation would shed light on many other complex systems relevant to biological and medical research. Currently, a systematic characterization of gene expression and summarization within the context of a mathematical model is not yet available. Given the cyclic nature of the hair cycle, we felt it was important to consider a subset of genes with periodic expression. To this end, we combined several mathematical approaches with high-throughput, whole mouse skin, mRNA expression data to characterize aspects of the dynamics and the possible cell populations corresponding to potentially periodic patterns. In particular two gene clusters, demonstrating properties of out-of-phase synchronized expression, were identified. A mean field, phase coupled oscillator model was shown to quantitatively recapitulate the synchronization observed in the data. Furthermore, we found only one configuration of positive-negative coupling to be dynamically stable, which provided insight on general features of the regulation. Subsequent bifurcation analysis was able to identify and describe alternate states based on perturbation of system parameters. A 2-population mixture model and cell type enrichment was used to associate the two gene clusters to features of background mesenchymal populations and rapidly expanding follicular epithelial cells. Distinct timing and localization of expression was also shown by RNA and protein imaging for representative genes. Taken together, the evidence suggests that synchronization between expanding epithelial and background mesenchymal cells may be maintained, in part, by inhibitory regulation, and potential mediators of this regulation were identified. Furthermore, the model suggests that impairing this negative regulation will drive a bifurcation which may represent transition into a pathological state such as hair miniaturization. '),
(86860, 2014, 'plos', 'Deep supervised, but not unsupervised, models may explain IT cortical representation', 'Khaligh-Razavi, Seyed-Mahdi|Kriegeskorte, Nikolaus', 'Medical Research Council, Cognition and Brain Sciences Unit, Cambridge, United Kingdom.|Medical Research Council, Cognition and Brain Sciences Unit, Cambridge, United Kingdom.', 'United Kingdom|United Kingdom', 324, 'Animals|Computational Biology|Haplorhini|Humans|Models, Neurological|Support Vector Machine|Temporal Lobe', 'Journal Article', '10.1371/journal.pcbi.1003915', '25375136', 'Inferior temporal (IT) cortex in human and nonhuman primates serves visual object recognition. Computational object-vision models, although continually improving, do not yet reach human performance. It is unclear to what extent the internal representations of computational models can explain the IT representation. Here we investigate a wide range of computational model representations (37 in total), testing their categorization performance and their ability to account for the IT representational geometry. The models include well-known neuroscientific object-recognition models (e.g. HMAX, VisNet) along with several models from computer vision (e.g. SIFT, GIST, self-similarity features, and a deep convolutional neural network). We compared the representational dissimilarity matrices (RDMs) of the model representations with the RDMs obtained from human IT (measured with fMRI) and monkey IT (measured with cell recording) for the same set of stimuli (not used in training the models). Better performing models were more similar to IT in that they showed greater clustering of representational patterns by category. In addition, better performing models also more strongly resembled IT in terms of their within-category representational dissimilarities. Representational geometries were significantly correlated between IT and many of the models. However, the categorical clustering observed in IT was largely unexplained by the unsupervised models. The deep convolutional network, which was trained by supervision with over a million category-labeled images, reached the highest categorization performance and also best explained IT, although it did not fully explain the IT data. Combining the features of this model with appropriate weights and adding linear combinations that maximize the margin between animate and inanimate objects and between faces and other objects yielded a representation that fully explained our IT data. Overall, our results suggest that explaining IT requires computational features trained through supervised learning to emphasize the behaviorally important categorical divisions prominently reflected in IT. '),
(86861, 2014, 'plos', 'Stability depends on positive autoregulation in Boolean gene regulatory networks', 'Pinho, Ricardo|Garcia, Victor|Irimia, Manuel|Feldman, Marcus W', 'Department of Biology, Stanford University, Stanford, California, United States of America, PhD Program in Computational Biology, Instituto Gulbenkian de Ciência, Oeiras, Portugal.|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland.|EMBL/CRG Research Unit in Systems Biology, Centre for Genomic Regulation (CRG), Barcelona, Spain.|Department of Biology, Stanford University, Stanford, California, United States of America.', 'Portugal|Switzerland|Spain|United States', 0, 'Animals|Computational Biology|Diptera|Gene Regulatory Networks|Homeostasis|Mammals|Models, Biological|Phenotype|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1003916', '25375153', 'Network motifs have been identified as building blocks of regulatory networks, including gene regulatory networks (GRNs). The most basic motif, autoregulation, has been associated with bistability (when positive) and with homeostasis and robustness to noise (when negative), but its general importance in network behavior is poorly understood. Moreover, how specific autoregulatory motifs are selected during evolution and how this relates to robustness is largely unknown. Here, we used a class of GRN models, Boolean networks, to investigate the relationship between autoregulation and network stability and robustness under various conditions. We ran evolutionary simulation experiments for different models of selection, including mutation and recombination. Each generation simulated the development of a population of organisms modeled by GRNs. We found that stability and robustness positively correlate with autoregulation, in all investigated scenarios, stable networks had mostly positive autoregulation. Assuming biological networks correspond to stable networks, these results suggest that biological networks should often be dominated by positive autoregulatory loops. This seems to be the case for most studied eukaryotic transcription factor networks, including those in yeast, flies and mammals. '),
(86862, 2014, 'plos', 'Herpes simplex virus-2 genital tract shedding is not predictable over months or years in infected persons', 'Dhankani, Varsha|Kutz, J Nathan|Schiffer, Joshua T', 'Department of Applied Mathematics, University of Washington, Seattle, Washington, United States of America.|Department of Applied Mathematics, University of Washington, Seattle, Washington, United States of America.|Department of Medicine, University of Washington, Seattle, Washington, United States of America, Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.', 'United States|United States|United States', 0, 'Computational Biology|Herpes Genitalis|Herpesvirus 2, Human|Host-Pathogen Interactions|Humans|Models, Biological|Principal Component Analysis|Virus Shedding', 'Journal Article', '10.1371/journal.pcbi.1003922', '25375183', 'Herpes simplex virus-2 (HSV-2) is a chronic reactivating infection that leads to recurrent shedding episodes in the genital tract. A minority of episodes are prolonged, and associated with development of painful ulcers. However, currently, available tools poorly predict viral trajectories and timing of reactivations in infected individuals. We employed principal components analysis (PCA) and singular value decomposition (SVD) to interpret HSV-2 genital tract shedding time series data, as well as simulation output from a stochastic spatial mathematical model. Empirical and model-derived, time-series data gathered over >30 days consists of multiple complex episodes that could not be reduced to a manageable number of descriptive features with PCA and SVD. However, single HSV-2 shedding episodes, even those with prolonged duration and complex morphologies consisting of multiple erratic peaks, were consistently described using a maximum of four dominant features. Modeled and clinical episodes had equivalent distributions of dominant features, implying similar dynamics in real and simulated episodes. We applied linear discriminant analysis (LDA) to simulation output and identified that local immune cell density at the viral reactivation site had a predictive effect on episode duration, though longer term shedding suggested chaotic dynamics and could not be predicted based on spatial patterns of immune cell density. These findings suggest that HSV-2 shedding patterns within an individual are impossible to predict over weeks or months, and that even highly complex single HSV-2 episodes can only be partially predicted based on spatial distribution of immune cell density. '),
(86863, 2014, 'plos', 'A comparative study and a phylogenetic exploration of the compositional architectures of mammalian nuclear genomes', 'Elhaik, Eran|Graur, Dan', 'Department of Animal and Plant Sciences, University of Sheffield, Sheffield, United Kingdom.|Department of Biology & Biochemistry, University of Houston, Houston, Texas, United States of America.', 'United Kingdom|United States', 4, 'Animals|Cell Nucleus|Genome|Genomics|Humans|Mammals|Phylogeny', 'Comparative Study', '10.1371/journal.pcbi.1003925', '25375262', 'For the past four decades the compositional organization of the mammalian genome posed a formidable challenge to molecular evolutionists attempting to explain it from an evolutionary perspective. Unfortunately, most of the explanations adhered to the isochore theory, which has long been rebutted. Recently, an alternative compositional domain model was proposed depicting the human and cow genomes as composed mostly of short compositionally homogeneous and nonhomogeneous domains and a few long ones. We test the validity of this model through a rigorous sequence-based analysis of eleven completely sequenced mammalian and avian genomes. Seven attributes of compositional domains are used in the analyses: (1) the number of compositional domains, (2) compositional domain-length distribution, (3) density of compositional domains, (4) genome coverage by the different domain types, (5) degree of fit to a power-law distribution, (6) compositional domain GC content, and (7) the joint distribution of GC content and length of the different domain types. We discuss the evolution of these attributes in light of two competing phylogenetic hypotheses that differ from each other in the validity of clade Euarchontoglires. If valid, the murid genome compositional organization would be a derived state and exhibit a high similarity to that of other mammals. If invalid, the murid genome compositional organization would be closer to an ancestral state. We demonstrate that the compositional organization of the murid genome differs from those of primates and laurasiatherians, a phenomenon previously termed the murid shift, and in many ways resembles the genome of opossum. We find no support to the isochore theory. Instead, our findings depict the mammalian genome as a tapestry of mostly short homogeneous and nonhomogeneous domains and few long ones thus providing strong evidence in favor of the compositional domain model and seem to invalidate clade Euarchontoglires. '),
(86864, 2014, 'plos', 'Low probability of initiating nirS transcription explains observed gas kinetics and growth of bacteria switching from aerobic respiration to denitrification', 'Hassan, Junaid|Bergaust, Linda L|Wheat, I David|Bakken, Lars R', 'Department of Environmental Sciences, Norwegian University of Life Sciences, xc3x85s, Norway.|Department of Environmental Sciences, Norwegian University of Life Sciences, xc3x85s, Norway.|Department of Geography, University of Bergen, Bergen, Norway.|Department of Environmental Sciences, Norwegian University of Life Sciences, xc3x85s, Norway.', 'Norway|Norway|Norway|Norway', 0, 'Aerobiosis|Bacterial Proteins|Computational Biology|Denitrification|Gene Expression Regulation, Bacterial|Models, Biological|Nitrogen Oxides|Paracoccus denitrificans|Proteome', 'Journal Article', '10.1371/journal.pcbi.1003933', '25375393', 'In response to impending anoxic conditions, denitrifying bacteria sustain respiratory metabolism by producing enzymes for reducing nitrogen oxyanions/-oxides (NOx) to N2 (denitrification). Since denitrifying bacteria are non-fermentative, the initial production of denitrification proteome depends on energy from aerobic respiration. Thus, if a cell fails to synthesise a minimum of denitrification proteome before O2 is completely exhausted, it will be unable to produce it later due to energy-limitation. Such entrapment in anoxia is recently claimed to be a major phenomenon in batch cultures of the model organism Paracoccus denitrificans on the basis of measured e(-)-flow rates to O2 and NOx. Here we constructed a dynamic model and explicitly simulated actual kinetics of recruitment of the cells to denitrification to directly and more accurately estimate the recruited fraction (Fden). Transcription of nirS is pivotal for denitrification, for it triggers a cascade of events leading to the synthesis of a full-fledged denitrification proteome. The model is based on the hypothesis that nirS has a low probability (rden, h(-1)) of initial transcription, but once initiated, the transcription is greatly enhanced through positive feedback by NO, resulting in the recruitment of the transcribing cell to denitrification. We assume that the recruitment is initiated as [O2] falls below a critical threshold and terminates (assuming energy-limitation) as [O2] exhausts. With rdenxe2x80x8a=xe2x80x8a0.005 h(-1), the model robustly simulates observed denitrification kinetics for a range of culture conditions. The resulting Fden (fraction of the cells recruited to denitrification) falls within 0.038-0.161. In contrast, if the recruitment of the entire population is assumed, the simulated denitrification kinetics deviate grossly from those observed. The phenomenon can be understood as a bet-hedging strategy: switching to denitrification is a gain if anoxic spell lasts long but is a waste of energy if anoxia turns out to be a false alarm.'),
(86865, 2014, 'plos', 'Phosphorylation by PINK1 releases the UBL domain and initializes the conformational opening of the E3 ubiquitin ligase Parkin', 'Caulfield, Thomas R|Fiesel, Fabienne C|Moussaud-Lamodière, Elisabeth L|Dourado, Daniel F A R|Flores, Samuel C|Springer, Wolfdieter', 'Department of Neuroscience, Mayo Clinic Jacksonville, Florida, United States of America.|Department of Neuroscience, Mayo Clinic Jacksonville, Florida, United States of America.|Department of Neuroscience, Mayo Clinic Jacksonville, Florida, United States of America.|Department of Cell & Molecular Biology, Computational & Systems Biology, Uppsala University, Uppsala, Sweden.|Department of Cell & Molecular Biology, Computational & Systems Biology, Uppsala University, Uppsala, Sweden.|Department of Neuroscience, Mayo Clinic Jacksonville, Florida, United States of America, Mayo Graduate School, Neurobiology of Disease, Mayo Clinic, Jacksonville, Florida, United States of America.', 'United States|United States|United States|Sweden|Sweden|United States', 61, 'HeLa Cells|Humans|Models, Molecular|Molecular Dynamics Simulation|Parkinson Disease|Phosphorylation|Protein Binding|Protein Conformation|Protein Kinases|Protein Structure, Tertiary|Ubiquitin-Protein Ligases', 'Journal Article', '10.1371/journal.pcbi.1003935', '25375667', 'Loss-of-function mutations in PINK1 or PARKIN are the most common causes of autosomal recessive Parkinsons disease. Both gene products, the Ser/Thr kinase PINK1 and the E3 Ubiquitin ligase Parkin, functionally cooperate in a mitochondrial quality control pathway. Upon stress, PINK1 activates Parkin and enables its translocation to and ubiquitination of damaged mitochondria to facilitate their clearance from the cell. Though PINK1-dependent phosphorylation of Ser65 is an important initial step, the molecular mechanisms underlying the activation of Parkins enzymatic functions remain unclear. Using molecular modeling, we generated a complete structural model of human Parkin at all atom resolution. At steady state, the Ub ligase is maintained inactive in a closed, auto-inhibited conformation that results from intra-molecular interactions. Evidently, Parkin has to undergo major structural rearrangements in order to unleash its catalytic activity. As a spark, we have modeled PINK1-dependent Ser65 phosphorylation in silico and provide the first molecular dynamics simulation of Parkin conformations along a sequential unfolding pathway that could release its intertwined domains and enable its catalytic activity. We combined free (unbiased) molecular dynamics simulation, Monte Carlo algorithms, and minimal-biasing methods with cell-based high content imaging and biochemical assays. Phosphorylation of Ser65 results in widening of a newly defined cleft and dissociation of the regulatory N-terminal UBL domain. This motion propagates through further opening conformations that allow binding of an Ub-loaded E2 co-enzyme. Subsequent spatial reorientation of the catalytic centers of both enzymes might facilitate the transfer of the Ub moiety to charge Parkin. Our structure-function study provides the basis to elucidate regulatory mechanisms and activity of the neuroprotective Parkin. This may open up new avenues for the development of small molecule Parkin activators through targeted drug design. '),
(86866, 2014, 'plos', 'Estimating HIV-1 fitness characteristics from cross-sectional genotype data', 'Gopalakrishnan, Sathej|Montazeri, Hesam|Menz, Stephan|Beerenwinkel, Niko|Huisinga, Wilhelm', 'Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany, Graduate Research Training Program PharMetrX: Pharmacometrics & Computational Disease Modelling, Free University of Berlin and University of Potsdam, Berlin/Potsdam, Germany.|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland, SIB Swiss Institute of Bioinformatics, Basel, Switzerland.|Institute of Mathematics, University of Potsdam, Potsdam, Germany.|Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland, SIB Swiss Institute of Bioinformatics, Basel, Switzerland.|Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany, Institute of Mathematics, University of Potsdam, Potsdam, Germany.', 'Germany|Switzerland|Germany|Switzerland|Germany', 0, 'Anti-HIV Agents|Cross-Sectional Studies|Drug Resistance, Viral|Genetic Fitness|Genotype|HIV Infections|HIV-1|Humans|Indinavir|Models, Biological|Mutation|Treatment Outcome|Zidovudine', 'Journal Article', '10.1371/journal.pcbi.1003886', '25375675', 'Despite the success of highly active antiretroviral therapy (HAART) in the management of human immunodeficiency virus (HIV)-1 infection, virological failure due to drug resistance development remains a major challenge. Resistant mutants display reduced drug susceptibilities, but in the absence of drug, they generally have a lower fitness than the wild type, owing to a mutation-incurred cost. The interaction between these fitness costs and drug resistance dictates the appearance of mutants and influences viral suppression and therapeutic success. Assessing in vivo viral fitness is a challenging task and yet one that has significant clinical relevance. Here, we present a new computational modelling approach for estimating viral fitness that relies on common sparse cross-sectional clinical data by combining statistical approaches to learn drug-specific mutational pathways and resistance factors with viral dynamics models to represent the host-virus interaction and actions of drug mechanistically. We estimate in vivo fitness characteristics of mutant genotypes for two antiretroviral drugs, the reverse transcriptase inhibitor zidovudine (ZDV) and the protease inhibitor indinavir (IDV). Well-known features of HIV-1 fitness landscapes are recovered, both in the absence and presence of drugs. We quantify the complex interplay between fitness costs and resistance by computing selective advantages for different mutants. Our approach extends naturally to multiple drugs and we illustrate this by simulating a dual therapy with ZDV and IDV to assess therapy failure. The combined statistical and dynamical modelling approach may help in dissecting the effects of fitness costs and resistance with the ultimate aim of assisting the choice of salvage therapies after treatment failure. '),
(86867, 2014, 'plos', 'Statistical computations underlying the dynamics of memory updating', 'Gershman, Samuel J|Radulescu, Angela|Norman, Kenneth A|Niv, Yael', 'Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachussetts, United States of America.|Department of Psychology and Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey, United States of America.|Department of Psychology and Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey, United States of America.|Department of Psychology and Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey, United States of America.', 'United States|Jersey|Jersey|Jersey', 22, 'Computational Biology|Humans|Memory|Models, Neurological|Models, Statistical|Task Performance and Analysis', 'Journal Article', '10.1371/journal.pcbi.1003939', '25375816', 'Psychophysical and neurophysiological studies have suggested that memory is not simply a carbon copy of our experience: Memories are modified or new memories are formed depending on the dynamic structure of our experience, and specifically, on how gradually or abruptly the world changes. We present a statistical theory of memory formation in a dynamic environment, based on a nonparametric generalization of the switching Kalman filter. We show that this theory can qualitatively account for several psychophysical and neural phenomena, and present results of a new visual memory experiment aimed at testing the theory directly. Our experimental findings suggest that humans can use temporal discontinuities in the structure of the environment to determine when to form new memory traces. The statistical perspective we offer provides a coherent account of the conditions under which new experience is integrated into an old memory versus forming a new memory, and shows that memory formation depends on inferences about the underlying structure of our experience. '),
(86868, 2014, 'plos', 'Size does matter: an integrative in vivo-in silico approach for the treatment of critical size bone defects', 'Carlier, Aurélie|van Gastel, Nick|Geris, Liesbet|Carmeliet, Geert|Van Oosterwyck, Hans', 'Biomechanics Section, KU Leuven, Leuven, Belgium, Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium, Biomechanics Research Unit, University of Liège, Liège, Belgium.|Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium, Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.|Biomechanics Section, KU Leuven, Leuven, Belgium, Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium, Biomechanics Research Unit, University of Liège, Liège, Belgium.|Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium, Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.|Biomechanics Section, KU Leuven, Leuven, Belgium, Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium.', 'Belgium|Belgium|Belgium|Belgium|Belgium', 24, 'Animals|Cartilage|Cells, Cultured|Computer Simulation|Fracture Healing|Fractures, Bone|Male|Mice|Mice, Inbred C57BL|Models, Biological|Oxygen|Periosteum|Tissue Engineering|Tissue Scaffolds', 'Journal Article', '10.1371/journal.pcbi.1003888', '25375821', 'Although bone has a unique restorative capacity, i.e., it has the potential to heal scarlessly, the conditions for spontaneous bone healing are not always present, leading to a delayed union or a non-union. In this work, we use an integrative in vivo-in silico approach to investigate the occurrence of non-unions, as well as to design possible treatment strategies thereof. The gap size of the domain geometry of a previously published mathematical model was enlarged in order to study the complex interplay of blood vessel formation, oxygen supply, growth factors and cell proliferation on the final healing outcome in large bone defects. The multiscale oxygen model was not only able to capture the essential aspects of in vivo non-unions, it also assisted in understanding the underlying mechanisms of action, i.e., the delayed vascularization of the central callus region resulted in harsh hypoxic conditions, cell death and finally disrupted bone healing. Inspired by the importance of a timely vascularization, as well as by the limited biological potential of the fracture hematoma, the influence of the host environment on the bone healing process in critical size defects was explored further. Moreover, dependent on the host environment, several treatment strategies were designed and tested for effectiveness. A qualitative correspondence between the predicted outcomes of certain treatment strategies and experimental observations was obtained, clearly illustrating the models potential. In conclusion, the results of this study demonstrate that due to the complex non-linear dynamics of blood vessel formation, oxygen supply, growth factor production and cell proliferation and the interactions thereof with the host environment, an integrative in silico-in vivo approach is a crucial tool to further unravel the occurrence and treatments of challenging critical sized bone defects.'),
(86869, 2014, 'plos', 'Improved contact predictions using the recognition of protein like contact patterns', 'Skwark, Marcin J|Raimondi, Daniele|Michel, Mirco|Elofsson, Arne', 'Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden, Science for Life Laboratory, Stockholm University, Solna, Sweden, Department of Information and Computer Science, Aalto University, Aalto, Finland.|Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden, Science for Life Laboratory, Stockholm University, Solna, Sweden, Interuniversity Institute of Bioinformatics in Brussels, ULB-VUB, La Plaine Campus, Triomflaan, Brussels, Belgium.|Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden, Science for Life Laboratory, Stockholm University, Solna, Sweden.|Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden, Science for Life Laboratory, Stockholm University, Solna, Sweden.', 'Finland|Belgium|Sweden|Sweden', 96, 'Artificial Intelligence|Computational Biology|Databases, Protein|Pattern Recognition, Automated|Protein Conformation|Protein Structure, Secondary|Proteins|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1003889', '25375897', 'Given sufficient large protein families, and using a global statistical inference approach, it is possible to obtain sufficient accuracy in protein residue contact predictions to predict the structure of many proteins. However, these approaches do not consider the fact that the contacts in a protein are neither randomly, nor independently distributed, but actually follow precise rules governed by the structure of the protein and thus are interdependent. Here, we present PconsC2, a novel method that uses a deep learning approach to identify protein-like contact patterns to improve contact predictions. A substantial enhancement can be seen for all contacts independently on the number of aligned sequences, residue separation or secondary structure type, but is largest for xcexb2-sheet containing proteins. In addition to being superior to earlier methods based on statistical inferences, in comparison to state of the art methods using machine learning, PconsC2 is superior for families with more than 100 effective sequence homologs. The improved contact prediction enables improved structure prediction. '),
(86870, 2014, 'plos', 'Effect of global cardiac ischemia on human ventricular fibrillation: insights from a multi-scale mechanistic model of the human heart', 'Kazbanov, Ivan V|Clayton, Richard H|Nash, Martyn P|Bradley, Chris P|Paterson, David J|Hayward, Martin P|Taggart, Peter|Panfilov, Alexander V', 'Department of Physics and Astronomy, Ghent University, Ghent, Belgium.|INSIGNEO Institute for In-Silico Medicine, University of Sheffield, Sheffield, United Kingdom, Department of Computer Science, University of Sheffield, Sheffield, United Kingdom.|Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand, Department of Engineering Science, University of Auckland, Auckland, New Zealand.|Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand.|Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.|Departments of Cardiology and Cardiothoracic Surgery, University College Hospital, London, United Kingdom.|Departments of Cardiology and Cardiothoracic Surgery, University College Hospital, London, United Kingdom.|Department of Physics and Astronomy, Ghent University, Ghent, Belgium, Moscow Institute of Physics and Technology (State University), Dolgoprudny, Moscow Region, Russia.', 'Belgium|United Kingdom|New Zealand|New Zealand|United Kingdom|United Kingdom|United Kingdom|Belgium', 25, 'Computer Simulation|Heart|Humans|Hyperkalemia|Hypoxia|Imaging, Three-Dimensional|Models, Cardiovascular|Myocardial Ischemia|Myocardium|Ventricular Fibrillation', 'Journal Article', '10.1371/journal.pcbi.1003891', '25375999', 'Acute regional ischemia in the heart can lead to cardiac arrhythmias such as ventricular fibrillation (VF), which in turn compromise cardiac output and result in secondary global cardiac ischemia. The secondary ischemia may influence the underlying arrhythmia mechanism. A recent clinical study documents the effect of global cardiac ischaemia on the mechanisms of VF. During 150 seconds of global ischemia the dominant frequency of activation decreased, while after reperfusion it increased rapidly. At the same time the complexity of epicardial excitation, measured as the number of epicardical phase singularity points, remained approximately constant during ischemia. Here we perform numerical studies based on these clinical data and propose explanations for the observed dynamics of the period and complexity of activation patterns. In particular, we study the effects on ischemia in pseudo-1D and 2D cardiac tissue models as well as in an anatomically accurate model of human heart ventricles. We demonstrate that the fall of dominant frequency in VF during secondary ischemia can be explained by an increase in extracellular potassium, while the increase during reperfusion is consistent with washout of potassium and continued activation of the ATP-dependent potassium channels. We also suggest that memory effects are responsible for the observed complexity dynamics. In addition, we present unpublished clinical results of individual patient recordings and propose a way of estimating extracellular potassium and activation of ATP-dependent potassium channels from these measurements. '),
(86871, 2014, 'plos', 'Relationships between Th1 or Th2 iNKT cell activity and structures of CD1d-antigen complexes: meta-analysis of CD1d-glycolipids dynamics simulations', 'Laurent, Xavier|Renault, Nicolas|Farce, Amaury|Chavatte, Philippe|Hxc3xa9non, Eric', 'Intestinal Biotech Development, Facultxc3xa9 de Mxc3xa9decine, Lille, France, Laboratoire de Chimie Thxc3xa9rapeutique EA4481, Universitxc3xa9 Lille 2, Lille, France.|Laboratoire de Chimie Thxc3xa9rapeutique EA4481, Universitxc3xa9 Lille 2, Lille, France.|Laboratoire de Chimie Thxc3xa9rapeutique EA4481, Universitxc3xa9 Lille 2, Lille, France.|Laboratoire de Chimie Thxc3xa9rapeutique EA4481, Universitxc3xa9 Lille 2, Lille, France, Institut de Chimie Pharmaceutique Albert Lespagnol EA4481, Universitxc3xa9 Lille 2, Lille, France.|Institut de Chimie Molxc3xa9culaire de Reims UMR CNRS 7312, University of Reims Champagne-Ardenne, Reims, France.', 'France|France|France|France|France', 4, 'Animals|Antigens, CD1d|Glycolipids|Humans|Mice|Molecular Dynamics Simulation|Natural Killer T-Cells|Th1 Cells|Th2 Cells|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003902', '25376021', 'A number of potentially bioactive molecules can be found in nature. In particular, marine organisms are a valuable source of bioactive compounds. The activity of an xcexb1-galactosylceramide was first discovered in 1993 via screening of a Japanese marine sponge (Agelas mauritanius). Very rapidly, a synthetic glycololipid analogue of this natural molecule was discovered, called KRN7000. Associated with the CD1d protein, this xcexb1-galactosylceramide 1 (KRN7000) interacts with the T-cell antigen receptor to form a ternary complex that yields T helper (Th) 1 and Th2 responses with opposing effects. In our work, we carried out molecular dynamics simulations (11.5 xc2xb5s in total) involving eight different ligands (conducted in triplicate) in an effort to find out correlation at the molecular level, if any, between chemical modulation of 1 and the orientation of the known biological response, Th1 or Th2. Comparative investigations of human versus mouse and Th1 versus Th2 data have been carried out. A large set of analysis tools was employed including free energy landscapes. One major result is the identification of a specific conformational state of the sugar polar head, which could be correlated, in the present study, to the biological Th2 biased response. These theoretical tools provide a structural basis for predicting the very different dynamical behaviors of xcexb1-glycosphingolipids in CD1d and might aid in the future design of new analogues of 1. '),
(86872, 2014, 'plos', 'Global disease monitoring and forecasting with Wikipedia', 'Generous, Nicholas|Fairchild, Geoffrey|Deshpande, Alina|Del Valle, Sara Y|Priedhorsky, Reid', 'Defense Systems and Analysis Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Defense Systems and Analysis Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Defense Systems and Analysis Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Defense Systems and Analysis Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Defense Systems and Analysis Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.', 'Mexico|Mexico|Mexico|Mexico|Mexico', 86, 'Communicable Diseases|Databases, Factual|Disease Outbreaks|Environmental Monitoring|Forecasting|Global Health|Humans|Internet|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1003892', '25392913', 'Infectious disease is a leading threat to public health, economic stability, and other key social structures. Efforts to mitigate these impacts depend on accurate and timely monitoring to measure the risk and progress of disease. Traditional, biologically-focused monitoring techniques are accurate but costly and slow, in response, new techniques based on social internet data, such as social media and search queries, are emerging. These efforts are promising, but important challenges in the areas of scientific peer review, breadth of diseases and countries, and forecasting hamper their operational usefulness. We examine a freely available, open data source for this use: access logs from the online encyclopedia Wikipedia. Using linear models, language as a proxy for location, and a systematic yet simple article selection procedure, we tested 14 location-disease combinations and demonstrate that these data feasibly support an approach that overcomes these challenges. Specifically, our proof-of-concept yields models with r2 up to 0.92, forecasting value up to the 28 days tested, and several pairs of models similar enough to suggest that transferring models from one location to another without re-training is feasible. Based on these preliminary results, we close with a research agenda designed to overcome these challenges and produce a disease monitoring and forecasting system that is significantly more effective, robust, and globally comprehensive than the current state of the art.'),
(86873, 2014, 'plos', 'Characterization of K-complexes and slow wave activity in a neural mass model', 'Weigenand, Arne|Schellenberger Costa, Michael|Ngo, Hong-Viet Victor|Claussen, Jens Christian|Martinetz, Thomas', 'Institute for Neuro- and Bioinformatics, University of Lübeck, Lübeck, Germany, Graduate School for Computing in Medicine and Life Science, University of Lübeck, Lübeck, Germany.|Institute for Neuro- and Bioinformatics, University of Lübeck, Lübeck, Germany, Institute for Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany.|Institute for Neuro- and Bioinformatics, University of Lübeck, Lübeck, Germany, Graduate School for Computing in Medicine and Life Science, University of Lübeck, Lübeck, Germany, Institute for Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany.|Institute for Neuro- and Bioinformatics, University of Lübeck, Lübeck, Germany, Computational Systems Biology, Jacobs University Bremen, Bremen, Germany.|Institute for Neuro- and Bioinformatics, University of Lübeck, Lübeck, Germany, Graduate School for Computing in Medicine and Life Science, University of Lübeck, Lübeck, Germany.', 'Germany|Germany|Germany|Germany|Germany', 8, 'Cerebral Cortex|Computational Biology|Electroencephalography|Humans|Models, Neurological|Models, Statistical|Neurons|Sleep', 'Journal Article', '10.1371/journal.pcbi.1003923', '25392991', 'NREM sleep is characterized by two hallmarks, namely K-complexes (KCs) during sleep stage N2 and cortical slow oscillations (SOs) during sleep stage N3. While the underlying dynamics on the neuronal level is well known and can be easily measured, the resulting behavior on the macroscopic population level remains unclear. On the basis of an extended neural mass model of the cortex, we suggest a new interpretation of the mechanisms responsible for the generation of KCs and SOs. As the cortex transitions from wake to deep sleep, in our model it approaches an oscillatory regime via a Hopf bifurcation. Importantly, there is a canard phenomenon arising from a homoclinic bifurcation, whose orbit determines the shape of large amplitude SOs. A KC corresponds to a single excursion along the homoclinic orbit, while SOs are noise-driven oscillations around a stable focus. The model generates both time series and spectra that strikingly resemble real electroencephalogram data and points out possible differences between the different stages of natural sleep. '),
(86874, 2014, 'plos', 'A neural population model incorporating dopaminergic neurotransmission during complex voluntary behaviors', 'Fürtinger, Stefan|Zinn, Joel C|Simonyan, Kristina', 'Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America, Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.', 'United States|United States|United States', 5, 'Adult|Brain|Connectome|Dopamine|Female|Humans|Male|Middle Aged|Models, Neurological|Speech|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1003924', '25393005', 'Assessing brain activity during complex voluntary motor behaviors that require the recruitment of multiple neural sites is a field of active research. Our current knowledge is primarily based on human brain imaging studies that have clear limitations in terms of temporal and spatial resolution. We developed a physiologically informed non-linear multi-compartment stochastic neural model to simulate functional brain activity coupled with neurotransmitter release during complex voluntary behavior, such as speech production. Due to its state-dependent modulation of neural firing, dopaminergic neurotransmission plays a key role in the organization of functional brain circuits controlling speech and language and thus has been incorporated in our neural population model. A rigorous mathematical proof establishing existence and uniqueness of solutions to the proposed model as well as a computationally efficient strategy to numerically approximate these solutions are presented. Simulated brain activity during the resting state and sentence production was analyzed using functional network connectivity, and graph theoretical techniques were employed to highlight differences between the two conditions. We demonstrate that our model successfully reproduces characteristic changes seen in empirical data between the resting state and speech production, and dopaminergic neurotransmission evokes pronounced changes in modeled functional connectivity by acting on the underlying biological stochastic neural model. Specifically, model and data networks in both speech and rest conditions share task-specific network features: both the simulated and empirical functional connectivity networks show an increase in nodal influence and segregation in speech over the resting state. These commonalities confirm that dopamine is a key neuromodulator of the functional connectome of speech control. Based on reproducible characteristic aspects of empirical data, we suggest a number of extensions of the proposed methodology building upon the current model. '),
(86875, 2014, 'plos', 'Power laws from linear neuronal cable theory: power spectral densities of the soma potential, soma membrane current and single-neuron contribution to the EEG', 'Pettersen, Klas H|Lindxc3xa9n, Henrik|Tetzlaff, Tom|Einevoll, Gaute T', 'Dept. of Mathematical Sciences and Technology, Norwegian University of Life Sciences, xc3x85s, Norway, Letten Centre and GliaLab, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway, Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway.|Dept. of Mathematical Sciences and Technology, Norwegian University of Life Sciences, xc3x85s, Norway, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark, Dept. of Computational Biology, School of Computer Science and Communication, Royal Institute of Technology (KTH), Stockholm, Sweden.|Dept. of Mathematical Sciences and Technology, Norwegian University of Life Sciences, xc3x85s, Norway, Inst. of Neuroscience and Medicine (INM-6), Computational and Systems Neuroscience & Inst. for Advanced Simulation (IAS-6), Theoretical Neuroscience, Jxc3xbclich Research Centre and JARA, Jxc3xbclich, Germany.|Dept. of Mathematical Sciences and Technology, Norwegian University of Life Sciences, xc3x85s, Norway, Dept. of Physics, University of Oslo, Oslo, Norway.', 'Norway|Denmark|Germany|Norway', 19, 'Computational Biology|Computer Simulation|Electroencephalography|Membrane Potentials|Models, Neurological|Neurons', 'Journal Article', '10.1371/journal.pcbi.1003928', '25393030', 'Power laws, that is, power spectral densities (PSDs) exhibiting 1/f(xcexb1) behavior for large frequencies f, have been observed both in microscopic (neural membrane potentials and currents) and macroscopic (electroencephalography, EEG) recordings. While complex network behavior has been suggested to be at the root of this phenomenon, we here demonstrate a possible origin of such power laws in the biophysical properties of single neurons described by the standard cable equation. Taking advantage of the analytical tractability of the so called ball and stick neuron model, we derive general expressions for the PSD transfer functions for a set of measures of neuronal activity: the soma membrane current, the current-dipole moment (corresponding to the single-neuron EEG contribution), and the soma membrane potential. These PSD transfer functions relate the PSDs of the respective measurements to the PSDs of the noisy input currents. With homogeneously distributed input currents across the neuronal membrane we find that all PSD transfer functions express asymptotic high-frequency 1/f(xcexb1) power laws with power-law exponents analytically identified as xcexb1xe2x88x9e(I) = 1/2 for the soma membrane current, xcexb1xe2x88x9e(p) = 3/2 for the current-dipole moment, and xcexb1xe2x88x9e(V) = 2 for the soma membrane potential. Comparison with available data suggests that the apparent power laws observed in the high-frequency end of the PSD spectra may stem from uncorrelated current sources which are homogeneously distributed across the neural membranes and themselves exhibit pink (1/f) noise distributions. While the PSD noise spectra at low frequencies may be dominated by synaptic noise, our findings suggest that the high-frequency power laws may originate in noise from intrinsic ion channels. The significance of this finding goes beyond neuroscience as it demonstrates how 1/f(xcexb1) power laws with a wide range of values for the power-law exponent xcexb1 may arise from a simple, linear partial differential equation.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86876, 2014, 'plos', 'Multi-level modeling of light-induced stomatal opening offers new insights into its regulation by drought', 'Sun, Zhongyao|Jin, Xiaofen|Albert, Réka|Assmann, Sarah M', 'Department of Physics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Department of Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Department of Physics, The Pennsylvania State University, University Park, Pennsylvania, United States of America, Department of Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Department of Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America.', 'United States|United States|United States|United States', 39, 'Abscisic Acid|Computational Biology|Computer Simulation|Droughts|Light|Plant Growth Regulators|Plant Physiological Phenomena|Plant Stomata|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1003930', '25393147', 'Plant guard cells gate CO2 uptake and transpirational water loss through stomatal pores. As a result of decades of experimental investigation, there is an abundance of information on the involvement of specific proteins and secondary messengers in the regulation of stomatal movements and on the pairwise relationships between guard cell components. We constructed a multi-level dynamic model of guard cell signal transduction during light-induced stomatal opening and of the effect of the plant hormone abscisic acid (ABA) on this process. The model integrates into a coherent network the direct and indirect biological evidence regarding the regulation of seventy components implicated in stomatal opening. Analysis of this signal transduction network identified robust cross-talk between blue light and ABA, in which [Ca2+]c plays a key role, and indicated an absence of cross-talk between red light and ABA. The dynamic model captured more than 10(31) distinct states for the system and yielded outcomes that were in qualitative agreement with a wide variety of previous experimental results. We obtained novel model predictions by simulating single component knockout phenotypes. We found that under white light or blue light, over 60%, and under red light, over 90% of all simulated knockouts had similar opening responses as wild type, showing that the system is robust against single node loss. The model revealed an open question concerning the effect of ABA on red light-induced stomatal opening. We experimentally showed that ABA is able to inhibit red light-induced stomatal opening, and our model offers possible hypotheses for the underlying mechanism, which point to potential future experiments. Our modelling methodology combines simplicity and flexibility with dynamic richness, making it well suited for a wide class of biological regulatory systems.'),
(86877, 2014, 'plos', 'Pattern of tick aggregation on mice: larger than expected distribution tail enhances the spread of tick-borne pathogens', 'Ferreri, Luca|Giacobini, Mario|Bajardi, Paolo|Bertolotti, Luigi|Bolzoni, Luca|Tagliapietra, Valentina|Rizzoli, Annapaola|Rosà, Roberto', 'Computational Epidemiology Group, Department of Veterinary Sciences, University of Torino, Torino, Italy, Applied Research on Computational Complex Systems Group, Department of Computer Science, University of Torino, Torino, Italy.|Computational Epidemiology Group, Department of Veterinary Sciences, University of Torino, Torino, Italy, Applied Research on Computational Complex Systems Group, Department of Computer Science, University of Torino, Torino, Italy, Complex Systems Unit, Molecular Biotechnology Centre, University of Torino, Torino, Italy.|Computational Epidemiology Group, Department of Veterinary Sciences, University of Torino, Torino, Italy, Applied Research on Computational Complex Systems Group, Department of Computer Science, University of Torino, Torino, Italy.|Computational Epidemiology Group, Department of Veterinary Sciences, University of Torino, Torino, Italy.|Istituto Zooprofilattico Sperimentale della Lombardia e dellEmilia Romagna, Parma, Italy, Dipartimento Biodiversità ed Ecologia Molecolare, Centro Ricerca e Innovazione, Fondazione Edmund Mach, San Michele allAdige, Italy.|Dipartimento Biodiversità ed Ecologia Molecolare, Centro Ricerca e Innovazione, Fondazione Edmund Mach, San Michele allAdige, Italy.|Dipartimento Biodiversità ed Ecologia Molecolare, Centro Ricerca e Innovazione, Fondazione Edmund Mach, San Michele allAdige, Italy.|Dipartimento Biodiversità ed Ecologia Molecolare, Centro Ricerca e Innovazione, Fondazione Edmund Mach, San Michele allAdige, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy|Italy|Italy', 11, 'Animals|Computational Biology|Disease Reservoirs|Female|Male|Mice|Models, Biological|Seasons|Tick Infestations|Ticks', 'Journal Article', '10.1371/journal.pcbi.1003931', '25393293', 'The spread of tick-borne pathogens represents an important threat to human and animal health in many parts of Eurasia. Here, we analysed a 9-year time series of Ixodes ricinus ticks feeding on Apodemus flavicollis mice (main reservoir-competent host for tick-borne encephalitis, TBE) sampled in Trentino (Northern Italy). The tail of the distribution of the number of ticks per host was fitted by three theoretical distributions: Negative Binomial (NB), Poisson-LogNormal (PoiLN), and Power-Law (PL). The fit with theoretical distributions indicated that the tail of the tick infestation pattern on mice is better described by the PL distribution. Moreover, we found that the tail of the distribution significantly changes with seasonal variations in host abundance. In order to investigate the effect of different tails of tick distribution on the invasion of a non-systemically transmitted pathogen, we simulated the transmission of a TBE-like virus between susceptible and infective ticks using a stochastic model. Model simulations indicated different outcomes of disease spreading when considering different distribution laws of ticks among hosts. Specifically, we found that the epidemic threshold and the prevalence equilibria obtained in epidemiological simulations with PL distribution are a good approximation of those observed in simulations feed by the empirical distribution. Moreover, we also found that the epidemic threshold for disease invasion was lower when considering the seasonal variation of tick aggregation. '),
(86878, 2014, 'plos', 'Inferring viral dynamics in chronically HCV infected patients from the spatial distribution of infected hepatocytes', 'Graw, Frederik|Balagopal, Ashwin|Kandathil, Abraham J|Ray, Stuart C|Thomas, David L|Ribeiro, Ruy M|Perelson, Alan S', 'Los Alamos National Laboratory, Theoretical Biology and Biophysics, Los Alamos, New Mexico, United States of America, Center for Modeling and Simulation in the Biosciences, Heidelberg University, Heidelberg, Germany.|Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.|Los Alamos National Laboratory, Theoretical Biology and Biophysics, Los Alamos, New Mexico, United States of America.|Los Alamos National Laboratory, Theoretical Biology and Biophysics, Los Alamos, New Mexico, United States of America.', 'Germany|United States|United States|United States|United States|Mexico|Mexico', 27, 'Adult|Algorithms|Computational Biology|Female|Hepacivirus|Hepatitis C|Hepatocytes|Host-Pathogen Interactions|Humans|Laser Capture Microdissection|Liver|Male|Middle Aged|Models, Biological|Single-Cell Analysis', 'Journal Article', '10.1371/journal.pcbi.1003934', '25393308', 'Chronic liver infection by hepatitis C virus (HCV) is a major public health concern. Despite partly successful treatment options, several aspects of intrahepatic HCV infection dynamics are still poorly understood, including the preferred mode of viral propagation, as well as the proportion of infected hepatocytes. Answers to these questions have important implications for the development of therapeutic interventions. In this study, we present methods to analyze the spatial distribution of infected hepatocytes obtained by single cell laser capture microdissection from liver biopsy samples of patients chronically infected with HCV. By characterizing the internal structure of clusters of infected cells, we are able to evaluate hypotheses about intrahepatic infection dynamics. We found that individual clusters on biopsy samples range in size from 4-50 infected cells. In addition, the HCV RNA content in a cluster declines from the cell that presumably founded the cluster to cells at the maximal cluster extension. These observations support the idea that HCV infection in the liver is seeded randomly (e.g. from the blood) and then spreads locally. Assuming that the amount of intracellular HCV RNA is a proxy for how long a cell has been infected, we estimate based on models of intracellular HCV RNA replication and accumulation that cells in clusters have been infected on average for less than a week. Further, we do not find a relationship between the cluster size and the estimated cluster expansion time. Our method represents a novel approach to make inferences about infection dynamics in solid tissues from static spatial data.'),
(86879, 2014, 'plos', 'In the multi-domain protein adenylate kinase, domain insertion facilitates cooperative folding while accommodating function at domain interfaces', 'Giri Rao, V V Hemanth|Gosavi, Shachi', 'National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India.|National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India.', 'India|India', 20, 'Adenylate Kinase|Computational Biology|Escherichia coli Proteins|Models, Molecular|Mutation|Protein Folding|Protein Structure, Tertiary|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003938', '25393408', 'Having multiple domains in proteins can lead to partial folding and increased aggregation. Folding cooperativity, the all or nothing folding of a protein, can reduce this aggregation propensity. In agreement with bulk experiments, a coarse-grained structure-based model of the three-domain protein, E. coli Adenylate kinase (AKE), folds cooperatively. Domain interfaces have previously been implicated in the cooperative folding of multi-domain proteins. To understand their role in AKE folding, we computationally create mutants with deleted inter-domain interfaces and simulate their folding. We find that inter-domain interfaces play a minor role in the folding cooperativity of AKE. On further analysis, we find that unlike other multi-domain proteins whose folding has been studied, the domains of AKE are not singly-linked. Two of its domains have two linkers to the third one, i.e., they are inserted into the third one. We use circular permutation to modify AKE chain-connectivity and convert inserted-domains into singly-linked domains. We find that domain insertion in AKE achieves the following: (1) It facilitates folding cooperativity even when domains have different stabilities. Insertion constrains the N- and C-termini of inserted domains and stabilizes their folded states. Therefore, domains that perform conformational transitions can be smaller with fewer stabilizing interactions. (2) Inter-domain interactions are not needed to promote folding cooperativity and can be tuned for function. In AKE, these interactions help promote conformational dynamics limited catalysis. Finally, using structural bioinformatics, we suggest that domain insertion may also facilitate the cooperative folding of other multi-domain proteins. '),
(86880, 2014, 'plos', 'Spinal mechanisms may provide a combination of intermittent and continuous control of human posture: predictions from a biologically based neuromusculoskeletal model', 'Elias, Leonardo Abdala|Watanabe, Renato Naville|Kohn, André Fabio', 'Biomedical Engineering Laboratory, Escola Politécnica, University of Sao Paulo, Sao Paulo, Brazil.|Biomedical Engineering Laboratory, Escola Politécnica, University of Sao Paulo, Sao Paulo, Brazil.|Biomedical Engineering Laboratory, Escola Politécnica, University of Sao Paulo, Sao Paulo, Brazil.', 'Brazil|Brazil|Brazil', 38, 'Adult|Computational Biology|Feedback, Physiological|Humans|Models, Biological|Motor Neurons|Musculoskeletal Physiological Phenomena|Posture|Reproducibility of Results|Spinal Cord|Torque|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1003944', '25393548', 'Several models have been employed to study human postural control during upright quiet stance. Most have adopted an inverted pendulum approximation to the standing human and theoretical models to account for the neural feedback necessary to keep balance. The present study adds to the previous efforts in focusing more closely on modelling the physiological mechanisms of important elements associated with the control of human posture. This paper studies neuromuscular mechanisms behind upright stance control by means of a biologically based large-scale neuromusculoskeletal (NMS) model. It encompasses: i) conductance-based spinal neuron models (motor neurons and interneurons), ii) muscle proprioceptor models (spindle and Golgi tendon organ) providing sensory afferent feedback, iii) Hill-type muscle models of the leg plantar and dorsiflexors, and iv) an inverted pendulum model for the body biomechanics during upright stance. The motor neuron pools are driven by stochastic spike trains. Simulation results showed that the neuromechanical outputs generated by the NMS model resemble experimental data from subjects standing on a stable surface. Interesting findings were that: i) an intermittent pattern of muscle activation emerged from this posture control model for two of the leg muscles (Medial and Lateral Gastrocnemius), and ii) the Soleus muscle was mostly activated in a continuous manner. These results suggest that the spinal cord anatomy and neurophysiology (e.g., motor unit types, synaptic connectivities, ordered recruitment), along with the modulation of afferent activity, may account for the mixture of intermittent and continuous control that has been a subject of debate in recent studies on postural control. Another finding was the occurrence of the so-called paradoxical behaviour of muscle fibre lengths as a function of postural sway. The simulations confirmed previous conjectures that reciprocal inhibition is possibly contributing to this effect, but on the other hand showed that this effect may arise without any anticipatory neural control mechanism. '),
(86881, 2014, 'plos', 'Evolution of all-or-none strategies in repeated public goods dilemmas', 'Pinheiro, Flávio L|Vasconcelos, Vítor V|Santos, Francisco C|Pacheco, Jorge M', 'Centro de Biologia Molecular e Ambiental da Universidade do Minho, Braga, Portugal, INESC-ID & Instituto Superior Técnico, Universidade de Lisboa, Taguspark, Porto Salvo, Portugal, Centro de Física da Universidade do Minho, Braga, Portugal, ATP-group, CMAF, Instituto para a Investigação Interdisciplinar, Lisboa, Portugal.|Centro de Biologia Molecular e Ambiental da Universidade do Minho, Braga, Portugal, INESC-ID & Instituto Superior Técnico, Universidade de Lisboa, Taguspark, Porto Salvo, Portugal, Centro de Física da Universidade do Minho, Braga, Portugal, ATP-group, CMAF, Instituto para a Investigação Interdisciplinar, Lisboa, Portugal.|INESC-ID & Instituto Superior Técnico, Universidade de Lisboa, Taguspark, Porto Salvo, Portugal, ATP-group, CMAF, Instituto para a Investigação Interdisciplinar, Lisboa, Portugal.|Centro de Biologia Molecular e Ambiental da Universidade do Minho, Braga, Portugal, ATP-group, CMAF, Instituto para a Investigação Interdisciplinar, Lisboa, Portugal, Departamento de Matemática e Aplicações da Universidade do Minho, Braga, Portugal.', 'Portugal|Portugal|Portugal|Portugal', 27, 'Computer Simulation|Cooperative Behavior|Game Theory|Group Processes|Humans|Models, Psychological|Models, Statistical', 'Journal Article', '10.1371/journal.pcbi.1003945', '25393661', 'Many problems of cooperation involve repeated interactions among the same groups of individuals. When collective action is at stake, groups often engage in Public Goods Games (PGG), where individuals contribute (or not) to a common pool, subsequently sharing the resources. Such scenarios of repeated group interactions materialize situations in which direct reciprocation to groups may be at work. Here we study direct group reciprocity considering the complete set of reactive strategies, where individuals behave conditionally on what they observed in the previous round. We study both analytically and by computer simulations the evolutionary dynamics encompassing this extensive strategy space, witnessing the emergence of a surprisingly simple strategy that we call All-Or-None (AoN). AoN consists in cooperating only after a round of unanimous group behavior (cooperation or defection), and proves robust in the presence of errors, thus fostering cooperation in a wide range of group sizes. The principles encapsulated in this strategy share a level of complexity reminiscent of that found already in 2-person games under direct and indirect reciprocity, reducing, in fact, to the well-known Win-Stay-Lose-Shift strategy in the limit of the repeated 2-person Prisoners Dilemma. '),
(86882, 2014, 'plos', 'Dynamics on networks: the role of local dynamics and global networks on the emergence of hypersynchronous neural activity', 'Schmidt, Helmut|Petkov, George|Richardson, Mark P|Terry, John R', 'College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, United Kingdom.|College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, United Kingdom.|Institute of Psychiatry, Kings College London, London, United Kingdom.|College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 39, 'Adult|Brain|Brain Mapping|Case-Control Studies|Computational Biology|Electroencephalography|Epilepsy, Generalized|Female|Humans|Magnetic Resonance Imaging|Male|Models, Neurological|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.1003947', '25393751', 'Graph theory has evolved into a useful tool for studying complex brain networks inferred from a variety of measures of neural activity, including fMRI, DTI, MEG and EEG. In the study of neurological disorders, recent work has discovered differences in the structure of graphs inferred from patient and control cohorts. However, most of these studies pursue a purely observational approach, identifying correlations between properties of graphs and the cohort which they describe, without consideration of the underlying mechanisms. To move beyond this necessitates the development of computational modeling approaches to appropriately interpret network interactions and the alterations in brain dynamics they permit, which in the field of complexity sciences is known as dynamics on networks. In this study we describe the development and application of this framework using modular networks of Kuramoto oscillators. We use this framework to understand functional networks inferred from resting state EEG recordings of a cohort of 35 adults with heterogeneous idiopathic generalized epilepsies and 40 healthy adult controls. Taking emergent synchrony across the global network as a proxy for seizures, our study finds that the critical strength of coupling required to synchronize the global network is significantly decreased for the epilepsy cohort for functional networks inferred from both theta (3-6 Hz) and low-alpha (6-9 Hz) bands. We further identify left frontal regions as a potential driver of seizure activity within these networks. We also explore the ability of our method to identify individuals with epilepsy, observing up to 80% predictive power through use of receiver operating characteristic analysis. Collectively these findings demonstrate that a computer model based analysis of routine clinical EEG provides significant additional information beyond standard clinical interpretation, which should ultimately enable a more appropriate mechanistic stratification of people with epilepsy leading to improved diagnostics and therapeutics.'),
(86883, 2014, 'plos', 'A statistical method of identifying interactions in neuron-glia systems based on functional multicell Ca2+ imaging', 'Nakae, Ken|Ikegaya, Yuji|Ishikawa, Tomoe|Oba, Shigeyuki|Urakubo, Hidetoshi|Koyama, Masanori|Ishii, Shin', 'Integrated Systems Biology Laboratory, Graduate School of Informatics, Kyoto University, Sakyo-ku, Kyoto, Japan.|Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan, Center for Information and Neural Networks, Suita City, Osaka, Japan.|Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.|Integrated Systems Biology Laboratory, Graduate School of Informatics, Kyoto University, Sakyo-ku, Kyoto, Japan.|Integrated Systems Biology Laboratory, Graduate School of Informatics, Kyoto University, Sakyo-ku, Kyoto, Japan.|Integrated Systems Biology Laboratory, Graduate School of Informatics, Kyoto University, Sakyo-ku, Kyoto, Japan.|Integrated Systems Biology Laboratory, Graduate School of Informatics, Kyoto University, Sakyo-ku, Kyoto, Japan.', 'Japan|Japan|Japan|Japan|Japan|Japan|Japan', 5, 'Animals|CA3 Region, Hippocampal|Calcium|Computational Biology|Models, Neurological|Models, Statistical|Neuroglia|Neurons|Rats|Rats, Wistar', 'Journal Article', '10.1371/journal.pcbi.1003949', '25393874', 'Crosstalk between neurons and glia may constitute a significant part of information processing in the brain. We present a novel method of statistically identifying interactions in a neuron-glia network. We attempted to identify neuron-glia interactions from neuronal and glial activities via maximum-a-posteriori (MAP)-based parameter estimation by developing a generalized linear model (GLM) of a neuron-glia network. The interactions in our interest included functional connectivity and response functions. We evaluated the cross-validated likelihood of GLMs that resulted from the addition or removal of connections to confirm the existence of specific neuron-to-glia or glia-to-neuron connections. We only accepted addition or removal when the modification improved the cross-validated likelihood. We applied the method to a high-throughput, multicellular in vitro Ca2+ imaging dataset obtained from the CA3 region of a rat hippocampus, and then evaluated the reliability of connectivity estimates using a statistical test based on a surrogate method. Our findings based on the estimated connectivity were in good agreement with currently available physiological knowledge, suggesting our method can elucidate undiscovered functions of neuron-glia systems. '),
(86884, 2014, 'plos', 'Teaching bioinformatics in concert', 'Goodman, Anya L|Dekhtyar, Alex', 'Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California, United States of America.|Department of Computer Science, California Polytechnic State University, San Luis Obispo, California, United States of America.', 'United States|United States', 11, 'Biology|Computational Biology|Cooperative Behavior|Humans|Software|Students', 'Journal Article', '10.1371/journal.pcbi.1003896', '25411792', 'Can biology students without programming skills solve problems that require computational solutions? They can if they learn to cooperate effectively with computer science students. The goal of the in-concert teaching approach is to introduce biology students to computational thinking by engaging them in collaborative projects structured around the software development process. Our approach emphasizes development of interdisciplinary communication and collaboration skills for both life science and computer science students. '),
(86885, 2014, 'plos', 'Computational thinking in life science education', 'Rubinstein, Amir|Chor, Benny', 'School of Computer Science, Tel-Aviv University, Tel Aviv, Israel.|School of Computer Science, Tel-Aviv University, Tel Aviv, Israel.', 'Israel|Israel', 0, 'Algorithms|Biological Science Disciplines|Computational Biology|Humans|Information Science|Software', 'Journal Article', '10.1371/journal.pcbi.1003897', '25411839', 'We join the increasing call to take computational education of life science students a step further, beyond teaching mere programming and employing existing software tools. We describe a new course, focusing on enriching the curriculum of life science students with abstract, algorithmic, and logical thinking, and exposing them to the computational culture. The design, structure, and content of our course are influenced by recent efforts in this area, collaborations with life scientists, and our own instructional experience. Specifically, we suggest that an effective course of this nature should: (1) devote time to explicitly reflect upon computational thinking processes, resisting the temptation to drift to purely practical instruction, (2) focus on discrete notions, rather than on continuous ones, and (3) have basic programming as a prerequisite, so students need not be preoccupied with elementary programming issues. We strongly recommend that the mere use of existing bioinformatics tools and packages should not replace hands-on programming. Yet, we suggest that programming will mostly serve as a means to practice computational thinking processes. This paper deals with the challenges and considerations of such computational education for life science students. It also describes a concrete implementation of the course and encourages its use by others. '),
(86886, 2014, 'plos', 'Ten simple rules to achieve conference speaker gender balance', 'Martin, Jennifer L', 'Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.', 'Australia', 52, 'Congresses as Topic|Databases, Factual|Female|Humans|Male|Policy|Sex Distribution|Sexism', 'Editorial', '10.1371/journal.pcbi.1003903', '25411977', '-'),
(86887, 2014, 'plos', 'BiomeNet: a Bayesian model for inference of metabolic divergence among microbial communities', 'Shafiei, Mahdi|Dunn, Katherine A|Chipman, Hugh|Gu, Hong|Bielawski, Joseph P', 'Department of Mathematics & Statistics, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Biology, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Mathematics & Statistics, Acadia University, Wolfville, Nova Scotia, Canada.|Department of Mathematics & Statistics, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Mathematics & Statistics, Dalhousie University, Halifax, Nova Scotia, Canada, Department of Biology, Dalhousie University, Halifax, Nova Scotia, Canada.', 'Canada|Canada|Canada|Canada|Canada', 0, 'Algorithms|Animals|Bayes Theorem|Carnivory|Computational Biology|Herbivory|Humans|Inflammatory Bowel Diseases|Metagenome|Microbiota|Models, Biological|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1003918', '25412107', 'Metagenomics yields enormous numbers of microbial sequences that can be assigned a metabolic function. Using such data to infer community-level metabolic divergence is hindered by the lack of a suitable statistical framework. Here, we describe a novel hierarchical Bayesian model, called BiomeNet (Bayesian inference of metabolic networks), for inferring differential prevalence of metabolic subnetworks among microbial communities. To infer the structure of community-level metabolic interactions, BiomeNet applies a mixed-membership modelling framework to enzyme abundance information. The basic idea is that the mixture components of the model (metabolic reactions, subnetworks, and networks) are shared across all groups (microbiome samples), but the mixture proportions vary from group to group. Through this framework, the model can capture nested structures within the data. BiomeNet is unique in modeling each metagenome sample as a mixture of complex metabolic systems (metabosystems). The metabosystems are composed of mixtures of tightly connected metabolic subnetworks. BiomeNet differs from other unsupervised methods by allowing researchers to discriminate groups of samples through the metabolic patterns it discovers in the data, and by providing a framework for interpreting them. We describe a collapsed Gibbs sampler for inference of the mixture weights under BiomeNet, and we use simulation to validate the inference algorithm. Application of BiomeNet to human gut metagenomes revealed a metabosystem with greater prevalence among inflammatory bowel disease (IBD) patients. Based on the discriminatory subnetworks for this metabosystem, we inferred that the community is likely to be closely associated with the human gut epithelium, resistant to dietary interventions, and interfere with human uptake of an antioxidant connected to IBD. Because this metabosystem has a greater capacity to exploit host-associated glycans, we speculate that IBD-associated communities might arise from opportunist growth of bacteria that can circumvent the hosts nutrient-based mechanism for bacterial partner selection. '),
(86888, 2014, 'plos', 'Epidemic spreading model to characterize misfolded proteins propagation in aging and associated neurodegenerative disorders', 'Iturria-Medina, Yasser|Sotero, Roberto C|Toussaint, Paule J|Evans, Alan C|Alzheimers Disease Neuroimaging Initiative', 'Montreal Neurological Institute, Montreal, Quebec, Canada.|Montreal Neurological Institute, Montreal, Quebec, Canada.|Montreal Neurological Institute, Montreal, Quebec, Canada.|Montreal Neurological Institute, Montreal, Quebec, Canada.|Montreal Neurological Institute, Montreal, Quebec, Canada.', 'Canada|Canada|Canada|Canada|Canada', 62, 'Adolescent|Adult|Aging|Amyloid beta-Peptides|Brain|Epidemics|Female|Humans|Male|Middle Aged|Models, Molecular|Neurodegenerative Diseases|Prions|Protein Folding|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1003956', '25412207', 'Misfolded proteins (MP) are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-xc3x9f (Axc3x9f) and tau proteins are two neuropathogenic hallmarks of Alzheimers disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM) for MP dynamics that considers propagation-like interactions between MP agents and the brains clearance response across the structural connectome. The ESM reproduces advanced Axc3x9f deposition patterns in the human brain (explaining 46xe2x88xbc56% of the variance in regional Axc3x9f loads, in 733 subjects from the ADNI database). Furthermore, this model strongly supports a) the leading role of Axc3x9f clearance deficiency and early Axc3x9f onset age during Alzheimers disease progression, b) that effective anatomical distance from Axc3x9f outbreak region explains regional Axc3x9f arrival time and Axc3x9f deposition likelihood, c) the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Axc3x9f propagation, and d) the modulatory impact of Axc3x9f propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Axc3x9f pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders. '),
(86889, 2014, 'plos', 'Estimating relative changes of metabolic fluxes', 'Huang, Lei|Kim, Dongsung|Liu, Xiaojing|Myers, Christopher R|Locasale, Jason W', 'Graduate Field of Computational Biology, Cornell University, Ithaca, New York, United States of America.|Graduate Field of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York, United States of America.|Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States of America.|Laboratory of Atomic and Solid State Physics, and Institute of Biotechnology, Cornell University, Ithaca, New York, United States of America, Field of Computational Biology and Medicine, Cornell University, Ithaca, New York, United States of America.|Graduate Field of Computational Biology, Cornell University, Ithaca, New York, United States of America, Graduate Field of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York, United States of America, Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States of America, Field of Computational Biology and Medicine, Cornell University, Ithaca, New York, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Carbon Isotopes|Glucose|Glycolysis|Kinetics|Metabolic Flux Analysis|Metabolome|Models, Biological|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1003958', '25412287', 'Fluxes are the central trait of metabolism and Kinetic Flux Profiling (KFP) is an effective method of measuring them. To generalize its applicability, we present an extension of the method that estimates the relative changes of fluxes using only relative quantitation of 13C-labeled metabolites. Such features are directly tailored to the more common experiment that performs only relative quantitation and compares fluxes between two conditions. We call our extension rKFP. Moreover, we examine the effects of common missing data and common modeling assumptions on (r)KFP, and provide practical suggestions. We also investigate the selection of measuring times for (r)KFP and provide a simple recipe. We then apply rKFP to 13C-labeled glucose time series data collected from cells under normal and glucose-deprived conditions, estimating the relative flux changes of glycolysis and its branching pathways. We identify an adaptive response in which de novo serine biosynthesis is compromised to maintain the glycolytic flux backbone. Together, these results greatly expand the capabilities of KFP and are suitable for broad biological applications. '),
(86890, 2014, 'plos', 'Impact of dimensionality and network disruption on microrheology of cancer cells in 3D environments', 'Mak, Michael|Kamm, Roger D|Zaman, Muhammad H', 'Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America.|Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America.', 'United States|United States|United States', 21, 'Cell Culture Techniques|Cell Line, Tumor|Computer Simulation|Cytoskeleton|Equipment Design|Humans|Intracellular Space|Microfluidics|Tumor Microenvironment', 'Journal Article', '10.1371/journal.pcbi.1003959', '25412385', 'Dimensionality is a fundamental component that can have profound implications on the characteristics of physical systems. In cell biology, however, the majority of studies on cell physical properties, from rheology to force generation to migration, have been performed on 2D substrates, and it is not clear how a more realistic 3D environment influences cell properties. Here, we develop an integrated approach and demonstrate the combination of mitochondria-tracking microrheology, microfluidics, and Brownian dynamics simulations to explore the impact of dimensionality on intracellular mechanics and on the effects of intracellular disruption. Additionally, we consider both passive thermal and active motor-driven processes within the cell and demonstrate through modeling how active internal fluctuations are modulated via dimensionality. Our results demonstrate that metastatic breast cancer cells (MDA-MB-231) exhibit more solid-like internal motions in 3D compared to 2D, and actin network disruption via Cytochalasin D has a more pronounced effect on internal cell fluctuations in 2D. Our computational results and modeling show that motor-induced active stress fluctuations are enhanced in 2D, leading to increased local intracellular particle fluctuations and apparent fluid-like behavior. '),
(86891, 2014, 'plos', 'High-fidelity coding with correlated neurons', 'da Silveira, Rava Azeredo|Berry, Michael J', 'Department of Physics, Ecole Normale Supérieure, Paris, France, Laboratoire de Physique Statistique, Centre National de la Recherche Scientifique, Université Pierre et Marie Curie, Université Denis Diderot, Paris, France, Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey, United States of America.|Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey, United States of America, Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America.', 'France|Jersey', 21, 'Action Potentials|Computational Biology|Models, Neurological|Neurons', 'Journal Article', '10.1371/journal.pcbi.1003970', '25412463', 'Positive correlations in the activity of neurons are widely observed in the brain. Previous studies have shown these correlations to be detrimental to the fidelity of population codes, or at best marginally favorable compared to independent codes. Here, we show that positive correlations can enhance coding performance by astronomical factors. Specifically, the probability of discrimination error can be suppressed by many orders of magnitude. Likewise, the number of stimuli encoded--the capacity--can be enhanced more than tenfold. These effects do not necessitate unrealistic correlation values, and can occur for populations with a few tens of neurons. We further show that both effects benefit from heterogeneity commonly seen in population activity. Error suppression and capacity enhancement rest upon a pattern of correlation. Tuning of one or several effective parameters can yield a limit of perfect coding: the corresponding pattern of positive correlation leads to a lock-in of response probabilities that eliminates variability in the subspace relevant for stimulus discrimination. We discuss the nature of this pattern and we suggest experimental tests to identify it.'),
(86892, 2014, 'plos', 'How anacetrapib inhibits the activity of the cholesteryl ester transfer protein? Perspective through atomistic simulations', 'Äijänen, Tarja|Koivuniemi, Artturi|Javanainen, Matti|Rissanen, Sami|Rog, Tomasz|Vattulainen, Ilpo', 'Department of Physics, Tampere University of Technology, Tampere, Finland.|VTT Technical Research Center of Finland, Espoo, Finland.|Department of Physics, Tampere University of Technology, Tampere, Finland.|Department of Physics, Tampere University of Technology, Tampere, Finland.|Department of Physics, Tampere University of Technology, Tampere, Finland.|Department of Physics, Tampere University of Technology, Tampere, Finland, MEMPHYS - Centre for Biomembrane Physics, University of Southern Denmark, Odense, Denmark.', 'Finland|Finland|Finland|Finland|Finland|Denmark', 0, 'Cholesterol|Cholesterol Ester Transfer Proteins|Humans|Molecular Docking Simulation|Oxazolidinones|Phospholipids|Static Electricity|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003987', '25412509', 'Cholesteryl ester transfer protein (CETP) mediates the reciprocal transfer of neutral lipids (cholesteryl esters, triglycerides) and phospholipids between different lipoprotein fractions in human blood plasma. A novel molecular agent known as anacetrapib has been shown to inhibit CETP activity and thereby raise high density lipoprotein (HDL)-cholesterol and decrease low density lipoprotein (LDL)-cholesterol, thus rendering CETP inhibition an attractive target to prevent and treat the development of various cardiovascular diseases. Our objective in this work is to use atomistic molecular dynamics simulations to shed light on the inhibitory mechanism of anacetrapib and unlock the interactions between the drug and CETP. The results show an evident affinity of anacetrapib towards the concave surface of CETP, and especially towards the region of the N-terminal tunnel opening. The primary binding site of anacetrapib turns out to reside in the tunnel inside CETP, near the residues surrounding the N-terminal opening. Free energy calculations show that when anacetrapib resides in this area, it hinders the ability of cholesteryl ester to diffuse out from CETP. The simulations further bring out the ability of anacetrapib to regulate the structure-function relationships of phospholipids and helix X, the latter representing the structural region of CETP important to the process of neutral lipid exchange with lipoproteins. Altogether, the simulations propose CETP inhibition to be realized when anacetrapib is transferred into the lipid binding pocket. The novel insight gained in this study has potential use in the development of new molecular agents capable of preventing the progression of cardiovascular diseases. '),
(86893, 2014, 'plos', 'Yielding elastic tethers stabilize robust cell adhesion', 'Whitfield, Matt J|Luo, Jonathon P|Thomas, Wendy E', 'Department of Bioengineering, University of Washington, Seattle, Washington, United States of America.|Department of Bioengineering, University of Washington, Seattle, Washington, United States of America.|Department of Bioengineering, University of Washington, Seattle, Washington, United States of America.', 'United States|United States|United States', 7, 'Cell Adhesion|Computational Biology|Elasticity|Escherichia coli|Fimbriae Proteins|Kinetics|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1003971', '25473833', 'Many bacteria and eukaryotic cells express adhesive proteins at the end of tethers that elongate reversibly at constant or near constant force, which we refer to as yielding elasticity. Here we address the function of yielding elastic adhesive tethers with Escherichia coli bacteria as a model for cell adhesion, using a combination of experiments and simulations. The adhesive bond kinetics and tether elasticity was modeled in the simulations with realistic biophysical models that were fit to new and previously published single molecule force spectroscopy data. The simulations were validated by comparison to experiments measuring the adhesive behavior of E. coli in flowing fluid. Analysis of the simulations demonstrated that yielding elasticity is required for the bacteria to remain bound in high and variable flow conditions, because it allows the force to be distributed evenly between multiple bonds. In contrast, strain-hardening and linear elastic tethers concentrate force on the most vulnerable bonds, which leads to failure of the entire adhesive contact. Load distribution is especially important to noncovalent receptor-ligand bonds, because they become exponentially shorter lived at higher force above a critical force, even if they form catch bonds. The advantage of yielding is likely to extend to any blood cells or pathogens adhering in flow, or to any situation where bonds are stretched unequally due to surface roughness, unequal native bond lengths, or conditions that act to unzip the bonds. '),
(86894, 2014, 'plos', 'Lattice-based model of ductal carcinoma in situ suggests rules for breast cancer progression to an invasive state', 'Boghaert, Eline|Radisky, Derek C|Nelson, Celeste M', 'Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey, United States of America.|Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, United States of America.|Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey, United States of America, Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America.', 'Jersey|United States|Jersey', 0, 'Apoptosis|Breast Neoplasms|Carcinoma, Intraductal, Noninfiltrating|Cell Adhesion|Computational Biology|Female|Humans|Models, Biological|Neoplasm Invasiveness|Phenotype|Tumor Cells, Cultured', 'Journal Article', '10.1371/journal.pcbi.1003997', '25473842', 'Ductal carcinoma in situ (DCIS) is a heterogeneous group of non-invasive lesions of the breast that result from abnormal proliferation of mammary epithelial cells. Pathologists characterize DCIS by four tissue morphologies (micropapillary, cribriform, solid, and comedo), but the underlying mechanisms that distinguish the development and progression of these morphologies are not well understood. Here we explored the conditions leading to the emergence of the different morphologies of DCIS using a two-dimensional multi-cell lattice-based model that incorporates cell proliferation, apoptosis, necrosis, adhesion, and contractility. We found that the relative rates of cell proliferation and apoptosis governed which of the four morphologies emerged. High proliferation and low apoptosis favored the emergence of solid and comedo morphologies. In contrast, low proliferation and high apoptosis led to the micropapillary morphology, whereas high proliferation and high apoptosis led to the cribriform morphology. The natural progression between morphologies cannot be investigated in vivo since lesions are usually surgically removed upon detection, however, our model suggests probable transitions between these morphologies during breast cancer progression. Importantly, cribriform and comedo appear to be the ultimate morphologies of DCIS. Motivated by previous experimental studies demonstrating that tumor cells behave differently depending on where they are located within the mammary duct in vivo or in engineered tissues, we examined the effects of tissue geometry on the progression of DCIS. In agreement with our previous experimental work, we found that cells are more likely to invade from the end of ducts and that this preferential invasion is regulated by cell adhesion and contractility. This model provides additional insight into tumor cell behavior and allows the exploration of phenotypic transitions not easily monitored in vivo. '),
(86895, 2014, 'plos', 'Uncoupled analysis of stochastic reaction networks in fluctuating environments', 'Zechner, Christoph|Koeppl, Heinz', 'Department of Information Technology and Electrical Engineering, ETH Zurich, Zurich, Switzerland.|Department of Electrical Engineering and Information Technology, Technische Universität Darmstadt, Darmstadt, Germany.', 'Switzerland|Germany', 0, 'Algorithms|Computational Biology|Gene Regulatory Networks|Models, Biological|Ribosomes|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1003942', '25473849', 'The dynamics of stochastic reaction networks within cells are inevitably modulated by factors considered extrinsic to the network such as, for instance, the fluctuations in ribosome copy numbers for a gene regulatory network. While several recent studies demonstrate the importance of accounting for such extrinsic components, the resulting models are typically hard to analyze. In this work we develop a general mathematical framework that allows to uncouple the network from its dynamic environment by incorporating only the environments effect onto the network into a new model. More technically, we show how such fluctuating extrinsic components (e.g., chemical species) can be marginalized in order to obtain this decoupled model. We derive its corresponding process- and master equations and show how stochastic simulations can be performed. Using several case studies, we demonstrate the significance of the approach. ');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86896, 2014, 'plos', 'The amino acid alphabet and the architecture of the protein sequence-structure map I Binary alphabets', 'Ferrada, Evandro', 'Santa Fe Institute, Santa Fe, New Mexico, United States of America.', 'Mexico', 3, 'Amino Acid Sequence|Amino Acids|Cluster Analysis|Computational Biology|Genotype|Models, Biological|Models, Molecular|Phenotype|Protein Conformation|Protein Folding|Proteins|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1003946', '25473967', 'The correspondence between protein sequences and structures, or sequence-structure map, relates to fundamental aspects of structural, evolutionary and synthetic biology. The specifics of the mapping, such as the fraction of accessible sequences and structures, or the sequences ability to fold fast, are dictated by the type of interactions between the monomers that compose the sequences. The set of possible interactions between monomers is encapsulated by the potential energy function. In this study, I explore the impact of the relative forces of the potential on the architecture of the sequence-structure map. My observations rely on simple exact models of proteins and random samples of the space of potential energy functions of binary alphabets. I adopt a graph perspective and study the distribution of viable sequences and the structures they produce, as networks of sequences connected by point mutations. I observe that the relative proportion of attractive, neutral and repulsive forces defines types of potentials, that induce sequence-structure maps of vastly different architectures. I characterize the properties underlying these differences and relate them to the structure of the potential. Among these properties are the expected number and relative distribution of sequences associated to specific structures and the diversity of structures as a function of sequence divergence. I study the types of binary potentials observed in natural amino acids and show that there is a strong bias towards only some types of potentials, a bias that seems to characterize the folding code of natural proteins. I discuss implications of these observations for the architecture of the sequence-structure map of natural proteins, the construction of random libraries of peptides, and the early evolution of the natural amino acid alphabet. '),
(86897, 2014, 'plos', 'Extensive error in the number of genes inferred from draft genome assemblies', 'Denton, James F|Lugo-Martinez, Jose|Tucker, Abraham E|Schrider, Daniel R|Warren, Wesley C|Hahn, Matthew W', 'School of Informatics and Computing, Indiana University, Bloomington, Indiana.|School of Informatics and Computing, Indiana University, Bloomington, Indiana.|Department of Biology, Indiana University, Bloomington, Indiana.|School of Informatics and Computing, Indiana University, Bloomington, Indiana, Department of Biology, Indiana University, Bloomington, Indiana.|The Genome Institute at Washington University, Washington University School of Medicine, Saint Louis, Missouri.|School of Informatics and Computing, Indiana University, Bloomington, Indiana, Department of Biology, Indiana University, Bloomington, Indiana.', 'India|India|India|India|-|India', 0, 'Animals|Chickens|Chromosome Mapping|Drosophila melanogaster|Genome|Genomics|Pan troglodytes|Sequence Analysis, DNA|Sequence Analysis, RNA', 'Journal Article', '10.1371/journal.pcbi.1003998', '25474019', 'Current sequencing methods produce large amounts of data, but genome assemblies based on these data are often woefully incomplete. These incomplete and error-filled assemblies result in many annotation errors, especially in the number of genes present in a genome. In this paper we investigate the magnitude of the problem, both in terms of total gene number and the number of copies of genes in specific families. To do this, we compare multiple draft assemblies against higher-quality versions of the same genomes, using several new assemblies of the chicken genome based on both traditional and next-generation sequencing technologies, as well as published draft assemblies of chimpanzee. We find that upwards of 40% of all gene families are inferred to have the wrong number of genes in draft assemblies, and that these incorrect assemblies both add and subtract genes. Using simulated genome assemblies of Drosophila melanogaster, we find that the major cause of increased gene numbers in draft genomes is the fragmentation of genes onto multiple individual contigs. Finally, we demonstrate the usefulness of RNA-Seq in improving the gene annotation of draft assemblies, largely by connecting genes that have been fragmented in the assembly process. '),
(86898, 2014, 'plos', 'Heterogeneity and convergence of olfactory first-order neurons account for the high speed and sensitivity of second-order neurons', 'Rospars, Jean-Pierre|Grémiaux, Alexandre|Jarriault, David|Chaffiol, Antoine|Monsempes, Christelle|Deisig, Nina|Anton, Sylvia|Lucas, Philippe|Martinez, Dominique', 'Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche 1392 Institut dEcologie et des Sciences de lEnvironnement de Paris, Versailles, France.|Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche 1392 Institut dEcologie et des Sciences de lEnvironnement de Paris, Versailles, France.|Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche 1392 Institut dEcologie et des Sciences de lEnvironnement de Paris, Versailles, France.|Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche 1392 Institut dEcologie et des Sciences de lEnvironnement de Paris, Versailles, France.|Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche 1392 Institut dEcologie et des Sciences de lEnvironnement de Paris, Versailles, France.|Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche 1392 Institut dEcologie et des Sciences de lEnvironnement de Paris, Versailles, France.|Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche 1392 Institut dEcologie et des Sciences de lEnvironnement de Paris, Versailles, France.|Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche 1392 Institut dEcologie et des Sciences de lEnvironnement de Paris, Versailles, France.|Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche 1392 Institut dEcologie et des Sciences de lEnvironnement de Paris, Versailles, France, Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Unité Mixte de Recherche 7503, Centre National de la Recherche Scientifique (CNRS), Vandœuvre-lès-Nancy, France.', 'France|France|France|France|France|France|France|France|France', 0, 'Animals|Computational Biology|Male|Models, Neurological|Moths|Neurons|Olfactory Pathways|Olfactory Receptor Neurons|Pheromones', 'Journal Article', '10.1371/journal.pcbi.1003975', '25474026', 'In the olfactory system of male moths, a specialized subset of neurons detects and processes the main component of the sex pheromone emitted by females. It is composed of several thousand first-order olfactory receptor neurons (ORNs), all expressing the same pheromone receptor, that contact synaptically a few tens of second-order projection neurons (PNs) within a single restricted brain area. The functional simplicity of this system makes it a favorable model for studying the factors that contribute to its exquisite sensitivity and speed. Sensory information--primarily the identity and intensity of the stimulus--is encoded as the firing rate of the action potentials, and possibly as the latency of the neuron response. We found that over all their dynamic range, PNs respond with a shorter latency and a higher firing rate than most ORNs. Modelling showed that the increased sensitivity of PNs can be explained by the ORN-to-PN convergent architecture alone, whereas their faster response also requires cell-to-cell heterogeneity of the ORN population. So, far from being detrimental to signal detection, the ORN heterogeneity is exploited by PNs, and results in two different schemes of population coding based either on the response of a few extreme neurons (latency) or on the average response of many (firing rate). Moreover, ORN-to-PN transformations are linear for latency and nonlinear for firing rate, suggesting that latency could be involved in concentration-invariant coding of the pheromone blend and that sensitivity at low concentrations is achieved at the expense of precise encoding at high concentrations.'),
(86899, 2014, 'plos', 'Contradictory behavioral biases result from the influence of past stimuli on perception', 'Raviv, Ofri|Lieder, Itay|Loewenstein, Yonatan|Ahissar, Merav', 'The Edmond & Lily Safra Center for Brain Sciences, Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel.|The Edmond & Lily Safra Center for Brain Sciences, Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel.|The Edmond & Lily Safra Center for Brain Sciences, Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel, Departments of Neurobiology and Cognitive Sciences and the Center for the Study of Rationality, Hebrew University, Jerusalem, Israel.|The Edmond & Lily Safra Center for Brain Sciences, Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel, Departments of Psychology and Cognitive Sciences, Hebrew University, Jerusalem, Israel.', 'Israel|Israel|Israel|Israel', 0, 'Acoustic Stimulation|Adult|Choice Behavior|Computational Biology|Female|Humans|Male|Memory|Models, Neurological|Perception|Psychoacoustics|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1003948', '25474117', 'Biases such as the preference of a particular response for no obvious reason, are an integral part of psychophysics. Such biases have been reported in the common two-alternative forced choice (2AFC) experiments, where participants are instructed to compare two consecutively presented stimuli. However, the principles underlying these biases are largely unknown and previous studies have typically used ad-hoc explanations to account for them. Here we consider human performance in the 2AFC tone frequency discrimination task, utilizing two standard protocols. In both protocols, each trial contains a reference stimulus. In one (Reference-Lower protocol), the frequency of the reference stimulus is always lower than that of the comparison stimulus, whereas in the other (Reference protocol), the frequency of the reference stimulus is either lower or higher than that of the comparison stimulus. We find substantial interval biases. Namely, participants perform better when the reference is in a specific interval. Surprisingly, the biases in the two experiments are opposite: performance is better when the reference is in the first interval in the Reference protocol, but is better when the reference is second in the Reference-Lower protocol. This inconsistency refutes previous accounts of the interval bias, and is resolved when experiments statistics is considered. Viewing perception as incorporation of sensory input with prior knowledge accumulated during the experiment accounts for the seemingly contradictory biases both qualitatively and quantitatively. The success of this account implies that even simple discriminations reflect a combination of sensory limitations, memory limitations, and the ability to utilize stimuli statistics. '),
(86900, 2014, 'plos', 'Structure, dynamics and implied gating mechanism of a human cyclic nucleotide-gated channel', 'Gofman, Yana|Schärfe, Charlotta|Marks, Debora S|Haliloglu, Turkan|Ben-Tal, Nir', 'Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel.|Center for Bioinformatics, Quantitative Biology Center, and Department of Computer Science, Tübingen University, Tübingen, Germany, Department of Systems Biology, Harvard University, Boston, Massachusetts, United States of America.|Department of Systems Biology, Harvard University, Boston, Massachusetts, United States of America.|Polymer Research Centre and Chemical Engineering Department, Bogazici University, Bebek-Istanbul, Turkey.|Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel.', 'Israel|Germany|United States|Turkey|Israel', 0, 'Animals|Computational Biology|Cyclic Nucleotide-Gated Cation Channels|Humans|Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels|Mice|Molecular Dynamics Simulation|Nucleotides, Cyclic|Protein Structure, Tertiary', 'Journal Article', '10.1371/journal.pcbi.1003976', '25474149', 'Cyclic nucleotide-gated (CNG) ion channels are nonselective cation channels, essential for visual and olfactory sensory transduction. Although the channels include voltage-sensor domains (VSDs), their conductance is thought to be independent of the membrane potential, and their gating regulated by cytosolic cyclic nucleotide-binding domains. Mutations in these channels result in severe, degenerative retinal diseases, which remain untreatable. The lack of structural information on CNG channels has prevented mechanistic understanding of disease-causing mutations, precluded structure-based drug design, and hampered in silico investigation of the gating mechanism. To address this, we built a 3D model of the cone tetrameric CNG channel, based on homology to two distinct templates with known structures: the transmembrane (TM) domain of a bacterial channel, and the cyclic nucleotide-binding domain of the mouse HCN2 channel. Since the TM-domain template had low sequence-similarity to the TM domains of the CNG channels, and to reconcile conflicts between the two templates, we developed a novel, hybrid approach, combining homology modeling with evolutionary coupling constraints. Next, we used elastic network analysis of the model structure to investigate global motions of the channel and to elucidate its gating mechanism. We found the following: (i) In the main mode of motion, the TM and cytosolic domains counter-rotated around the membrane normal. We related this motion to gating, a proposition that is supported by previous experimental data, and by comparison to the known gating mechanism of the bacterial KirBac channel. (ii) The VSDs could facilitate gating (supplementing the pore gate), explaining their presence in such voltage-insensitive channels. (iii) Our elastic network model analysis of the CNGA3 channel supports a modular model of allosteric gating, according to which protein domains are quasi-independent: they can move independently, but are coupled to each other allosterically. '),
(86901, 2014, 'plos', 'Some work and some play: microscopic and macroscopic approaches to labor and leisure', 'Niyogi, Ritwik K|Shizgal, Peter|Dayan, Peter', 'Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom.|Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, Quebec, Canada.|Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom.', 'United Kingdom|Canada|United Kingdom', 4, 'Algorithms|Animals|Computational Biology|Decision Making|Humans|Leisure Activities|Models, Biological|Nonlinear Dynamics|Stochastic Processes|Work', 'Journal Article', '10.1371/journal.pcbi.1003894', '25474151', 'Given the option, humans and other animals elect to distribute their time between work and leisure, rather than choosing all of one and none of the other. Traditional accounts of partial allocation have characterised behavior on a macroscopic timescale, reporting and studying the mean times spent in work or leisure. However, averaging over the more microscopic processes that govern choices is known to pose tricky theoretical problems, and also eschews any possibility of direct contact with the neural computations involved. We develop a microscopic framework, formalized as a semi-Markov decision process with possibly stochastic choices, in which subjects approximately maximise their expected returns by making momentary commitments to one or other activity. We show macroscopic utilities that arise from microscopic ones, and demonstrate how facets such as imperfect substitutability can arise in a more straightforward microscopic manner. '),
(86902, 2014, 'plos', 'Exploring O2 diffusion in A-type cytochrome c oxidases: molecular dynamics simulations uncover two alternative channels towards the binuclear site', 'Oliveira, A Sofia F|Damas, João M|Baptista, António M|Soares, Cláudio M', 'ITQB - Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal.|ITQB - Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal.|ITQB - Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal.|ITQB - Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal.', 'Portugal|Portugal|Portugal|Portugal', 0, 'Bacterial Proteins|Diffusion|Electron Transport Complex IV|Molecular Dynamics Simulation|Oxygen|Rhodobacter sphaeroides', 'Journal Article', '10.1371/journal.pcbi.1004010', '25474152', 'Cytochrome c oxidases (Ccoxs) are the terminal enzymes of the respiratory chain in mitochondria and most bacteria. These enzymes couple dioxygen (O2) reduction to the generation of a transmembrane electrochemical proton gradient. Despite decades of research and the availability of a large amount of structural and biochemical data available for the A-type Ccox family, little is known about the channel(s) used by O2 to travel from the solvent/membrane to the heme a3-CuB binuclear center (BNC). Moreover, the identification of all possible O2 channels as well as the atomic details of O2 diffusion is essential for the understanding of the working mechanisms of the A-type Ccox. In this work, we determined the O2 distribution within Ccox from Rhodobacter sphaeroides, in the fully reduced state, in order to identify and characterize all the putative O2 channels leading towards the BNC. For that, we use an integrated strategy combining atomistic molecular dynamics (MD) simulations (with and without explicit O2 molecules) and implicit ligand sampling (ILS) calculations. Based on the 3D free energy map for O2 inside Ccox, three channels were identified, all starting in the membrane hydrophobic region and connecting the surface of the protein to the BNC. One of these channels corresponds to the pathway inferred from the X-ray data available, whereas the other two are alternative routes for O2 to reach the BNC. Both alternative O2 channels start in the membrane spanning region and terminate close to Y288I. These channels are a combination of multiple transiently interconnected hydrophobic cavities, whose opening and closure is regulated by the thermal fluctuations of the lining residues. Furthermore, our results show that, in this Ccox, the most likely (energetically preferred) routes for O2 to reach the BNC are the alternative channels, rather than the X-ray inferred pathway. '),
(86903, 2014, 'plos', 'The HIV mutation browser: a resource for human immunodeficiency virus mutagenesis and polymorphism data', 'Davey, Norman E|Satagopam, Venkata P|Santiago-Mozos, Salvador|Villacorta-Martin, Carlos|Bharat, Tanmay A M|Schneider, Reinhard|Briggs, John A G', 'Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany, Department of Physiology and Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States of America.|Luxembourg Centre for Systems Biomedicine, Belval, Luxembourg.|Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.|Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.|Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.|Luxembourg Centre for Systems Biomedicine, Belval, Luxembourg.|Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany, Molecular Medicine Partnership Unit, EMBL/Universitätsklinikum Heidelberg, Heidelberg, Germany.', 'Germany|Luxembourg|Germany|Germany|Germany|Luxembourg|Germany', 0, 'Amino Acid Sequence|Computational Biology|Databases, Genetic|HIV Infections|HIV-1|Humans|Molecular Sequence Data|Mutation', 'Journal Article', '10.1371/journal.pcbi.1003951', '25474213', 'Huge research effort has been invested over many years to determine the phenotypes of natural or artificial mutations in HIV proteins--interpretation of mutation phenotypes is an invaluable source of new knowledge. The results of this research effort are recorded in the scientific literature, but it is difficult for virologists to rapidly find it. Manually locating data on phenotypic variation within the approximately 270,000 available HIV-related research articles, or the further 1,500 articles that are published each month is a daunting task. Accordingly, the HIV research community would benefit from a resource cataloguing the available HIV mutation literature. We have applied computational text-mining techniques to parse and map mutagenesis and polymorphism information from the HIV literature, have enriched the data with ancillary information and have developed a public, web-based interface through which it can be intuitively explored: the HIV mutation browser. The current release of the HIV mutation browser describes the phenotypes of 7,608 unique mutations at 2,520 sites in the HIV proteome, resulting from the analysis of 120,899 papers. The mutation information for each protein is organised in a residue-centric manner and each residue is linked to the relevant experimental literature. The importance of HIV as a global health burden advocates extensive effort to maximise the efficiency of HIV research. The HIV mutation browser provides a valuable new resource for the research community. The HIV mutation browser is available at: http://hivmut.org.'),
(86904, 2014, 'plos', 'Detecting functional divergence after gene duplication through evolutionary changes in posttranslational regulatory sequences', 'Nguyen Ba, Alex N|Strome, Bob|Hua, Jun Jie|Desmond, Jonathan|Gagnon-Arsenault, Isabelle|Weiss, Eric L|Landry, Christian R|Moses, Alan M', 'Department of Cell & Systems Biology, University of Toronto, Toronto, Canada, Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Canada.|Department of Cell & Systems Biology, University of Toronto, Toronto, Canada.|Department of Cell & Systems Biology, University of Toronto, Toronto, Canada.|Department of Cell & Systems Biology, University of Toronto, Toronto, Canada.|Département de Biologie, IBIS and PROTEO, Pavillon Charles-Eugene-Marchand, Laval University, Québec City, Canada.|Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America.|Département de Biologie, IBIS and PROTEO, Pavillon Charles-Eugene-Marchand, Laval University, Québec City, Canada.|Department of Cell & Systems Biology, University of Toronto, Toronto, Canada, Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Canada.', 'Canada|Canada|Canada|Canada|Canada|United States|Canada|Canada', 0, 'Amino Acid Sequence|Base Sequence|Computational Biology|Computer Simulation|Evolution, Molecular|Gene Duplication|Models, Genetic|Molecular Sequence Data|Protein Processing, Post-Translational|Regulatory Sequences, Nucleic Acid|Saccharomycetales|Sequence Alignment|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1003977', '25474245', 'Gene duplication is an important evolutionary mechanism that can result in functional divergence in paralogs due to neo-functionalization or sub-functionalization. Consistent with functional divergence after gene duplication, recent studies have shown accelerated evolution in retained paralogs. However, little is known in general about the impact of this accelerated evolution on the molecular functions of retained paralogs. For example, do new functions typically involve changes in enzymatic activities, or changes in protein regulation? Here we study the evolution of posttranslational regulation by examining the evolution of important regulatory sequences (short linear motifs) in retained duplicates created by the whole-genome duplication in budding yeast. To do so, we identified short linear motifs whose evolutionary constraint has relaxed after gene duplication with a likelihood-ratio test that can account for heterogeneity in the evolutionary process by using a non-central chi-squared null distribution. We find that short linear motifs are more likely to show changes in evolutionary constraints in retained duplicates compared to single-copy genes. We examine changes in constraints on known regulatory sequences and show that for the Rck1/Rck2, Fkh1/Fkh2, Ace2/Swi5 paralogs, they are associated with previously characterized differences in posttranslational regulation. Finally, we experimentally confirm our prediction that for the Ace2/Swi5 paralogs, Cbk1 regulated localization was lost along the lineage leading to SWI5 after gene duplication. Our analysis suggests that changes in posttranslational regulation mediated by short regulatory motifs systematically contribute to functional divergence after gene duplication. '),
(86905, 2014, 'plos', 'Membrane partitioning of anionic, ligand-coated nanoparticles is accompanied by ligand snorkeling, local disordering, and cholesterol depletion', 'Gkeka, Paraskevi|Angelikopoulos, Panagiotis|Sarkisov, Lev|Cournia, Zoe', 'Biomedical Research Foundation, Academy of Athens, Athens, Greece.|Computational Science and Engineering Laboratory, Institute of Computational Science, D-MAVT, ETH Zurich, Switzerland.|Institute for Materials and Processes, School of Engineering, The University of Edinburgh, Edinburgh, United Kingdom.|Biomedical Research Foundation, Academy of Athens, Athens, Greece.', 'Greece|Switzerland|United Kingdom|Greece', 42, '1,2-Dipalmitoylphosphatidylcholine|Anions|Cholesterol|Computational Biology|Ligands|Lipid Bilayers|Models, Biological|Nanoparticles', 'Journal Article', '10.1371/journal.pcbi.1003917', '25474252', 'Intracellular uptake of nanoparticles (NPs) may induce phase transitions, restructuring, stretching, or even complete disruption of the cell membrane. Therefore, NP cytotoxicity assessment requires a thorough understanding of the mechanisms by which these engineered nanostructures interact with the cell membrane. In this study, extensive Coarse-Grained Molecular Dynamics (MD) simulations are performed to investigate the partitioning of an anionic, ligand-decorated NP in model membranes containing dipalmitoylphosphatidylcholine (DPPC) phospholipids and different concentrations of cholesterol. Spontaneous fusion and translocation of the anionic NP is not observed in any of the 10-µs unbiased MD simulations, indicating that longer timescales may be required for such phenomena to occur. This picture is supported by the free energy analysis, revealing a considerable free energy barrier for NP translocation across the lipid bilayer. 5-µs unbiased MD simulations with the NP inserted in the bilayer core reveal that the hydrophobic and hydrophilic ligands of the NP surface rearrange to form optimal contacts with the lipid bilayer, leading to the so-called snorkeling effect. Inside cholesterol-containing bilayers, the NP induces rearrangement of the structure of the lipid bilayer in its vicinity from the liquid-ordered to the liquid phase spanning a distance almost twice its core radius (8-10 nm). Based on the physical insights obtained in this study, we propose a mechanism of cellular anionic NP partitioning, which requires structural rearrangements of both the NP and the bilayer, and conclude that the translocation of anionic NPs through cholesterol-rich membranes must be accompanied by formation of cholesterol-lean regions in the proximity of NPs.'),
(86906, 2014, 'plos', 'A systematic computational analysis of biosynthetic gene cluster evolution: lessons for engineering biosynthesis', 'Medema, Marnix H|Cimermancic, Peter|Sali, Andrej|Takano, Eriko|Fischbach, Michael A', 'Department of Microbial Physiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands, Groningen Bioinformatics Centre, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.|Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America, California Institute for Quantitative Biosciences, San Francisco, California, United States of America.|Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America, California Institute for Quantitative Biosciences, San Francisco, California, United States of America, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, United States of America.|Manchester Institute of Biotechnology, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.|Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America, California Institute for Quantitative Biosciences, San Francisco, California, United States of America.', 'Netherlands|United States|United States|United Kingdom|United States', 77, 'Bioengineering|Computational Biology|Evolution, Molecular|Models, Genetic|Multigene Family', 'Journal Article', '10.1371/journal.pcbi.1004016', '25474254', 'Bacterial secondary metabolites are widely used as antibiotics, anticancer drugs, insecticides and food additives. Attempts to engineer their biosynthetic gene clusters (BGCs) to produce unnatural metabolites with improved properties are often frustrated by the unpredictability and complexity of the enzymes that synthesize these molecules, suggesting that genetic changes within BGCs are limited by specific constraints. Here, by performing a systematic computational analysis of BGC evolution, we derive evidence for three findings that shed light on the ways in which, despite these constraints, nature successfully invents new molecules: 1) BGCs for complex molecules often evolve through the successive merger of smaller sub-clusters, which function as independent evolutionary entities. 2) An important subset of polyketide synthases and nonribosomal peptide synthetases evolve by concerted evolution, which generates sets of sequence-homogenized domains that may hold promise for engineering efforts since they exhibit a high degree of functional interoperability, 3) Individual BGC families evolve in distinct ways, suggesting that design strategies should take into account family-specific functional constraints. These findings suggest novel strategies for using synthetic biology to rationally engineer biosynthetic pathways. '),
(86907, 2014, 'plos', 'A reaction-diffusion model of cholinergic retinal waves', 'Lansdell, Benjamin|Ford, Kevin|Kutz, J Nathan', 'Department of Applied Mathematics, University of Washington, Seattle, Washington, United States of America.|Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, United States of America.|Department of Applied Mathematics, University of Washington, Seattle, Washington, United States of America.', 'United States|United States|United States', 6, 'Acetylcholine|Action Potentials|Animals|Computational Biology|Diffusion|Mice|Models, Neurological|Reproducibility of Results|Retina|Single-Cell Analysis', 'Journal Article', '10.1371/journal.pcbi.1003953', '25474327', 'Prior to receiving visual stimuli, spontaneous, correlated activity in the retina, called retinal waves, drives activity-dependent developmental programs. Early-stage waves mediated by acetylcholine (ACh) manifest as slow, spreading bursts of action potentials. They are believed to be initiated by the spontaneous firing of Starburst Amacrine Cells (SACs), whose dense, recurrent connectivity then propagates this activity laterally. Their inter-wave interval and shifting wave boundaries are the result of the slow after-hyperpolarization of the SACs creating an evolving mosaic of recruitable and refractory cells, which can and cannot participate in waves, respectively. Recent evidence suggests that cholinergic waves may be modulated by the extracellular concentration of ACh. Here, we construct a simplified, biophysically consistent, reaction-diffusion model of cholinergic retinal waves capable of recapitulating wave dynamics observed in mice retina recordings. The dense, recurrent connectivity of SACs is modeled through local, excitatory coupling occurring via the volume release and diffusion of ACh. In addition to simulation, we are thus able to use non-linear wave theory to connect wave features to underlying physiological parameters, making the model useful in determining appropriate pharmacological manipulations to experimentally produce waves of a prescribed spatiotemporal character. The model is used to determine how ACh mediated connectivity may modulate wave activity, and how parameters such as the spontaneous activation rate and sAHP refractory period contribute to critical wave size variability. '),
(86908, 2014, 'plos', 'A network convergence zone in the hippocampus', 'Mixc5xa1ixc4x87, Bratislav|Goxc3xb1i, Joaquxc3xadn|Betzel, Richard F|Sporns, Olaf|McIntosh, Anthony R', 'Rotman Research Institute, Baycrest Centre, Toronto, Canada, Department of Psychology, University of Toronto, Toronto, Canada, Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States of America.|Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States of America.|Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States of America.|Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States of America.|Rotman Research Institute, Baycrest Centre, Toronto, Canada, Department of Psychology, University of Toronto, Toronto, Canada.', 'Canada|India|India|India|Canada', 35, 'Animals|Computational Biology|Connectome|Databases, Factual|Hippocampus|Macaca|Models, Neurological|Neural Pathways', 'Journal Article', '10.1371/journal.pcbi.1003982', '25474350', 'The hippocampal formation is a key structure for memory function in the brain. The functional anatomy of the brain suggests that the hippocampus may be a convergence zone, as it receives polysensory input from distributed association areas throughout the neocortex. However, recent quantitative graph-theoretic analyses of the static large-scale connectome have failed to demonstrate the centrality of the hippocampus, in the context of the whole brain, the hippocampus is not among the most connected or reachable nodes. Here we show that when communication dynamics are taken into account, the hippocampus is a key hub in the connectome. Using a novel computational model, we demonstrate that large-scale brain network topology is organized to funnel and concentrate information flow in the hippocampus, supporting the long-standing hypothesis that this region acts as a critical convergence zone. Our results indicate that the functional capacity of the hippocampus is shaped by its embedding in the large-scale connectome. '),
(86909, 2014, 'plos', 'Bayesian inference of sampled ancestor trees for epidemiology and fossil calibration', 'Gavryushkina, Alexandra|Welch, David|Stadler, Tanja|Drummond, Alexei J', 'Department of Computer Science, University of Auckland, Auckland, New Zealand, Allan Wilson Centre for Molecular Ecology and Evolution, Massey University, Palmerston North, New Zealand.|Department of Computer Science, University of Auckland, Auckland, New Zealand.|Department of Biosystems Science and Engineering, ETH Zürich, Switzerland.|Department of Computer Science, University of Auckland, Auckland, New Zealand, Allan Wilson Centre for Molecular Ecology and Evolution, Massey University, Palmerston North, New Zealand.', 'New Zealand|New Zealand|Switzerland|New Zealand', 110, 'Algorithms|Bayes Theorem|Computational Biology|Evolution, Molecular|Fossils|HIV Infections|HIV-1|Humans|Models, Genetic|Phylogeny|Software', 'Journal Article', '10.1371/journal.pcbi.1003919', '25474353', 'Phylogenetic analyses which include fossils or molecular sequences that are sampled through time require models that allow one sample to be a direct ancestor of another sample. As previously available phylogenetic inference tools assume that all samples are tips, they do not allow for this possibility. We have developed and implemented a Bayesian Markov Chain Monte Carlo (MCMC) algorithm to infer what we call sampled ancestor trees, that is, trees in which sampled individuals can be direct ancestors of other sampled individuals. We use a family of birth-death models where individuals may remain in the tree process after sampling, in particular we extend the birth-death skyline model [Stadler et al., 2013] to sampled ancestor trees. This method allows the detection of sampled ancestors as well as estimation of the probability that an individual will be removed from the process when it is sampled. We show that even if sampled ancestors are not of specific interest in an analysis, failing to account for them leads to significant bias in parameter estimates. We also show that sampled ancestor birth-death models where every sample comes from a different time point are non-identifiable and thus require one parameter to be known in order to infer other parameters. We apply our phylogenetic inference accounting for sampled ancestors to epidemiological data, where the possibility of sampled ancestors enables us to identify individuals that infected other individuals after being sampled and to infer fundamental epidemiological parameters. We also apply the method to infer divergence times and diversification rates when fossils are included along with extant species samples, so that fossilisation events are modelled as a part of the tree branching process. Such modelling has many advantages as argued in the literature. The sampler is available as an open-source BEAST2 package (https://github.com/CompEvol/sampled-ancestors). '),
(86910, 2014, 'plos', 'Ten simple rules for finishing your PhD', 'Marino, Jacopo|Stefan, Melanie I|Blackford, Sarah', 'Department of Chemistry, University of Zurich, Zurich, Switzerland.|Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, United States of America.|Society for Experimental Biology (SEB), Lancaster University, Lancaster, United Kingdom.', 'Switzerland|United States|United Kingdom', 6, 'Career Choice|Education, Graduate|Humans|Social Networking', 'Editorial', '10.1371/journal.pcbi.1003954', '25474445', '-'),
(86911, 2014, 'plos', 'Dissecting dynamic genetic variation that controls temporal gene response in yeast', 'Brodt, Avital|Botzman, Maya|David, Eyal|Gat-Viks, Irit', 'Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel.|Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel.|Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel.|Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel.', 'Israel|Israel|Israel|Israel', 2, 'Algorithms|Antifungal Agents|Computational Biology|Gene Expression Regulation, Fungal|Genetic Variation|Signal Transduction|Sirolimus|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1003984', '25474467', 'Inter-individual variation in regulatory circuits controlling gene expression is a powerful source of functional information. The study of associations among genetic variants and gene expression provides important insights about cell circuitry but cannot specify whether and when potential variants dynamically alter their genetic effect during the course of response. Here we develop a computational procedure that captures temporal changes in genetic effects, and apply it to analyze transcription during inhibition of the TOR signaling pathway in segregating yeast cells. We found a high-order coordination of gene modules: sets of genes co-associated with the same genetic variant and sharing a common temporal genetic effect pattern. The temporal genetic effects of some modules represented a single state-transitioning pattern, for example, at 10-30 minutes following stimulation, genetic effects in the phosphate utilization module attained a characteristic transition to a new steady state. In contrast, another module showed an impulse pattern of genetic effects, for example, in the poor nitrogen sources utilization module, a spike up of a genetic effect at 10-20 minutes following stimulation reflected inter-individual variation in the timing (rather than magnitude) of response. Our analysis suggests that the same mechanism typically leads to both inter-individual variation and the temporal genetic effect pattern in a module. Our methodology provides a quantitative genetic approach to studying the molecular mechanisms that shape dynamic changes in transcriptional responses. '),
(86912, 2014, 'plos', 'ECOD: an evolutionary classification of protein domains', 'Cheng, Hua|Schaeffer, R Dustin|Liao, Yuxing|Kinch, Lisa N|Pei, Jimin|Shi, Shuoyong|Kim, Bong-Hyun|Grishin, Nick V', 'Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America, Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 115, 'Computational Biology|Databases, Protein|Evolution, Molecular|Models, Molecular|Protein Structure, Tertiary|Proteins', 'Journal Article', '10.1371/journal.pcbi.1003926', '25474468', 'Understanding the evolution of a protein, including both close and distant relationships, often reveals insight into its structure and function. Fast and easy access to such up-to-date information facilitates research. We have developed a hierarchical evolutionary classification of all proteins with experimentally determined spatial structures, and presented it as an interactive and updatable online database. ECOD (Evolutionary Classification of protein Domains) is distinct from other structural classifications in that it groups domains primarily by evolutionary relationships (homology), rather than topology (or fold). This distinction highlights cases of homology between domains of differing topology to aid in understanding of protein structure evolution. ECOD uniquely emphasizes distantly related homologs that are difficult to detect, and thus catalogs the largest number of evolutionary links among structural domain classifications. Placing distant homologs together underscores the ancestral similarities of these proteins and draws attention to the most important regions of sequence and structure, as well as conserved functional sites. ECOD also recognizes closer sequence-based relationships between protein domains. Currently, approximately 100,000 protein structures are classified in ECOD into 9,000 sequence families clustered into close to 2,000 evolutionary groups. The classification is assisted by an automated pipeline that quickly and consistently classifies weekly releases of PDB structures and allows for continual updates. This synchronization with PDB uniquely distinguishes ECOD among all protein classifications. Finally, we present several case studies of homologous proteins not recorded in other classifications, illustrating the potential of how ECOD can be used to further biological and evolutionary studies. '),
(86913, 2014, 'plos', 'Live imaging-based model selection reveals periodic regulation of the stochastic G1/S phase transition in vertebrate axial development', 'Sugiyama, Mayu|Saitou, Takashi|Kurokawa, Hiroshi|Sakaue-Sawano, Asako|Imamura, Takeshi|Miyawaki, Atsushi|Iimura, Tadahiro', 'Laboratory for Cell Function and Dynamics, Advanced Technology Development Group, Brain Science Institute, RIKEN, Wako-city, Saitama, Japan.|Department of Molecular Medicine for Pathogenesis, Graduate School of Medicine, Ehime University, Shitsukawa, Toon-city, Ehime, Japan.|Laboratory for Cell Function and Dynamics, Advanced Technology Development Group, Brain Science Institute, RIKEN, Wako-city, Saitama, Japan.|Laboratory for Cell Function and Dynamics, Advanced Technology Development Group, Brain Science Institute, RIKEN, Wako-city, Saitama, Japan.|Department of Molecular Medicine for Pathogenesis, Graduate School of Medicine, Ehime University, Shitsukawa, Toon-city, Ehime, Japan, Division of Bio-Imaging, Proteo-Science Center (PROS), Ehime University, Shitsukawa, Toon-city, Ehime, Japan, Translational Research Center, Ehime University Hospital, Shitsukawa, Toon-city, Ehime, Japan.|Laboratory for Cell Function and Dynamics, Advanced Technology Development Group, Brain Science Institute, RIKEN, Wako-city, Saitama, Japan.|Laboratory for Cell Function and Dynamics, Advanced Technology Development Group, Brain Science Institute, RIKEN, Wako-city, Saitama, Japan, Division of Bio-Imaging, Proteo-Science Center (PROS), Ehime University, Shitsukawa, Toon-city, Ehime, Japan, Translational Research Center, Ehime University Hospital, Shitsukawa, Toon-city, Ehime, Japan.', 'Japan|Japan|Japan|Japan|Japan|Japan|Japan', 10, 'Animals|Cell Cycle|Computational Biology|Computer Simulation|Embryo, Nonmammalian|Embryonic Development|Microscopy, Fluorescence|Models, Biological|Zebrafish', 'Journal Article', '10.1371/journal.pcbi.1003957', '25474567', 'In multicellular organism development, a stochastic cellular response is observed, even when a population of cells is exposed to the same environmental conditions. Retrieving the spatiotemporal regulatory mode hidden in the heterogeneous cellular behavior is a challenging task. The G1/S transition observed in cell cycle progression is a highly stochastic process. By taking advantage of a fluorescence cell cycle indicator, Fucci technology, we aimed to unveil a hidden regulatory mode of cell cycle progression in developing zebrafish. Fluorescence live imaging of Cecyil, a zebrafish line genetically expressing Fucci, demonstrated that newly formed notochordal cells from the posterior tip of the embryonic mesoderm exhibited the red (G1) fluorescence signal in the developing notochord. Prior to their initial vacuolation, these cells showed a fluorescence color switch from red to green, indicating G1/S transitions. This G1/S transition did not occur in a synchronous manner, but rather exhibited a stochastic process, since a mixed population of red and green cells was always inserted between newly formed red (G1) notochordal cells and vacuolating green cells. We termed this mixed population of notochordal cells, the G1/S transition window. We first performed quantitative analyses of live imaging data and a numerical estimation of the probability of the G1/S transition, which demonstrated the existence of a posteriorly traveling regulatory wave of the G1/S transition window. To obtain a better understanding of this regulatory mode, we constructed a mathematical model and performed a model selection by comparing the results obtained from the models with those from the experimental data. Our analyses demonstrated that the stochastic G1/S transition window in the notochord travels posteriorly in a periodic fashion, with doubled the periodicity of the neighboring paraxial mesoderm segmentation. This approach may have implications for the characterization of the pathophysiological tissue growth mode. ');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86914, 2014, 'plos', 'Hippocampal remapping is constrained by sparseness rather than capacity', 'Kammerer, Axel|Leibold, Christian', 'Department Biologie II, Ludwig-Maximilians-Universität München, Planegg, Germany, Graduate School for Systemic Neurosciences, Ludwig-Maximilians-Universität München, Planegg, Germany.|Department Biologie II, Ludwig-Maximilians-Universität München, Planegg, Germany.', 'Germany|Germany', 6, 'Animals|Computational Biology|Entorhinal Cortex|Hippocampus|Mammals|Models, Neurological', 'Journal Article', '10.1371/journal.pcbi.1003986', '25474570', 'Grid cells in the medial entorhinal cortex encode space with firing fields that are arranged on the nodes of spatial hexagonal lattices. Potential candidates to read out the space information of this grid code and to combine it with other sensory cues are hippocampal place cells. In this paper, we investigate a population of grid cells providing feed-forward input to place cells. The capacity of the underlying synaptic transformation is determined by both spatial acuity and the number of different spatial environments that can be represented. The codes for different environments arise from phase shifts of the periodical entorhinal cortex patterns that induce a global remapping of hippocampal place fields, i.e., a new random assignment of place fields for each environment. If only a single environment is encoded, the grid code can be read out at high acuity with only few place cells. A surplus in place cells can be used to store a space code for more environments via remapping. The number of stored environments can be increased even more efficiently by stronger recurrent inhibition and by partitioning the place cell population such that learning affects only a small fraction of them in each environment. We find that the spatial decoding acuity is much more resilient to multiple remappings than the sparseness of the place code. Since the hippocampal place code is sparse, we thus conclude that the projection from grid cells to the place cells is not using its full capacity to transfer space information. Both populations may encode different aspects of space. '),
(86915, 2014, 'plos', 'Evolution of the division of labor between genes and enzymes in the RNA world', 'Boza, Gergely|Szilágyi, András|Kun, Ádám|Santos, Mauro|Szathmáry, Eörs', 'Department of Plant Systematics, Ecology and Theoretical Biology, Institute of Biology, Eötvös Loránd University, Budapest, Hungary, MTA-ELTE-MTMT Ecology Research Group, Budapest, Hungary.|Department of Plant Systematics, Ecology and Theoretical Biology, Institute of Biology, Eötvös Loránd University, Budapest, Hungary, Parmenides Center for the Conceptual Foundations of Science, Pullach, Germany, MTA-ELTE Research Group in Theoretical Biology and Evolutionary Ecology, Budapest, Hungary.|Department of Plant Systematics, Ecology and Theoretical Biology, Institute of Biology, Eötvös Loránd University, Budapest, Hungary, MTA-ELTE-MTMT Ecology Research Group, Budapest, Hungary, Parmenides Center for the Conceptual Foundations of Science, Pullach, Germany.|Departament de Genètica i de Microbiologia, Grup de Biologia Evolutiva, Universitat Autònoma de Barcelona, Barcelona, Spain.|Department of Plant Systematics, Ecology and Theoretical Biology, Institute of Biology, Eötvös Loránd University, Budapest, Hungary, Parmenides Center for the Conceptual Foundations of Science, Pullach, Germany, MTA-ELTE Research Group in Theoretical Biology and Evolutionary Ecology, Budapest, Hungary.', 'Hungary|Germany|Germany|Spain|Germany', 12, 'Biological Evolution|Computational Biology|DNA Replication|Models, Genetic|RNA|RNA, Catalytic', 'Journal Article', '10.1371/journal.pcbi.1003936', '25474573', 'The RNA world is a very likely interim stage of the evolution after the first replicators and before the advent of the genetic code and translated proteins. Ribozymes are known to be able to catalyze many reaction types, including cofactor-aided metabolic transformations. In a metabolically complex RNA world, early division of labor between genes and enzymes could have evolved, where the ribozymes would have been transcribed from the genes more often than the other way round, benefiting the encapsulating cells through this dosage effect. Here we show, by computer simulations of protocells harboring unlinked RNA replicators, that the origin of replicational asymmetry producing more ribozymes from a gene template than gene strands from a ribozyme template is feasible and robust. Enzymatic activities of the two modeled ribozymes are in trade-off with their replication rates, and the relative replication rates compared to those of complementary strands are evolvable traits of the ribozymes. The degree of trade-off is shown to have the strongest effect in favor of the division of labor. Although some asymmetry between gene and enzymatic strands could have evolved even in earlier, surface-bound systems, the shown mechanism in protocells seems inevitable and under strong positive selection. This could have preadapted the genetic system for transcription after the subsequent origin of chromosomes and DNA. '),
(86916, 2014, 'plos', 'The social Bayesian brain: does mentalizing make a difference when we learn?', 'Devaine, Marie|Hollard, Guillaume|Daunizeau, Jean', 'Brain and Spine Institute, Paris, France, INSERM, Paris, France.|Maison des Sciences Economiques, Paris, France, CNRS UMR, Paris, France.|Brain and Spine Institute, Paris, France, INSERM, Paris, France, ETH, Zurich, Switzerland.', 'France|France|Switzerland', 30, 'Adult|Bayes Theorem|Brain|Computational Biology|Emotions|Female|Game Theory|Humans|Learning|Male|Social Perception|Theory of Mind|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1003992', '25474637', 'When it comes to interpreting others behaviour, we almost irrepressibly engage in the attribution of mental states (beliefs, emotions…). Such mentalizing can become very sophisticated, eventually endowing us with highly adaptive skills such as convincing, teaching or deceiving. Here, sophistication can be captured in terms of the depth of our recursive beliefs, as in I think that you think that I think… In this work, we test whether such sophisticated recursive beliefs subtend learning in the context of social interaction. We asked participants to play repeated games against artificial (Bayesian) mentalizing agents, which differ in their sophistication. Critically, we made people believe either that they were playing against each other, or that they were gambling like in a casino. Although both framings are similarly deceiving, participants win against the artificial (sophisticated) mentalizing agents in the social framing of the task, and lose in the non-social framing. Moreover, we find that participants choice sequences are best explained by sophisticated mentalizing Bayesian learning models only in the social framing. This study is the first demonstration of the added-value of mentalizing on learning in the context of repeated social interactions. Importantly, our results show that we would not be able to decipher intentional behaviour without a priori attributing mental states to others. '),
(86917, 2014, 'plos', 'Molecular dynamics study of the opening mechanism for DNA polymerase I', 'Miller, Bill R|Parish, Carol A|Wu, Eugene Y', 'Department of Biology, University of Richmond, Richmond, Virginia, United States of America, Department of Chemistry, University of Richmond, Richmond, Virginia, United States of America.|Department of Chemistry, University of Richmond, Richmond, Virginia, United States of America.|Department of Biology, University of Richmond, Richmond, Virginia, United States of America.', 'United States|United States|United States', 21, 'Bacterial Proteins|Catalytic Domain|DNA Polymerase I|Geobacillus stearothermophilus|Molecular Dynamics Simulation|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1003961', '25474643', 'During DNA replication, DNA polymerases follow an induced fit mechanism in order to rapidly distinguish between correct and incorrect dNTP substrates. The dynamics of this process are crucial to the overall effectiveness of catalysis. Although X-ray crystal structures of DNA polymerase I with substrate dNTPs have revealed key structural states along the catalytic pathway, solution fluorescence studies indicate that those key states are populated in the absence of substrate. Herein, we report the first atomistic simulations showing the conformational changes between the closed, open, and ajar conformations of DNA polymerase I in the binary (enzyme:DNA) state to better understand its dynamics. We have applied long time-scale, unbiased molecular dynamics to investigate the opening process of the fingers domain in the absence of substrate for B. stearothermophilis DNA polymerase in silico. These simulations are biologically and/or physiologically relevant as they shed light on the transitions between states in this important enzyme. All closed and ajar simulations successfully transitioned into the fully open conformation, which is known to be the dominant binary enzyme-DNA conformation from solution and crystallographic studies. Furthermore, we have detailed the key stages in the opening process starting from the open and ajar crystal structures, including the observation of a previously unknown key intermediate structure. Four backbone dihedrals were identified as important during the opening process, and their movements provide insight into the recognition of dNTP substrate molecules by the polymerase binary state. In addition to revealing the opening mechanism, this study also demonstrates our ability to study biological events of DNA polymerase using current computational methods without biasing the dynamics.'),
(86918, 2014, 'plos', 'Dynamics from seconds to hours in Hodgkin-Huxley model with time-dependent ion concentrations and buffer reservoirs', 'Hübel, Niklas|Dahlem, Markus A', 'Department of Theoretical Physics, Technische Universität Berlin, Berlin, Germany.|Department of Physics, Humboldt Universität zu Berlin, Berlin, Germany.', 'Germany|Germany', 25, 'Buffers|Chlorides|Ion Channels|Membrane Potentials|Models, Neurological|Neurons|Potassium|Sodium', 'Journal Article', '10.1371/journal.pcbi.1003941', '25474648', 'The classical Hodgkin-Huxley (HH) model neglects the time-dependence of ion concentrations in spiking dynamics. The dynamics is therefore limited to a time scale of milliseconds, which is determined by the membrane capacitance multiplied by the resistance of the ion channels, and by the gating time constants. We study slow dynamics in an extended HH framework that includes time-dependent ion concentrations, pumps, and buffers. Fluxes across the neuronal membrane change intra- and extracellular ion concentrations, whereby the latter can also change through contact to reservoirs in the surroundings. Ion gain and loss of the system is identified as a bifurcation parameter whose essential importance was not realized in earlier studies. Our systematic study of the bifurcation structure and thus the phase space structure helps to understand activation and inhibition of a new excitability in ion homeostasis which emerges in such extended models. Also modulatory mechanisms that regulate the spiking rate can be explained by bifurcations. The dynamics on three distinct slow times scales is determined by the cell volume-to-surface-area ratio and the membrane permeability (seconds), the buffer time constants (tens of seconds), and the slower backward buffering (minutes to hours). The modulatory dynamics and the newly emerging excitable dynamics corresponds to pathological conditions observed in epileptiform burst activity, and spreading depression in migraine aura and stroke, respectively. '),
(86919, 2014, 'plos', 'Developmental self-construction and -configuration of functional neocortical neuronal networks', 'Bauer, Roman|Zubler, Frédéric|Pfister, Sabina|Hauri, Andreas|Pfeiffer, Michael|Muir, Dylan R|Douglas, Rodney J', 'Institute of Neuroinformatics, University/ETH Zürich, Zürich, Switzerland, School of Computing Science, Newcastle University, Newcastle upon Tyne, United Kingdom.|Institute of Neuroinformatics, University/ETH Zürich, Zürich, Switzerland, Department of Neurology, Inselspital Bern, Bern University Hospital, University of Bern, Bern, Switzerland.|Institute of Neuroinformatics, University/ETH Zürich, Zürich, Switzerland.|Institute of Neuroinformatics, University/ETH Zürich, Zürich, Switzerland.|Institute of Neuroinformatics, University/ETH Zürich, Zürich, Switzerland.|Institute of Neuroinformatics, University/ETH Zürich, Zürich, Switzerland, Biozentrum, University of Basel, Basel, Switzerland.|Institute of Neuroinformatics, University/ETH Zürich, Zürich, Switzerland.', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 13, 'Animals|Axons|Computational Biology|Gene Regulatory Networks|Mice|Models, Neurological|Neocortex|Nerve Net|Neural Networks (Computer)|Neurites', 'Journal Article', '10.1371/journal.pcbi.1003994', '25474693', 'The prenatal development of neural circuits must provide sufficient configuration to support at least a set of core postnatal behaviors. Although knowledge of various genetic and cellular aspects of development is accumulating rapidly, there is less systematic understanding of how these various processes play together in order to construct such functional networks. Here we make some steps toward such understanding by demonstrating through detailed simulations how a competitive co-operative (winner-take-all, WTA) network architecture can arise by development from a single precursor cell. This precursor is granted a simplified gene regulatory network that directs cell mitosis, differentiation, migration, neurite outgrowth and synaptogenesis. Once initial axonal connection patterns are established, their synaptic weights undergo homeostatic unsupervised learning that is shaped by wave-like input patterns. We demonstrate how this autonomous genetically directed developmental sequence can give rise to self-calibrated WTA networks, and compare our simulation results with biological data. '),
(86920, 2014, 'plos', 'Intrinsic neuronal properties switch the mode of information transmission in networks', 'Gjorgjieva, Julijana|Mease, Rebecca A|Moody, William J|Fairhall, Adrienne L', 'Center for Brain Science, Harvard University, Cambridge, Massachusetts, United States of America.|Institute of Neuroscience, Technische Universität München, Munich, Germany.|Department of Biology, University of Washington, Seattle, Washington, United States of America.|Department of Physiology and Biophysics and the WRF UW Institute for Neuroengineering, University of Washington, Seattle, Washington, United States of America.', 'United States|Germany|United States|United States', 20, 'Action Potentials|Animals|Cerebral Cortex|Computational Biology|Ion Channels|Models, Neurological|Nerve Net|Neurons|Rats|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1003962', '25474701', 'Diverse ion channels and their dynamics endow single neurons with complex biophysical properties. These properties determine the heterogeneity of cell types that make up the brain, as constituents of neural circuits tuned to perform highly specific computations. How do biophysical properties of single neurons impact network function? We study a set of biophysical properties that emerge in cortical neurons during the first week of development, eventually allowing these neurons to adaptively scale the gain of their response to the amplitude of the fluctuations they encounter. During the same time period, these same neurons participate in large-scale waves of spontaneously generated electrical activity. We investigate the potential role of experimentally observed changes in intrinsic neuronal properties in determining the ability of cortical networks to propagate waves of activity. We show that such changes can strongly affect the ability of multi-layered feedforward networks to represent and transmit information on multiple timescales. With properties modeled on those observed at early stages of development, neurons are relatively insensitive to rapid fluctuations and tend to fire synchronously in response to wave-like events of large amplitude. Following developmental changes in voltage-dependent conductances, these same neurons become efficient encoders of fast input fluctuations over few layers, but lose the ability to transmit slower, population-wide input variations across many layers. Depending on the neurons intrinsic properties, noise plays different roles in modulating neuronal input-output curves, which can dramatically impact network transmission. The developmental change in intrinsic properties supports a transformation of a networks function from the propagation of network-wide information to one in which computations are scaled to local activity. This work underscores the significance of simple changes in conductance parameters in governing how neurons represent and propagate information, and suggests a role for background synaptic noise in switching the mode of information transmission. '),
(86921, 2014, 'plos', 'SteatoNet: the first integrated human metabolic model with multi-layered regulation to investigate liver-associated pathologies', 'Naik, Adviti|Rozman, Damjana|Belixc4x8d, Alexc5xa1', 'Faculty of Computer Sciences and Informatics, University of Ljubljana, Ljubljana, Slovenia, Faculty of Electrical Engineering, University of Ljubljana, Ljubljana, Slovenia.|Centre for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.|Faculty of Electrical Engineering, University of Ljubljana, Ljubljana, Slovenia.', 'Slovenia|Slovenia|Slovenia', 11, 'Adipose Tissue|Computational Biology|Computer Simulation|Databases, Factual|Fatty Liver|Humans|Internet|Liver|Models, Biological|Reproducibility of Results|Software', 'Journal Article', '10.1371/journal.pcbi.1003993', '25500563', 'Current state-of-the-art mathematical models to investigate complex biological processes, in particular liver-associated pathologies, have limited expansiveness, flexibility, representation of integrated regulation and rely on the availability of detailed kinetic data. We generated the SteatoNet, a multi-pathway, multi-tissue model and in silico platform to investigate hepatic metabolism and its associated deregulations. SteatoNet is based on object-oriented modelling, an approach most commonly applied in automotive and process industries, whereby individual objects correspond to functional entities. Objects were compiled to feature two novel hepatic modelling aspects: the interaction of hepatic metabolic pathways with extra-hepatic tissues and the inclusion of transcriptional and post-transcriptional regulation. SteatoNet identification at normalised steady state circumvents the need for constraining kinetic parameters. Validation and identification of flux disturbances that have been proven experimentally in liver patients and animal models highlights the ability of SteatoNet to effectively describe biological behaviour. SteatoNet identifies crucial pathway branches (transport of glucose, lipids and ketone bodies) where changes in flux distribution drive the healthy liver towards hepatic steatosis, the primary stage of non-alcoholic fatty liver disease. Cholesterol metabolism and its transcription regulators are highlighted as novel steatosis factors. SteatoNet thus serves as an intuitive in silico platform to identify systemic changes associated with complex hepatic metabolic disorders. '),
(86922, 2014, 'plos', 'Pyranose dehydrogenase ligand promiscuity: a generalized approach to simulate monosaccharide solvation, binding, and product formation', 'Graf, Michael M H|Zhixiong, Lin|Bren, Urban|Haltrich, Dietmar|van Gunsteren, Wilfred F|Oostenbrink, Chris', 'Food Biotechnology Laboratory, Department of Food Science and Technology, University of Natural Resources and Life Sciences (BOKU), Vienna, Austria.|Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH, Zxc3xbcrich, Switzerland.|Institute of Molecular Modeling and Simulation, University of Natural Resources and Life Sciences (BOKU), Vienna, Austria, Laboratory for Molecular Modeling, National Institute of Chemistry, Ljubljana, Slovenia.|Food Biotechnology Laboratory, Department of Food Science and Technology, University of Natural Resources and Life Sciences (BOKU), Vienna, Austria.|Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH, Zxc3xbcrich, Switzerland.|Institute of Molecular Modeling and Simulation, University of Natural Resources and Life Sciences (BOKU), Vienna, Austria.', 'Austria|Switzerland|Austria|Austria|Switzerland|Austria', 5, 'Agaricus|Fungal Proteins|Molecular Dynamics Simulation|Monosaccharides|Oxidoreductases|Protein Binding|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003995', '25500811', 'The flavoenzyme pyranose dehydrogenase (PDH) from the litter decomposing fungus Agaricus meleagris oxidizes many different carbohydrates occurring during lignin degradation. This promiscuous substrate specificity makes PDH a promising catalyst for bioelectrochemical applications. A generalized approach to simulate all 32 possible aldohexopyranoses in the course of one or a few molecular dynamics (MD) simulations is reported. Free energy calculations according to the one-step perturbation (OSP) method revealed the solvation free energies (xcex94Gsolv) of all 32 aldohexopyranoses in water, which have not yet been reported in the literature. The free energy difference between xcexb2- and xcexb1-anomers (xcex94Gxcexb2-xcexb1) of all d-stereoisomers in water were compared to experimental values with a good agreement. Moreover, the free-energy differences (xcex94G) of the 32 stereoisomers bound to PDH in two different poses were calculated from MD simulations. The relative binding free energies (xcex94xcex94Gbind) were calculated and, where available, compared to experimental values, approximated from Km values. The agreement was very good for one of the poses, in which the sugars are positioned in the active site for oxidation at C1 or C2. Distance analysis between hydrogens of the monosaccharide and the reactive N5-atom of the flavin adenine dinucleotide (FAD) revealed that oxidation is possible at HC1 or HC2 for pose A, and at HC3 or HC4 for pose B. Experimentally detected oxidation products could be rationalized for the majority of monosaccharides by combining xcex94xcex94Gbind and a reweighted distance analysis. Furthermore, several oxidation products were predicted for sugars that have not yet been tested experimentally, directing further analyses. This study rationalizes the relationship between binding free energies and substrate promiscuity in PDH, providing novel insights for its applicability in bioelectrochemistry. The results suggest that a similar approach could be applied to study promiscuity of other enzymes. '),
(86923, 2014, 'plos', 'Vesicular stomatitis virus polymerases strong affinity to its template suggests exotic transcription models', 'Tang, Xiaolin|Bendjennat, Mourad|Saffarian, Saveez', 'Department of Physics and Astronomy, University of Utah, Salt Lake City, Utah, United States of America.|Department of Physics and Astronomy, University of Utah, Salt Lake City, Utah, United States of America.|Department of Physics and Astronomy, University of Utah, Salt Lake City, Utah, United States of America, Center for Cell and Genome Science, University of Utah, Salt Lake City, Utah, United States of America, Department of Biology, University of Utah, Salt Lake City, Utah, United States of America.', 'United States|United States|United States', 1, 'Computational Biology|DNA-Directed RNA Polymerases|Genes, Viral|Models, Genetic|Models, Molecular|Monte Carlo Method|RNA, Viral|Transcription, Genetic|Vesiculovirus|Viral Proteins', 'Journal Article', '10.1371/journal.pcbi.1004004', '25501005', 'Vesicular stomatitis virus (VSV) is the prototype for negative sense non segmented (NNS) RNA viruses which include potent human and animal pathogens such as Rabies, Ebola and measles. The polymerases of NNS RNA viruses only initiate transcription at or near the 3 end of their genome template. We measured the dissociation constant of VSV polymerases from their whole genome template to be 20 pM. Given this low dissociation constant, initiation and sustainability of transcription becomes nontrivial. To explore possible mechanisms, we simulated the first hour of transcription using Monte Carlo methods and show that a one-time initial dissociation of all polymerases during entry is not sufficient to sustain transcription. We further show that efficient transcription requires a sliding mechanism for non-transcribing polymerases and can be realized with different polymerase-polymerase interactions and distinct template topologies. In conclusion, we highlight a model in which collisions between transcribing and sliding non-transcribing polymerases result in release of the non-transcribing polymerases allowing for redistribution of polymerases between separate templates during transcription and suggest specific experiments to further test these mechanisms. '),
(86924, 2014, 'plos', 'Molecular insights into the dynamics of pharmacogenetically important N-terminal variants of the human xcexb22-adrenergic receptor', 'Shahane, Ganesh|Parsania, Chirag|Sengupta, Durba|Joshi, Manali', 'CSIR-National Chemical Laboratory, Pune, India.|Bioinformatics Center, University of Pune, Pune, India.|CSIR-National Chemical Laboratory, Pune, India.|Bioinformatics Center, University of Pune, Pune, India.', 'India|India|India|India', 17, 'Albuterol|Asthma|Binding Sites|Humans|Molecular Dynamics Simulation|Pharmacogenetics|Polymorphism, Genetic|Receptors, Adrenergic, beta-2', 'Journal Article', '10.1371/journal.pcbi.1004006', '25501358', 'The human xcexb22-adrenergic receptor (xcexb22AR), a member of the G-protein coupled receptor (GPCR) family, is expressed in bronchial smooth muscle cells. Upon activation by agonists, xcexb22AR causes bronchodilation and relief in asthma patients. The N-terminal polymorphism of xcexb22AR at the 16th position, Arg16Gly, has warranted a lot of attention since it is linked to variations in response to albuterol (agonist) treatment. Although the xcexb22AR is one of the well-studied GPCRs, the N-terminus which harbors this mutation, is absent in all available experimental structures. The goal of this work was to study the molecular level differences between the N-terminal variants using structural modeling and atomistic molecular dynamics simulations. Our simulations reveal that the N-terminal region of the Arg variant shows greater dynamics than the Gly variant, leading to differential placement. Further, the position and dynamics of the N-terminal region, further, affects the ligand binding-site accessibility. Interestingly, long-range effects are also seen at the ligand binding site, which is marginally larger in the Gly as compared to the Arg variant resulting in the preferential docking of albuterol to the Gly variant. This study thus reveals key differences between the variants providing a molecular framework towards understanding the variable drug response in asthma patients. '),
(86925, 2014, 'plos', 'Disrupted calcium release as a mechanism for atrial alternans associated with human atrial fibrillation', 'Chang, Kelly C|Bayer, Jason D|Trayanova, Natalia A', 'Institute for Computational Medicine, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.|IHU-LIRYC - LInstitut de RYthmologie et Modélisation Cardiaque, University of Bordeaux, Bordeaux, France.|Institute for Computational Medicine, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.', 'United States|France|United States', 27, 'Action Potentials|Atrial Fibrillation|Calcium|Calcium Signaling|Heart Atria|Humans|Models, Cardiovascular|Ryanodine Receptor Calcium Release Channel', 'Journal Article', '10.1371/journal.pcbi.1004011', '25501557', 'Atrial fibrillation (AF) is the most common cardiac arrhythmia, but our knowledge of the arrhythmogenic substrate is incomplete. Alternans, the beat-to-beat alternation in the shape of cardiac electrical signals, typically occurs at fast heart rates and leads to arrhythmia. However, atrial alternans have been observed at slower pacing rates in AF patients than in controls, suggesting that increased vulnerability to arrhythmia in AF patients may be due to the proarrythmic influence of alternans at these slower rates. As such, alternans may present a useful therapeutic target for the treatment and prevention of AF, but the mechanism underlying alternans occurrence in AF patients at heart rates near rest is unknown. The goal of this study was to determine how cellular changes that occur in human AF affect the appearance of alternans at heart rates near rest. To achieve this, we developed a computational model of human atrial tissue incorporating electrophysiological remodeling associated with chronic AF (cAF) and performed parameter sensitivity analysis of ionic model parameters to determine which cellular changes led to alternans. Of the 20 parameters tested, only decreasing the ryanodine receptor (RyR) inactivation rate constant (kiCa) produced action potential duration (APD) alternans seen clinically at slower pacing rates. Using single-cell clamps of voltage, fluxes, and state variables, we determined that alternans onset was Ca2+-driven rather than voltage-driven and occurred as a result of decreased RyR inactivation which led to increased steepness of the sarcoplasmic reticulum (SR) Ca2+ release slope. Iterated map analysis revealed that because SR Ca2+ uptake efficiency was much higher in control atrial cells than in cAF cells, drastic reductions in kiCa were required to produce alternans at comparable pacing rates in control atrial cells. These findings suggest that RyR kinetics may play a critical role in altered Ca2+ homeostasis which drives proarrhythmic APD alternans in patients with AF. '),
(86926, 2014, 'plos', 'Protein-protein docking with dynamic residue protonation states', 'Kilambi, Krishna Praneeth|Reddy, Kavan|Gray, Jeffrey J', 'Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America, Program in Molecular Biophysics, Johns Hopkins University, Baltimore, Maryland, United States of America.', 'United States|United States|United States', 13, 'Algorithms|Computational Biology|Hydrogen Bonding|Molecular Docking Simulation|Protein Binding|Proteins|Protons', 'Journal Article', '10.1371/journal.pcbi.1004018', '25501663', 'Protein-protein interactions depend on a host of environmental factors. Local pH conditions influence the interactions through the protonation states of the ionizable residues that can change upon binding. In this work, we present a pH-sensitive docking approach, pHDock, that can sample side-chain protonation states of five ionizable residues (Asp, Glu, His, Tyr, Lys) on-the-fly during the docking simulation. pHDock produces successful local docking funnels in approximately half (79/161) the protein complexes, including 19 cases where standard RosettaDock fails. pHDock also performs better than the two control cases comprising docking at pH 7.0 or using fixed, predetermined protonation states. On average, the top-ranked pHDock structures have lower interface RMSDs and recover more native interface residue-residue contacts and hydrogen bonds compared to RosettaDock. Addition of backbone flexibility using a computationally-generated conformational ensemble further improves native contact and hydrogen bond recovery in the top-ranked structures. Although pHDock is designed to improve docking, it also successfully predicts a large pH-dependent binding affinity change in the Fc-FcRn complex, suggesting that it can be exploited to improve affinity predictions. The approaches in the study contribute to the goal of structural simulations of whole-cell protein-protein interactions including all the environmental factors, and they can be further expanded for pH-sensitive protein design. '),
(86927, 2014, 'plos', 'The role of membrane-mediated interactions in the assembly and architecture of chemoreceptor lattices', 'Haselwandter, Christoph A|Wingreen, Ned S', 'Departments of Physics & Astronomy and Biological Sciences, University of Southern California, Los Angeles, California, United States of America.|Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America.', 'United States|Jersey', 21, 'Cell Membrane|Computational Biology|Escherichia coli|Escherichia coli Proteins|Lipid Bilayers|Models, Biological|Models, Molecular|Receptors, Cell Surface', 'Journal Article', '10.1371/journal.pcbi.1003932', '25503274', 'In vivo fluorescence microscopy and electron cryo-tomography have revealed that chemoreceptors self-assemble into extended honeycomb lattices of chemoreceptor trimers with a well-defined relative orientation of trimers. The signaling response of the observed chemoreceptor lattices is remarkable for its extreme sensitivity, which relies crucially on cooperative interactions among chemoreceptor trimers. In common with other membrane proteins, chemoreceptor trimers are expected to deform the surrounding lipid bilayer, inducing membrane-mediated anisotropic interactions between neighboring trimers. Here we introduce a biophysical model of bilayer-chemoreceptor interactions, which allows us to quantify the role of membrane-mediated interactions in the assembly and architecture of chemoreceptor lattices. We find that, even in the absence of direct protein-protein interactions, membrane-mediated interactions can yield assembly of chemoreceptor lattices at very dilute trimer concentrations. The model correctly predicts the observed honeycomb architecture of chemoreceptor lattices as well as the observed relative orientation of chemoreceptor trimers, suggests a series of gateway states for chemoreceptor lattice assembly, and provides a simple mechanism for the localization of large chemoreceptor lattices to the cell poles. Our model of bilayer-chemoreceptor interactions also helps to explain the observed dependence of chemotactic signaling on lipid bilayer properties. Finally, we consider the possibility that membrane-mediated interactions might contribute to cooperativity among neighboring chemoreceptor trimers. '),
(86928, 2014, 'plos', 'Oscillation-induced signal transmission and gating in neural circuits', 'Jahnke, Sven|Memmesheimer, Raoul-Martin|Timme, Marc', 'Network Dynamics, Max Planck Institute for Dynamics and Self-Organization (MPIDS), Göttingen, Germany, Bernstein Center for Computational Neuroscience (BCCN), Göttingen, Germany, Institute for Nonlinear Dynamics, Fakultät für Physik, Georg-August Universität Göttingen, Göttingen Germany.|Department for Neuroinformatics, Donders Institute, Radboud University, Nijmegen, Netherlands.|Network Dynamics, Max Planck Institute for Dynamics and Self-Organization (MPIDS), Göttingen, Germany, Bernstein Center for Computational Neuroscience (BCCN), Göttingen, Germany, Institute for Nonlinear Dynamics, Fakultät für Physik, Georg-August Universität Göttingen, Göttingen Germany.', 'Germany|Netherlands|Germany', 15, 'Action Potentials|Models, Neurological|Nerve Net|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1003940', '25503492', 'Reliable signal transmission constitutes a key requirement for neural circuit function. The propagation of synchronous pulse packets through recurrent circuits is hypothesized to be one robust form of signal transmission and has been extensively studied in computational and theoretical works. Yet, although external or internally generated oscillations are ubiquitous across neural systems, their influence on such signal propagation is unclear. Here we systematically investigate the impact of oscillations on propagating synchrony. We find that for standard, additive couplings and a net excitatory effect of oscillations, robust propagation of synchrony is enabled in less prominent feed-forward structures than in systems without oscillations. In the presence of non-additive coupling (as mediated by fast dendritic spikes), even balanced oscillatory inputs may enable robust propagation. Here, emerging resonances create complex locking patterns between oscillations and spike synchrony. Interestingly, these resonances make the circuits capable of selecting specific pathways for signal transmission. Oscillations may thus promote reliable transmission and, in co-action with dendritic nonlinearities, provide a mechanism for information processing by selectively gating and routing of signals. Our results are of particular interest for the interpretation of sharp wave/ripple complexes in the hippocampus, where previously learned spike patterns are replayed in conjunction with global high-frequency oscillations. We suggest that the oscillations may serve to stabilize the replay. '),
(86929, 2014, 'plos', 'Bioinformatics: introduction and methods, a bilingual Massive Open Online Course (MOOC) as a new example for global bioinformatics education', 'Ding, Yang|Wang, Meng|He, Yao|Ye, Adam Yongxin|Yang, Xiaoxu|Liu, Fenglin|Meng, Yuqi|Gao, Ge|Wei, Liping', 'Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, Peoples Republic of China.|Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, Peoples Republic of China.|National Institute of Biological Sciences, Beijing, Peoples Republic of China, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, Peoples Republic of China.|Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, Peoples Republic of China, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, Peoples Republic of China.|Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, Peoples Republic of China.|Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, Peoples Republic of China.|Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, Peoples Republic of China.|Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, Peoples Republic of China.|Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, Peoples Republic of China, National Institute of Biological Sciences, Beijing, Peoples Republic of China.', 'China|China|China|China|China|China|China|China|China', 0, 'Adult|Computational Biology|Computer-Assisted Instruction|Humans|Internet|Middle Aged|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1003955', '25503717', '-'),
(86930, 2014, 'plos', 'Thermodynamic costs of information processing in sensory adaptation', 'Sartori, Pablo|Granger, Léo|Lee, Chiu Fan|Horowitz, Jordan M', 'Max Planck Institute for the Physics of Complex Systems, Dresden, Germany.|Departamento de Física Atómica, Molecular y Nuclear and GISC, Universidad Complutense de Madrid, Madrid, Spain.|Department of Bioengineering, Imperial College London, London, United Kingdom.|Department of Physics, University of Massachusetts at Boston, Boston, Massachusetts, United States of America.', 'Germany|Spain|United Kingdom|United States', 59, 'Adaptation, Physiological|Chemotaxis|Computational Biology|Escherichia coli|Models, Biological|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003974', '25503948', 'Biological sensory systems react to changes in their surroundings. They are characterized by fast response and slow adaptation to varying environmental cues. Insofar as sensory adaptive systems map environmental changes to changes of their internal degrees of freedom, they can be regarded as computational devices manipulating information. Landauer established that information is ultimately physical, and its manipulation subject to the entropic and energetic bounds of thermodynamics. Thus the fundamental costs of biological sensory adaptation can be elucidated by tracking how the information the system has about its environment is altered. These bounds are particularly relevant for small organisms, which unlike everyday computers, operate at very low energies. In this paper, we establish a general framework for the thermodynamics of information processing in sensing. With it, we quantify how during sensory adaptation information about the past is erased, while information about the present is gathered. This process produces entropy larger than the amount of old information erased and has an energetic cost bounded by the amount of new information written to memory. We apply these principles to the E. colis chemotaxis pathway during binary ligand concentration changes. In this regime, we quantify the amount of information stored by each methyl group and show that receptors consume energy in the range of the information-theoretic minimum. Our work provides a basis for further inquiries into more complex phenomena, such as gradient sensing and frequency response. '),
(86931, 2014, 'plos', 'Two-dimensionality of yeast colony expansion accompanied by pattern formation', 'Chen, Lin|Noorbakhsh, Javad|Adams, Rhys M|Samaniego-Evans, Joseph|Agollah, Germaine|Nevozhay, Dmitry|Kuzdzal-Fick, Jennie|Mehta, Pankaj|Balxc3xa1zsi, Gxc3xa1bor', 'Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Department of Physics, Metcalf Science Center (SCI), Boston University, Boston, Massachusetts, United States of America.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Department of Physics, Metcalf Science Center (SCI), Boston University, Boston, Massachusetts, United States of America.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America, School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Department of Physics, Metcalf Science Center (SCI), Boston University, Boston, Massachusetts, United States of America.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America, The Louis and Beatrice Laufer Center for Physical & Quantitative Biology, Stony Brook University, Stony Brook, New York, United States of America, Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 17, 'Cell Culture Techniques|Computer Simulation|Glucose|Membrane Glycoproteins|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins', 'Journal Article', '10.1371/journal.pcbi.1003979', '25504059', 'Yeasts can form multicellular patterns as they expand on agar plates, a phenotype that requires a functional copy of the FLO11 gene. Although the biochemical and molecular requirements for such patterns have been examined, the mechanisms underlying their formation are not entirely clear. Here we develop quantitative methods to accurately characterize the size, shape, and surface patterns of yeast colonies for various combinations of agar and sugar concentrations. We combine these measurements with mathematical and physical models and find that FLO11 gene constrains cells to grow near the agar surface, causing the formation of larger and more irregular colonies that undergo hierarchical wrinkling. Head-to-head competition assays on agar plates indicate that two-dimensional constraint on the expansion of FLO11 wild type (FLO11) cells confers a fitness advantage over FLO11 knockout (flo11xcex94) cells on the agar surface. '),
(86932, 2014, 'plos', 'Sliding of proteins non-specifically bound to DNA: Brownian dynamics studies with coarse-grained protein and DNA models', 'Ando, Tadashi|Skolnick, Jeffrey', 'Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, Atlanta, Georgia, United States of America.|Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, Atlanta, Georgia, United States of America.', 'Georgia|Georgia', 0, 'Algorithms|DNA|Molecular Dynamics Simulation|Protein Binding|Proteins', 'Journal Article', '10.1371/journal.pcbi.1003990', '25504215', 'DNA binding proteins efficiently search for their cognitive sites on long genomic DNA by combining 3D diffusion and 1D diffusion (sliding) along the DNA. Recent experimental results and theoretical analyses revealed that the proteins show a rotation-coupled sliding along DNA helical pitch. Here, we performed Brownian dynamics simulations using newly developed coarse-grained protein and DNA models for evaluating how hydrodynamic interactions between the protein and DNA molecules, binding affinity of the protein to DNA, and DNA fluctuations affect the one dimensional diffusion of the protein on the DNA. Our results indicate that intermolecular hydrodynamic interactions reduce 1D diffusivity by 30%. On the other hand, structural fluctuations of DNA give rise to steric collisions between the CG-proteins and DNA, resulting in faster 1D sliding of the protein. Proteins with low binding affinities consistent with experimental estimates of non-specific DNA binding show hopping along the CG-DNA. This hopping significantly increases sliding speed. These simulation studies provide additional insights into the mechanism of how DNA binding proteins find their target sites on the genome. '),
(86933, 2014, 'plos', 'The pharmacodynamics of the p53-Mdm2 targeting drug Nutlin: the role of gene-switching noise', 'Puszynski, Krzysztof|Gandolfi, Alberto|dOnofrio, Alberto', 'Silesian University of Technology, Institute of Automatic Control, Gliwice, Poland.|Istituto di Analisi dei Sistemi ed Informatica A. Ruberti - CNR, Rome, Italy.|Department of Experimental Oncology, European Institute of Oncology, Milan, Italy, International Prevention Research Institute, Lyon, France.', 'Poland|Italy|France', 0, 'Algorithms|Animals|Cell Line, Tumor|Computational Biology|Drug Delivery Systems|HCT116 Cells|Humans|Imidazoles|Mice|Models, Biological|Piperazines|Proto-Oncogene Proteins c-mdm2|Signal Transduction|Tumor Suppressor Protein p53', 'Journal Article', '10.1371/journal.pcbi.1003991', '25504419', 'In this work we investigate, by means of a computational stochastic model, how tumor cells with wild-type p53 gene respond to the drug Nutlin, an agent that interferes with the Mdm2-mediated p53 regulation. In particular, we show how the stochastic gene-switching controlled by p53 can explain experimental dose-response curves, i.e., the observed inter-cell variability of the cell viability under Nutlin action. The proposed model describes in some detail the regulation network of p53, including the negative feedback loop mediated by Mdm2 and the positive loop mediated by PTEN, as well as the reversible inhibition of Mdm2 caused by Nutlin binding. The fate of the individual cell is assumed to be decided by the rising of nuclear-phosphorylated p53 over a certain threshold. We also performed in silico experiments to evaluate the dose-response curve after a single drug dose delivered in mice, or after its fractionated administration. Our results suggest that dose-splitting may be ineffective at low doses and effective at high doses. This complex behavior can be due to the interplay among the existence of a threshold on the p53 level for its cell activity, the nonlinearity of the relationship between the bolus dose and the peak of active p53, and the relatively fast elimination of the drug. ');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86934, 2014, 'plos', 'Symmetry restoring bifurcation in collective decision-making', 'Zabzina, Natalia|Dussutour, Audrey|Mann, Richard P|Sumpter, David J T|Nicolis, Stamatios C', 'Mathematics Department, Uppsala University, Uppsala, Sweden.|Research Center on Animal Cognition, Université Paul Sabatier, Toulouse, France.|Mathematics Department, Uppsala University, Uppsala, Sweden.|Mathematics Department, Uppsala University, Uppsala, Sweden.|Mathematics Department, Uppsala University, Uppsala, Sweden.', 'Sweden|France|Sweden|Sweden|Sweden', 8, 'Decision Making|Feedback, Physiological|Models, Biological|Physarum polycephalum', 'Journal Article', '10.1371/journal.pcbi.1003960', '25521109', 'How social groups and organisms decide between alternative feeding sites or shelters has been extensively studied both experimentally and theoretically. One key result is the existence of a symmetry-breaking bifurcation at a critical system size, where there is a switch from evenly distributed exploitation of all options to a focussed exploitation of just one. Here we present a decision-making model in which symmetry-breaking is followed by a symmetry restoring bifurcation, whereby very large systems return to an even distribution of exploitation amongst options. The model assumes local positive feedback, coupled with a negative feedback regulating the flow toward the feeding sites. We show that the model is consistent with three different strains of the slime mold Physarum polycephalum, choosing between two feeding sites. We argue that this combination of feedbacks could allow collective foraging organisms to react flexibly in a dynamic environment. '),
(86935, 2014, 'plos', 'Deep neural networks rival the representation of primate IT cortex for core visual object recognition', 'Cadieu, Charles F|Hong, Ha|Yamins, Daniel L K|Pinto, Nicolas|Ardila, Diego|Solomon, Ethan A|Majaj, Najib J|DiCarlo, James J', 'Department of Brain and Cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Brain and Cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Brain and Cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Brain and Cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Brain and Cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Brain and Cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Brain and Cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Brain and Cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Algorithms|Animals|Macaca mulatta|Male|Models, Neurological|Nerve Net|Neural Networks (Computer)|Pattern Recognition, Visual|Temporal Lobe', 'Journal Article', '10.1371/journal.pcbi.1003963', '25521294', 'The primate visual system achieves remarkable visual object recognition performance even in brief presentations, and under changes to object exemplar, geometric transformations, and background variation (a.k.a. core visual object recognition). This remarkable performance is mediated by the representation formed in inferior temporal (IT) cortex. In parallel, recent advances in machine learning have led to ever higher performing models of object recognition using artificial deep neural networks (DNNs). It remains unclear, however, whether the representational performance of DNNs rivals that of the brain. To accurately produce such a comparison, a major difficulty has been a unifying metric that accounts for experimental limitations, such as the amount of noise, the number of neural recording sites, and the number of trials, and computational limitations, such as the complexity of the decoding classifier and the number of classifier training examples. In this work, we perform a direct comparison that corrects for these experimental limitations and computational considerations. As part of our methodology, we propose an extension of kernel analysis that measures the generalization accuracy as a function of representational complexity. Our evaluations show that, unlike previous bio-inspired models, the latest DNNs rival the representational performance of IT cortex on this visual object recognition task. Furthermore, we show that models that perform well on measures of representational performance also perform well on measures of representational similarity to IT, and on measures of predicting individual IT multi-unit responses. Whether these DNNs rely on computational mechanisms similar to the primate visual system is yet to be determined, but, unlike all previous bio-inspired models, that possibility cannot be ruled out merely on representational performance grounds. '),
(86936, 2014, 'plos', 'Glutamate mediated astrocytic filtering of neuronal activity', 'Wallach, Gilad|Lallouette, Jules|Herzog, Nitzan|De Pittà, Maurizio|Ben Jacob, Eshel|Berry, Hugues|Hanein, Yael', 'School of Electrical Engineering, Tel Aviv University, Ramat Aviv, Israel.|Team Beagle, INRIA Rhone-Alpes, Villeurbanne, France, University of Lyon, LIRIS UMR5205, Villeurbanne, France.|School of Electrical Engineering, Tel Aviv University, Ramat Aviv, Israel, Department of Electrical and Electronic Engineering, University of Nottingham, Nottingham, United Kingdom.|School of Electrical Engineering, Tel Aviv University, Ramat Aviv, Israel, Team Beagle, INRIA Rhone-Alpes, Villeurbanne, France, University of Lyon, LIRIS UMR5205, Villeurbanne, France, School of Physics and Astronomy, Tel Aviv University, Ramat Aviv, Israel.|School of Physics and Astronomy, Tel Aviv University, Ramat Aviv, Israel, Center for Theoretical Biological Physics, Rice University, Houston, Texas, United States of America.|Team Beagle, INRIA Rhone-Alpes, Villeurbanne, France, University of Lyon, LIRIS UMR5205, Villeurbanne, France.|School of Electrical Engineering, Tel Aviv University, Ramat Aviv, Israel.', 'Israel|France|United Kingdom|France|Israel|France|Israel', 0, 'Animals|Astrocytes|Calcium|Calcium Signaling|Cell Communication|Cells, Cultured|Cerebral Cortex|Computational Biology|Glutamic Acid|Models, Neurological|Neurons|Rats|Rats, Sprague-Dawley|Synapses', 'Journal Article', '10.1371/journal.pcbi.1003964', '25521344', 'Neuron-astrocyte communication is an important regulatory mechanism in various brain functions but its complexity and role are yet to be fully understood. In particular, the temporal pattern of astrocyte response to neuronal firing has not been fully characterized. Here, we used neuron-astrocyte cultures on multi-electrode arrays coupled to Ca2+ imaging and explored the range of neuronal stimulation frequencies while keeping constant the amount of stimulation. Our results reveal that astrocytes specifically respond to the frequency of neuronal stimulation by intracellular Ca2+ transients, with a clear onset of astrocytic activation at neuron firing rates around 3-5 Hz. The cell-to-cell heterogeneity of the astrocyte Ca2+ response was however large and increasing with stimulation frequency. Astrocytic activation by neurons was abolished with antagonists of type I metabotropic glutamate receptor, validating the glutamate-dependence of this neuron-to-astrocyte pathway. Using a realistic biophysical model of glutamate-based intracellular calcium signaling in astrocytes, we suggest that the stepwise response is due to the supralinear dynamics of intracellular IP3 and that the heterogeneity of the responses may be due to the heterogeneity of the astrocyte-to-astrocyte couplings via gap junction channels. Therefore our results present astrocyte intracellular Ca2+ activity as a nonlinear integrator of glutamate-dependent neuronal activity. '),
(86937, 2014, 'plos', 'Evolution of integrated causal structures in animats exposed to environments of increasing complexity', 'Albantakis, Larissa|Hintze, Arend|Koch, Christof|Adami, Christoph|Tononi, Giulio', 'Department of Psychiatry, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, United States of America, BEACON Center for the Study of Evolution in Action, Michigan State University, East Lansing, Michigan, United States of America.|Allen Institute for Brain Science, Seattle, Washington, United States of America.|Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, United States of America, BEACON Center for the Study of Evolution in Action, Michigan State University, East Lansing, Michigan, United States of America, Department of Physics and Astronomy, Michigan State University, East Lansing, Michigan, United States of America.|Department of Psychiatry, University of Wisconsin, Madison, Wisconsin, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Adaptation, Physiological|Algorithms|Biological Evolution|Computational Biology|Computer Simulation|Feedback, Physiological|Genetic Fitness|Models, Neurological|Selection, Genetic|Statistics, Nonparametric', 'Journal Article', '10.1371/journal.pcbi.1003966', '25521484', 'Natural selection favors the evolution of brains that can capture fitness-relevant features of the environments causal structure. We investigated the evolution of small, adaptive logic-gate networks (animats) in task environments where falling blocks of different sizes have to be caught or avoided in a Tetris-like game. Solving these tasks requires the integration of sensor inputs and memory. Evolved networks were evaluated using measures of information integration, including the number of evolved concepts and the total amount of integrated conceptual information. The results show that, over the course of the animats adaptation, i) the number of concepts grows, ii) integrated conceptual information increases, iii) this increase depends on the complexity of the environment, especially on the requirement for sequential memory. These results suggest that the need to capture the causal structure of a rich environment, given limited sensors and internal mechanisms, is an important driving force for organisms to develop highly integrated networks (brains) with many concepts, leading to an increase in their internal complexity. '),
(86938, 2014, 'plos', 'Segregating complex sound sources through temporal coherence', 'Krishnan, Lakshmi|Elhilali, Mounya|Shamma, Shihab', 'Department of Electrical and Computer Engineering, University of Maryland, College Park, Maryland, United States of America.|Department of Electrical and Computer Engineering, The Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Electrical and Computer Engineering, University of Maryland, College Park, Maryland, United States of America, Department Etudes Cognitive, Ecole Normale Superieure, Paris, France.', 'United States|United States|France', 0, 'Acoustic Stimulation|Algorithms|Auditory Cortex|Auditory Perception|Female|Humans|Male|Models, Neurological|Noise|Speech|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1003985', '25521593', 'A new approach for the segregation of monaural sound mixtures is presented based on the principle of temporal coherence and using auditory cortical representations. Temporal coherence is the notion that perceived sources emit coherently modulated features that evoke highly-coincident neural response patterns. By clustering the feature channels with coincident responses and reconstructing their input, one may segregate the underlying source from the simultaneously interfering signals that are uncorrelated with it. The proposed algorithm requires no prior information or training on the sources. It can, however, gracefully incorporate cognitive functions and influences such as memories of a target source or attention to a specific set of its attributes so as to segregate it from its background. Aside from its unusual structure and computational innovations, the proposed model provides testable hypotheses of the physiological mechanisms of this ubiquitous and remarkable perceptual ability, and of its psychophysical manifestations in navigating complex sensory environments. '),
(86939, 2014, 'plos', 'Competing ParA structures space bacterial plasmids equally over the nucleoid', 'Ietswaart, Robert|Szardenings, Florian|Gerdes, Kenn|Howard, Martin', 'Computational and Systems Biology, John Innes Centre, Norwich, United Kingdom.|Centre for Bacterial Cell Biology, Newcastle University, Newcastle upon Tyne, United Kingdom.|Centre for Bacterial Cell Biology, Newcastle University, Newcastle upon Tyne, United Kingdom, Department of Biology, University of Copenhagen, Copenhagen, Denmark.|Computational and Systems Biology, John Innes Centre, Norwich, United Kingdom.', 'United Kingdom|United Kingdom|Denmark|United Kingdom', 0, 'Computational Biology|DNA, Bacterial|Diffusion|Escherichia coli|Intracellular Space|Models, Biological|Plasmids', 'Journal Article', '10.1371/journal.pcbi.1004009', '25521716', 'Low copy number plasmids in bacteria require segregation for stable inheritance through cell division. This is often achieved by a parABC locus, comprising an ATPase ParA, DNA-binding protein ParB and a parC region, encoding ParB-binding sites. These minimal components space plasmids equally over the nucleoid, yet the underlying mechanism is not understood. Here we investigate a model where ParA-ATP can dynamically associate to the nucleoid and is hydrolyzed by plasmid-associated ParB, thereby creating nucleoid-bound, self-organizing ParA concentration gradients. We show mathematically that differences between competing ParA concentrations on either side of a plasmid can specify regular plasmid positioning. Such positioning can be achieved regardless of the exact mechanism of plasmid movement, including plasmid diffusion with ParA-mediated immobilization or directed plasmid motion induced by ParB/parC-stimulated ParA structure disassembly. However, we find experimentally that parABC from Escherichia coli plasmid pB171 increases plasmid mobility, inconsistent with diffusion/immobilization. Instead our observations favor directed plasmid motion. Our model predicts less oscillatory ParA dynamics than previously believed, a prediction we verify experimentally. We also show that ParA localization and plasmid positioning depend on the underlying nucleoid morphology, indicating that the chromosomal architecture constrains ParA structure formation. Our directed motion model unifies previously contradictory models for plasmid segregation and provides a robust mechanistic basis for self-organized plasmid spacing that may be widely applicable. '),
(86940, 2014, 'plos', 'Bilinearity in spatiotemporal integration of synaptic inputs', 'Li, Songting|Liu, Nan|Zhang, Xiao-Hui|Zhou, Douglas|Cai, David', 'Department of Mathematics, MOE-LSC and Institute of Natural Sciences, Shanghai Jiao Tong University, Shanghai, China.|State Key Laboratory of Cognitive Neuroscience and Learning and IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China.|State Key Laboratory of Cognitive Neuroscience and Learning and IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China.|Department of Mathematics, MOE-LSC and Institute of Natural Sciences, Shanghai Jiao Tong University, Shanghai, China.|Department of Mathematics, MOE-LSC and Institute of Natural Sciences, Shanghai Jiao Tong University, Shanghai, China, Courant Institute of Mathematical Sciences and Center for Neural Science, New York University, New York, New York, United States of America, NYUAD Institute, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.', 'China|China|China|China|United Arab Emirates', 6, 'Animals|CA1 Region, Hippocampal|Computer Simulation|Dendrites|Models, Neurological|Rats|Synapses', 'Journal Article', '10.1371/journal.pcbi.1004014', '25521832', 'Neurons process information via integration of synaptic inputs from dendrites. Many experimental results demonstrate dendritic integration could be highly nonlinear, yet few theoretical analyses have been performed to obtain a precise quantitative characterization analytically. Based on asymptotic analysis of a two-compartment passive cable model, given a pair of time-dependent synaptic conductance inputs, we derive a bilinear spatiotemporal dendritic integration rule. The summed somatic potential can be well approximated by the linear summation of the two postsynaptic potentials elicited separately, plus a third additional bilinear term proportional to their product with a proportionality coefficient [Formula: see text]. The rule is valid for a pair of synaptic inputs of all types, including excitation-inhibition, excitation-excitation, and inhibition-inhibition. In addition, the rule is valid during the whole dendritic integration process for a pair of synaptic inputs with arbitrary input time differences and input locations. The coefficient [Formula: see text] is demonstrated to be nearly independent of the input strengths but is dependent on input times and input locations. This rule is then verified through simulation of a realistic pyramidal neuron model and in electrophysiological experiments of rat hippocampal CA1 neurons. The rule is further generalized to describe the spatiotemporal dendritic integration of multiple excitatory and inhibitory synaptic inputs. The integration of multiple inputs can be decomposed into the sum of all possible pairwise integration, where each paired integration obeys the bilinear rule. This decomposition leads to a graph representation of dendritic integration, which can be viewed as functionally sparse. '),
(86941, 2014, 'plos', 'Metadynamics simulations reveal a Na+ independent exiting path of galactose for the inward-facing conformation of vSGLT', 'Bisha, Ina|Rodriguez, Alex|Laio, Alessandro|Magistrato, Alessandra', 'SISSA, Trieste, Italy.|SISSA, Trieste, Italy.|SISSA, Trieste, Italy.|CNR-IOM-Democritos National Simulation Center, SISSA, Trieste, Italy.', 'Italy|Italy|Italy|Italy', 16, 'Galactose|Kinetics|Molecular Dynamics Simulation|Sodium|Sodium-Glucose Transport Proteins|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1004017', '25522004', 'Sodium-Galactose Transporter (SGLT) is a secondary active symporter which accumulates sugars into cells by using the electrochemical gradient of Na+ across the membrane. Previous computational studies provided insights into the release process of the two ligands (galactose and sodium ion) into the cytoplasm from the inward-facing conformation of Vibrio parahaemolyticus sodium/galactose transporter (vSGLT). Several aspects of the transport mechanism of this symporter remain to be clarified: (i) a detailed kinetic and thermodynamic characterization of the exit path of the two ligands is still lacking, (ii) contradictory conclusions have been drawn concerning the gating role of Y263, (iii) the role of Na+ in modulating the release path of galactose is not clear. In this work, we use bias-exchange metadynamics simulations to characterize the free energy profile of the galactose and Na+ release processes toward the intracellular side. Surprisingly, we find that the exit of Na+ and galactose is non-concerted as the cooperativity between the two ligands is associated to a transition that is not rate limiting. The dissociation barriers are of the order of 11-12 kcal/mol for both the ion and the substrate, in line with kinetic information concerning this type of transporters. On the basis of these results we propose a branched six-state alternating access mechanism, which may be shared also by other members of the LeuT-fold transporters. '),
(86942, 2014, 'plos', 'Immuno-epidemiological modeling of HIV-1 predicts high heritability of the set-point virus load, while selection for CTL escape dominates virulence evolution', 'van Dorp, Christiaan H|van Boven, Michiel|de Boer, Rob J', 'Theoretical Biology and Bioinformatics, Universiteit Utrecht, Utrecht, The Netherlands, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.|National Institute for Public Health and the Environment, Bilthoven, The Netherlands.|Theoretical Biology and Bioinformatics, Universiteit Utrecht, Utrecht, The Netherlands.', 'Netherlands|Netherlands|Netherlands', 16, 'Computational Biology|Evolution, Molecular|HIV Infections|HIV-1|Humans|Immune Evasion|Models, Immunological|T-Lymphocytes, Cytotoxic|Viral Load', 'Journal Article', '10.1371/journal.pcbi.1003899', '25522184', 'It has been suggested that HIV-1 has evolved its set-point virus load to be optimized for transmission. Previous epidemiological models and studies into the heritability of set-point virus load confirm that this mode of adaptation within the human population is feasible. However, during the many cycles of replication between infection of a host and transmission to the next host, HIV-1 is under selection for escape from immune responses, and not transmission. Here we investigate with computational and mathematical models how these two levels of selection, within-host and between-host, are intertwined. We find that when the rate of immune escape is comparable to what has been observed in patients, immune selection within hosts is dominant over selection for transmission. Surprisingly, we do find high values for set-point virus load heritability, and argue that high heritability estimates can be caused by the footprints left by differing hosts immune systems on the virus. '),
(86943, 2014, 'plos', 'An extra dimension to decision-making in animals: the three-way trade-off between speed, effort per-unit-time and accuracy', 'de Froment, Adrian J|Rubenstein, Daniel I|Levin, Simon A', 'Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America.|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America.|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America.', 'Jersey|Jersey|Jersey', 6, 'Animals|Bees|Biological Evolution|Brain|Computational Biology|Decision Making|Humans|Mammals|Models, Biological|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1003937', '25522281', 'The standard view in biology is that all animals, from bumblebees to human beings, face a trade-off between speed and accuracy as they search for resources and mates, and attempt to avoid predators. For example, the more time a forager spends out of cover gathering information about potential food sources the more likely it is to make accurate decisions about which sources are most rewarding. However, when the cost of time spent out of cover rises (e.g. in the presence of a predator) the optimal strategy is for the forager to spend less time gathering information and to accept a corresponding decline in the accuracy of its decisions. We suggest that this familiar picture is missing a crucial dimension: the amount of effort an animal expends on gathering information in each unit of time. This is important because an animal that can respond to changing time costs by modulating its level of effort per-unit-time does not have to accept the same decrease in accuracy that an animal limited to a simple speed-accuracy trade-off must bear in the same situation. Instead, it can direct additional effort towards (i) reducing the frequency of perceptual errors in the samples it gathers or (ii) increasing the number of samples it gathers per-unit-time. Both of these have the effect of allowing it to gather more accurate information within a given period of time. We use a modified version of a canonical model of decision-making (the sequential probability ratio test) to show that this ability to substitute effort for time confers a fitness advantage in the face of changing time costs. We predict that the ability to modulate effort levels will therefore be widespread in nature, and we lay out testable predictions that could be used to detect adaptive modulation of effort levels in laboratory and field studies. Our understanding of decision-making in all species, including our own, will be improved by this more ecologically-complete picture of the three-way tradeoff between time, effort per-unit-time and accuracy. '),
(86944, 2014, 'plos', 'Multitask learning of signaling and regulatory networks with application to studying human response to flu', 'Jain, Siddhartha|Gitter, Anthony|Bar-Joseph, Ziv', 'Computer Science Department, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|Microsoft Research, Cambridge, Massachusetts, United States of America, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Lane Center for Computational Biology and Machine Learning Department, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.', 'United States|United States|United States', 7, 'Algorithms|Gene Regulatory Networks|Humans|Influenza A virus|Influenza, Human|Machine Learning|Signal Transduction|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1003943', '25522349', 'Reconstructing regulatory and signaling response networks is one of the major goals of systems biology. While several successful methods have been suggested for this task, some integrating large and diverse datasets, these methods have so far been applied to reconstruct a single response network at a time, even when studying and modeling related conditions. To improve network reconstruction we developed MT-SDREM, a multi-task learning method which jointly models networks for several related conditions. In MT-SDREM, parameters are jointly constrained across the networks while still allowing for condition-specific pathways and regulation. We formulate the multi-task learning problem and discuss methods for optimizing the joint target function. We applied MT-SDREM to reconstruct dynamic human response networks for three flu strains: H1N1, H5N1 and H3N2. Our multi-task learning method was able to identify known and novel factors and genes, improving upon prior methods that model each condition independently. The MT-SDREM networks were also better at identifying proteins whose removal affects viral load indicating that joint learning can still lead to accurate, condition-specific, networks. Supporting website with MT-SDREM implementation: http://sb.cs.cmu.edu/mtsdrem. '),
(86945, 2015, 'plos', 'Analysis of individual protein regions provides novel insights on cancer pharmacogenomics', 'Porta Pardo, Eduard|Godzik, Adam', 'Program on Bioinformatics and Systems Biology, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.|Program on Bioinformatics and Systems Biology, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.', 'United States|United States', 7, 'Antineoplastic Agents|Cell Line, Tumor|Databases, Genetic|Humans|Mutation|Pharmacogenetics|Precision Medicine|Protein Binding|Protein Interaction Maps|Protein Structure, Tertiary|Proteins|Survival Analysis', 'Journal Article', '10.1371/journal.pcbi.1004024', '25568936', 'The promise of personalized cancer medicine cannot be fulfilled until we gain better understanding of the connections between the genomic makeup of a patients tumor and its response to anticancer drugs. Several datasets that include both pharmacologic profiles of cancer cell lines as well as their genomic alterations have been recently developed and extensively analyzed. However, most analyses of these datasets assume that mutations in a gene will have the same consequences regardless of their location. While this assumption might be correct in some cases, such analyses may miss subtler, yet still relevant, effects mediated by mutations in specific protein regions. Here we study such perturbations by separating effects of mutations in different protein functional regions (PFRs), including protein domains and intrinsically disordered regions. Using this approach, we have been able to identify 171 novel associations between mutations in specific PFRs and changes in the activity of 24 drugs that couldnt be recovered by traditional gene-centric analyses. Our results demonstrate how focusing on individual protein regions can provide novel insights into the mechanisms underlying the drug sensitivity of cancer cell lines. Moreover, while these new correlations are identified using only data from cancer cell lines, we have been able to validate some of our predictions using data from actual cancer patients. Our findings highlight how gene-centric experiments (such as systematic knock-out or silencing of individual genes) are missing relevant effects mediated by perturbations of specific protein regions. All the associations described here are available from http://www.cancer3d.org. '),
(86946, 2015, 'plos', 'Mapping the Pareto optimal design space for a functionally deimmunized biotherapeutic candidate', 'Salvat, Regina S|Parker, Andrew S|Choi, Yoonjoo|Bailey-Kellogg, Chris|Griswold, Karl E', 'Thayer School of Engineering, Dartmouth, Hanover, New Hampshire, United States of America.|Department of Computer Science, Dartmouth, Hanover, New Hampshire, United States of America.|Department of Computer Science, Dartmouth, Hanover, New Hampshire, United States of America.|Department of Computer Science, Dartmouth, Hanover, New Hampshire, United States of America.|Thayer School of Engineering, Dartmouth, Hanover, New Hampshire, United States of America, Program in Molecular and Cellular Biology, Dartmouth, Hanover, New Hampshire, United States of America.', 'United States|United States|United States|United States|United States', 15, 'Algorithms|Computational Biology|Computer Simulation|Epitopes, T-Lymphocyte|Humans|Models, Statistical|Protein Binding|Protein Engineering|Recombinant Proteins', 'Journal Article', '10.1371/journal.pcbi.1003988', '25568954', 'The immunogenicity of biotherapeutics can bottleneck development pipelines and poses a barrier to widespread clinical application. As a result, there is a growing need for improved deimmunization technologies. We have recently described algorithms that simultaneously optimize proteins for both reduced T cell epitope content and high-level function. In silico analysis of this dual objective design space reveals that there is no single global optimum with respect to protein deimmunization. Instead, mutagenic epitope deletion yields a spectrum of designs that exhibit tradeoffs between immunogenic potential and molecular function. The leading edge of this design space is the Pareto frontier, i.e. the undominated variants for which no other single design exhibits better performance in both criteria. Here, the Pareto frontier of a therapeutic enzyme has been designed, constructed, and evaluated experimentally. Various measures of protein performance were found to map a functional sequence space that correlated well with computational predictions. These results represent the first systematic and rigorous assessment of the functional penalty that must be paid for pursuing progressively more deimmunized biotherapeutic candidates. Given this capacity to rapidly assess and design for tradeoffs between protein immunogenicity and functionality, these algorithms may prove useful in augmenting, accelerating, and de-risking experimental deimmunization efforts. '),
(86947, 2015, 'plos', 'Systems level analysis of systemic sclerosis shows a network of immune and profibrotic pathways connected with genetic polymorphisms', 'Mahoney, J Matthew|Taroni, Jaclyn|Martyanov, Viktor|Wood, Tammara A|Greene, Casey S|Pioli, Patricia A|Hinchcliff, Monique E|Whitfield, Michael L', 'Department of Genetics, Geisel School of Medicine at Dartmouth, Hannover, New Hampshire, United States of America.|Department of Genetics, Geisel School of Medicine at Dartmouth, Hannover, New Hampshire, United States of America.|Department of Genetics, Geisel School of Medicine at Dartmouth, Hannover, New Hampshire, United States of America.|Department of Genetics, Geisel School of Medicine at Dartmouth, Hannover, New Hampshire, United States of America.|Department of Genetics, Geisel School of Medicine at Dartmouth, Hannover, New Hampshire, United States of America.|Department of Obstetrics and Gynecology, Geisel School of Medicine at Dartmouth, Hannover, New Hampshire, United States of America.|Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.|Department of Genetics, Geisel School of Medicine at Dartmouth, Hannover, New Hampshire, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 56, 'Aged|Computational Biology|Databases, Genetic|Extracellular Matrix|Female|Gene Expression Profiling|Humans|Inflammation|Male|Middle Aged|Risk|Scleroderma, Systemic|Transcriptome', 'Journal Article', '10.1371/journal.pcbi.1004005', '25569146', 'Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by skin and organ fibrosis. The pathogenesis of SSc and its progression are poorly understood. The SSc intrinsic gene expression subsets (inflammatory, fibroproliferative, normal-like, and limited) are observed in multiple clinical cohorts of patients with SSc. Analysis of longitudinal skin biopsies suggests that a patients subset assignment is stable over 6-12 months. Genetically, SSc is multi-factorial with many genetic risk loci for SSc generally and for specific clinical manifestations. Here we identify the genes consistently associated with the intrinsic subsets across three independent cohorts, show the relationship between these genes using a gene-gene interaction network, and place the genetic risk loci in the context of the intrinsic subsets. To identify gene expression modules common to three independent datasets from three different clinical centers, we developed a consensus clustering procedure based on mutual information of partitions, an information theory concept, and performed a meta-analysis of these genome-wide gene expression datasets. We created a gene-gene interaction network of the conserved molecular features across the intrinsic subsets and analyzed their connections with SSc-associated genetic polymorphisms. The network is composed of distinct, but interconnected, components related to interferon activation, M2 macrophages, adaptive immunity, extracellular matrix remodeling, and cell proliferation. The network shows extensive connections between the inflammatory- and fibroproliferative-specific genes. The network also shows connections between these subset-specific genes and 30 SSc-associated polymorphic genes including STAT4, BLK, IRF7, NOTCH4, PLAUR, CSK, IRAK1, and several human leukocyte antigen (HLA) genes. Our analyses suggest that the gene expression changes underlying the SSc subsets may be long-lived, but mechanistically interconnected and related to a patients underlying genetic risk. '),
(86948, 2015, 'plos', 'Identification of constrained cancer driver genes based on mutation timing', 'Sakoparnig, Thomas|Fried, Patrick|Beerenwinkel, Niko', 'Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland, SIB Swiss Institute of Bioinformatics, Basel, Switzerland.|Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland, SIB Swiss Institute of Bioinformatics, Basel, Switzerland.|Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland, SIB Swiss Institute of Bioinformatics, Basel, Switzerland.', 'Switzerland|Switzerland|Switzerland', 14, 'Computational Biology|Databases, Genetic|Humans|Mutation|Neoplasms|Oncogenes|Polymorphism, Single Nucleotide|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1004027', '25569148', 'Cancer drivers are genomic alterations that provide cells containing them with a selective advantage over their local competitors, whereas neutral passengers do not change the somatic fitness of cells. Cancer-driving mutations are usually discriminated from passenger mutations by their higher degree of recurrence in tumor samples. However, there is increasing evidence that many additional driver mutations may exist that occur at very low frequencies among tumors. This observation has prompted alternative methods for driver detection, including finding groups of mutually exclusive mutations and incorporating prior biological knowledge about gene function or network structure. Dependencies among drivers due to epistatic interactions can also result in low mutation frequencies, but this effect has been ignored in driver detection so far. Here, we present a new computational approach for identifying genomic alterations that occur at low frequencies because they depend on other events. Unlike passengers, these constrained mutations display punctuated patterns of occurrence in time. We test this driver-passenger discrimination approach based on mutation timing in extensive simulation studies, and we apply it to cross-sectional copy number alteration (CNA) data from ovarian cancer, CNA and single-nucleotide variant (SNV) data from breast tumors and SNV data from colorectal cancer. Among the top ranked predicted drivers, we find low-frequency genes that have already been shown to be involved in carcinogenesis, as well as many new candidate drivers. The mutation timing approach is orthogonal and complementary to existing driver prediction methods. It will help identifying from cancer genome data the alterations that drive tumor progression. '),
(86949, 2015, 'plos', 'A RESTful API for accessing microbial community data for MG-RAST', 'Wilke, Andreas|Bischof, Jared|Harrison, Travis|Brettin, Tom|DSouza, Mark|Gerlach, Wolfgang|Matthews, Hunter|Paczian, Tobias|Wilkening, Jared|Glass, Elizabeth M|Desai, Narayan|Meyer, Folker', 'Mathematics and Computer Science Division, Argonne National Laboratory, Lemont, Illinois, United States of America, Computation Institute, University of Chicago, Chicago, Illinois, United States of America.|Mathematics and Computer Science Division, Argonne National Laboratory, Lemont, Illinois, United States of America, Computation Institute, University of Chicago, Chicago, Illinois, United States of America.|Mathematics and Computer Science Division, Argonne National Laboratory, Lemont, Illinois, United States of America, Computation Institute, University of Chicago, Chicago, Illinois, United States of America.|Mathematics and Computer Science Division, Argonne National Laboratory, Lemont, Illinois, United States of America.|Mathematics and Computer Science Division, Argonne National Laboratory, Lemont, Illinois, United States of America, Computation Institute, University of Chicago, Chicago, Illinois, United States of America.|Mathematics and Computer Science Division, Argonne National Laboratory, Lemont, Illinois, United States of America, Computation Institute, University of Chicago, Chicago, Illinois, United States of America.|Mathematics and Computer Science Division, Argonne National Laboratory, Lemont, Illinois, United States of America, Computation Institute, University of Chicago, Chicago, Illinois, United States of America.|Mathematics and Computer Science Division, Argonne National Laboratory, Lemont, Illinois, United States of America, Computation Institute, University of Chicago, Chicago, Illinois, United States of America.|Mathematics and Computer Science Division, Argonne National Laboratory, Lemont, Illinois, United States of America, Computation Institute, University of Chicago, Chicago, Illinois, United States of America.|Mathematics and Computer Science Division, Argonne National Laboratory, Lemont, Illinois, United States of America, Computation Institute, University of Chicago, Chicago, Illinois, United States of America.|Mathematics and Computer Science Division, Argonne National Laboratory, Lemont, Illinois, United States of America, Computation Institute, University of Chicago, Chicago, Illinois, United States of America.|Mathematics and Computer Science Division, Argonne National Laboratory, Lemont, Illinois, United States of America, Computation Institute, University of Chicago, Chicago, Illinois, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 35, 'Database Management Systems|Databases, Genetic|Genome, Bacterial|Internet|Metagenomics|Molecular Sequence Annotation|Software|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1004008', '25569221', 'Metagenomic sequencing has produced significant amounts of data in recent years. For example, as of summer 2013, MG-RAST has been used to annotate over 110,000 data sets totaling over 43 Terabases. With metagenomic sequencing finding even wider adoption in the scientific community, the existing web-based analysis tools and infrastructure in MG-RAST provide limited capability for data retrieval and analysis, such as comparative analysis between multiple data sets. Moreover, although the system provides many analysis tools, it is not comprehensive. By opening MG-RAST up via a web services API (application programmers interface) we have greatly expanded access to MG-RAST data, as well as provided a mechanism for the use of third-party analysis tools with MG-RAST data. This RESTful API makes all data and data objects created by the MG-RAST pipeline accessible as JSON objects. As part of the DOE Systems Biology Knowledgebase project (KBase, http://kbase.us) we have implemented a web services API for MG-RAST. This API complements the existing MG-RAST web interface and constitutes the basis of KBases microbial community capabilities. In addition, the API exposes a comprehensive collection of data to programmers. This API, which uses a RESTful (Representational State Transfer) implementation, is compatible with most programming environments and should be easy to use for end users and third parties. It provides comprehensive access to sequence data, quality control results, annotations, and many other data types. Where feasible, we have used standards to expose data and metadata. Code examples are provided in a number of languages both to show the versatility of the API and to provide a starting point for users. We present an API that exposes the data in MG-RAST for consumption by our users, greatly enhancing the utility of the MG-RAST service. '),
(86950, 2015, 'plos', 'Brain network adaptability across task states', 'Davison, Elizabeth N|Schlesinger, Kimberly J|Bassett, Danielle S|Lynall, Mary-Ellen|Miller, Michael B|Grafton, Scott T|Carlson, Jean M', 'Department of Mechanical & Aerospace Engineering, Princeton University, Princeton, New Jersey, United States of America, Department of Physics, University of California, Santa Barbara, Santa Barbara, California, United States of America.|Department of Physics, University of California, Santa Barbara, Santa Barbara, California, United States of America.|Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, Department of Electrical and Systems Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|University of Oxford Medical Sciences Division, John Radcliffe Hospital, Headington, Oxford, United Kingdom, Behavioural and Clinical Neuroscience Institute and Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom.|Department of Psychological and Brain Sciences, University of California, Santa Barbara, Santa Barbara, California, United States of America.|Department of Psychological and Brain Sciences, University of California, Santa Barbara, Santa Barbara, California, United States of America.|Department of Physics, University of California, Santa Barbara, Santa Barbara, California, United States of America.', 'Jersey|United States|United States|United Kingdom|United States|United States|United States', 64, 'Adult|Brain|Brain Mapping|Humans|Image Processing, Computer-Assisted|Magnetic Resonance Imaging|Task Performance and Analysis', 'Journal Article', '10.1371/journal.pcbi.1004029', '25569227', 'Activity in the human brain moves between diverse functional states to meet the demands of our dynamic environment, but fundamental principles guiding these transitions remain poorly understood. Here, we capitalize on recent advances in network science to analyze patterns of functional interactions between brain regions. We use dynamic network representations to probe the landscape of brain reconfigurations that accompany task performance both within and between four cognitive states: a task-free resting state, an attention-demanding state, and two memory-demanding states. Using the formalism of hypergraphs, we identify the presence of groups of functional interactions that fluctuate coherently in strength over time both within (task-specific) and across (task-general) brain states. In contrast to prior emphases on the complexity of many dyadic (region-to-region) relationships, these results demonstrate that brain adaptability can be described by common processes that drive the dynamic integration of cognitive systems. Moreover, our results establish the hypergraph as an effective measure for understanding functional brain dynamics, which may also prove useful in examining cross-task, cross-age, and cross-cohort functional change. '),
(86951, 2015, 'plos', '150 years of the mass action law', 'Voit, Eberhard O|Martens, Harald A|Omholt, Stig W', 'Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory University, Atlanta, Georgia, United States of America.|Department of Engineering Cybernetics, Norwegian University of Science & Technology, Trondheim, Norway.|Department of Engineering Cybernetics, Norwegian University of Science & Technology, Trondheim, Norway.', 'Georgia|Norway|Norway', 47, 'Biochemical Phenomena|Kinetics|Models, Biological|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1004012', '25569257', 'This year we celebrate the 150th anniversary of the law of mass action. This law is often assumed to have been there forever, but it has its own history, background, and a definite starting point. The law has had an impact on chemistry, biochemistry, biomathematics, and systems biology that is difficult to overestimate. It is easily recognized that it is the direct basis for computational enzyme kinetics, ecological systems models, and models for the spread of diseases. The article reviews the explicit and implicit role of the law of mass action in systems biology and reveals how the original, more general formulation of the law emerged one hundred years later ab initio as a very general, canonical representation of biological processes. ');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86952, 2015, 'plos', 'Activation of parallel fiber feedback by spatially diffuse stimuli reduces signal and noise correlations via independent mechanisms in a cerebellum-like structure', 'Simmonds, Benjamin|Chacron, Maurice J', 'Department of Physiology, McGill University, Montreal, Quebec, Canada.|Department of Physiology, McGill University, Montreal, Quebec, Canada.', 'Canada|Canada', 21, 'Action Potentials|Animals|Cerebellum|Computational Biology|Electric Fish|Feedback, Physiological|Models, Neurological|Nerve Fibers|Pyramidal Cells', 'Journal Article', '10.1371/journal.pcbi.1004034', '25569283', 'Correlations between the activities of neighboring neurons are observed ubiquitously across systems and species and are dynamically regulated by several factors such as the stimulus spatiotemporal extent as well as by the brains internal state. Using the electrosensory system of gymnotiform weakly electric fish, we recorded the activities of pyramidal cell pairs within the electrosensory lateral line lobe (ELL) under spatially localized and diffuse stimulation. We found that both signal and noise correlations were markedly reduced (>40%) under the latter stimulation. Through a network model incorporating key anatomical features of the ELL, we reveal how activation of diffuse parallel fiber feedback from granule cells by spatially diffuse stimulation can explain both the reduction in signal as well as the reduction in noise correlations seen experimentally through independent mechanisms. First, we show that burst-timing dependent plasticity, which leads to a negative image of the stimulus and thereby reduces single neuron responses, decreases signal but not noise correlations. Second, we show trial-to-trial variability in the responses of single granule cells to sensory input reduces noise but not signal correlations. Thus, our model predicts that the same feedback pathway can simultaneously reduce both signal and noise correlations through independent mechanisms. To test this prediction experimentally, we pharmacologically inactivated parallel fiber feedback onto ELL pyramidal cells. In agreement with modeling predictions, we found that inactivation increased both signal and noise correlations but that there was no significant relationship between magnitude of the increase in signal correlations and the magnitude of the increase in noise correlations. The mechanisms reported in this study are expected to be generally applicable to the cerebellum as well as other cerebellum-like structures. We further discuss the implications of such decorrelation on the neural coding strategies used by the electrosensory and by other systems to process natural stimuli. '),
(86953, 2015, 'plos', 'What makes a protein sequence a prion?', 'Sabate, Raimon|Rousseau, Frederic|Schymkowitz, Joost|Ventura, Salvador', 'Departament de Fisicoquímica, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain, Institut de Nanociència i Nanotecnologia (IN2UB), Universitat de Barcelona, Barcelona, Spain.|VIB Switch Laboratory, VIB, Leuven, Belgium, Departement for Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.|VIB Switch Laboratory, VIB, Leuven, Belgium, Departement for Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.|Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain, Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain.', 'Spain|Belgium|Belgium|Spain', 41, 'Amino Acid Sequence|Amyloid|Fungal Proteins|Hydrophobic and Hydrophilic Interactions|Molecular Sequence Data|Prions', 'Journal Article', '10.1371/journal.pcbi.1004013', '25569335', 'Typical amyloid diseases such as Alzheimers and Parkinsons were thought to exclusively result from de novo aggregation, but recently it was shown that amyloids formed in one cell can cross-seed aggregation in other cells, following a prion-like mechanism. Despite the large experimental effort devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the primary sequence. In many cases, prion structural conversion is driven by the presence of relatively large glutamine/asparagine (Q/N) enriched segments. Several studies suggest that it is the amino acid composition of these regions rather than their specific sequence that accounts for their priogenicity. However, our analysis indicates that it is instead the presence and potency of specific short amyloid-prone sequences that occur within intrinsically disordered Q/N-rich regions that determine their prion behaviour, modulated by the structural and compositional context. This provides a basis for the accurate identification and evaluation of prion candidate sequences in proteomes in the context of a unified framework for amyloid formation and prion propagation. '),
(86954, 2015, 'plos', 'Orientation selectivity in inhibition-dominated networks of spiking neurons: effect of single neuron properties and network dynamics', 'Sadeh, Sadra|Rotter, Stefan', 'Bernstein Center Freiberg & Faculty of Biology, University of Freiberg, Freiberg, Germany.|Bernstein Center Freiberg & Faculty of Biology, University of Freiberg, Freiberg, Germany.', 'Germany|Germany', 0, 'Action Potentials|Animals|Mice|Models, Neurological|Nerve Net|Neurons', 'Journal Article', '10.1371/journal.pcbi.1004045', '25569445', 'The neuronal mechanisms underlying the emergence of orientation selectivity in the primary visual cortex of mammals are still elusive. In rodents, visual neurons show highly selective responses to oriented stimuli, but neighboring neurons do not necessarily have similar preferences. Instead of a smooth map, one observes a salt-and-pepper organization of orientation selectivity. Modeling studies have recently confirmed that balanced random networks are indeed capable of amplifying weakly tuned inputs and generating highly selective output responses, even in absence of feature-selective recurrent connectivity. Here we seek to elucidate the neuronal mechanisms underlying this phenomenon by resorting to networks of integrate-and-fire neurons, which are amenable to analytic treatment. Specifically, in networks of perfect integrate-and-fire neurons, we observe that highly selective and contrast invariant output responses emerge, very similar to networks of leaky integrate-and-fire neurons. We then demonstrate that a theory based on mean firing rates and the detailed network topology predicts the output responses, and explains the mechanisms underlying the suppression of the common-mode, amplification of modulation, and contrast invariance. Increasing inhibition dominance in our networks makes the rectifying nonlinearity more prominent, which in turn adds some distortions to the otherwise essentially linear prediction. An extension of the linear theory can account for all the distortions, enabling us to compute the exact shape of every individual tuning curve in our networks. We show that this simple form of nonlinearity adds two important properties to orientation selectivity in the network, namely sharpening of tuning curves and extra suppression of the modulation. The theory can be further extended to account for the nonlinearity of the leaky model by replacing the rectifier by the appropriate smooth input-output transfer function. These results are robust and do not depend on the state of network dynamics, and hold equally well for mean-driven and fluctuation-driven regimes of activity. '),
(86955, 2015, 'plos', 'Novel inhibitors induce large conformational changes of GAB1 pleckstrin homology domain and kill breast cancer cells', 'Chen, Lu|Du-Cuny, Lei|Moses, Sylvestor|Dumas, Sabrina|Song, Zuohe|Rezaeian, Abdol Hossein|Lin, Hui-Kuan|Meuillet, Emmanuelle J|Zhang, Shuxing', 'Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.|Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.|Departments of Nutritional Sciences and Molecular and Cellular Biology, the University of Arizona Cancer Center, Tucson, Arizona, United States of America.|Departments of Nutritional Sciences and Molecular and Cellular Biology, the University of Arizona Cancer Center, Tucson, Arizona, United States of America.|Departments of Nutritional Sciences and Molecular and Cellular Biology, the University of Arizona Cancer Center, Tucson, Arizona, United States of America.|Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.|Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.|Departments of Nutritional Sciences and Molecular and Cellular Biology, the University of Arizona Cancer Center, Tucson, Arizona, United States of America.|Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 14, 'Adaptor Proteins, Signal Transducing|Amino Acid Sequence|Antineoplastic Agents|Blood Proteins|Breast Neoplasms|Cell Line, Tumor|Cell Proliferation|Cell Survival|Drug Discovery|Female|Humans|Molecular Dynamics Simulation|Molecular Sequence Data|Phosphoproteins|Protein Binding|Sequence Alignment|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1004021', '25569504', 'The Grb2-associated binding protein 1 (GAB1) integrates signals from different signaling pathways and is over-expressed in many cancers, therefore representing a new therapeutic target. In the present study, we aim to target the pleckstrin homology (PH) domain of GAB1 for cancer treatment. Using homology models we derived, high-throughput virtual screening of five million compounds resulted in five hits which exhibited strong binding affinities to GAB1 PH domain. Our prediction of ligand binding affinities is also in agreement with the experimental KD values. Furthermore, molecular dynamics studies showed that GAB1 PH domain underwent large conformational changes upon ligand binding. Moreover, these hits inhibited the phosphorylation of GAB1 and demonstrated potent, tumor-specific cytotoxicity against MDA-MB-231 and T47D breast cancer cell lines. This effort represents the discovery of first-in-class GAB1 PH domain inhibitors with potential for targeted breast cancer therapy and provides novel insights into structure-based approaches to targeting this protein. '),
(86956, 2015, 'plos', 'Advancements and challenges in computational biology', 'Nussinov, Ruth', 'Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America, Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.', 'Israel', 0, 'Computational Biology|Humans', 'Editorial', '10.1371/journal.pcbi.1004053', '25569585', '-'),
(86957, 2015, 'plos', 'A computational framework for 3D mechanical modeling of plant morphogenesis with cellular resolution', 'Boudon, Frédéric|Chopard, Jérôme|Ali, Olivier|Gilles, Benjamin|Hamant, Olivier|Boudaoud, Arezki|Traas, Jan|Godin, Christophe', 'Virtual Plants Inria team, UMR AGAP, CIRAD, INRIA, INRA, Montpellier, France.|Virtual Plants Inria team, UMR AGAP, CIRAD, INRIA, INRA, Montpellier, France.|Virtual Plants Inria team, UMR AGAP, CIRAD, INRIA, INRA, Montpellier, France, Laboratoire de Reproduction et Développement des Plantes, Université de Lyon 1, ENS-Lyon, INRA, CNRS, Lyon, France.|Laboratoire dInformatique, de Robotique et de Microélectronique de Montpellier, Université Montpellier 2, CNRS, Montpellier, France.|Laboratoire de Reproduction et Développement des Plantes, Université de Lyon 1, ENS-Lyon, INRA, CNRS, Lyon, France.|Laboratoire de Reproduction et Développement des Plantes, Université de Lyon 1, ENS-Lyon, INRA, CNRS, Lyon, France.|Laboratoire de Reproduction et Développement des Plantes, Université de Lyon 1, ENS-Lyon, INRA, CNRS, Lyon, France.|Virtual Plants Inria team, UMR AGAP, CIRAD, INRIA, INRA, Montpellier, France.', 'France|France|France|France|France|France|France|France', 0, 'Arabidopsis|Computational Biology|Computer Simulation|Flowers|Models, Biological|Plant Cells|Plant Development', 'Journal Article', '10.1371/journal.pcbi.1003950', '25569615', 'The link between genetic regulation and the definition of form and size during morphogenesis remains largely an open question in both plant and animal biology. This is partially due to the complexity of the process, involving extensive molecular networks, multiple feedbacks between different scales of organization and physical forces operating at multiple levels. Here we present a conceptual and modeling framework aimed at generating an integrated understanding of morphogenesis in plants. This framework is based on the biophysical properties of plant cells, which are under high internal turgor pressure, and are prevented from bursting because of the presence of a rigid cell wall. To control cell growth, the underlying molecular networks must interfere locally with the elastic and/or plastic extensibility of this cell wall. We present a model in the form of a three dimensional (3D) virtual tissue, where growth depends on the local modulation of wall mechanical properties and turgor pressure. The model shows how forces generated by turgor-pressure can act both cell autonomously and non-cell autonomously to drive growth in different directions. We use simulations to explore lateral organ formation at the shoot apical meristem. Although different scenarios lead to similar shape changes, they are not equivalent and lead to different, testable predictions regarding the mechanical and geometrical properties of the growing lateral organs. Using flower development as an example, we further show how a limited number of gene activities can explain the complex shape changes that accompany organ outgrowth. '),
(86958, 2015, 'plos', 'Fast and accurate resonance assignment of small-to-large proteins by combining automated and manual approaches', 'Niklasson, Markus|Ahlner, Alexandra|Andresen, Cecilia|Marsh, Joseph A|Lundström, Patrik', 'Division of Biomolecular Technology, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.|Division of Biomolecular Technology, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.|Division of Biomolecular Technology, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.|MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.|Division of Biomolecular Technology, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.', 'Sweden|Sweden|Sweden|United Kingdom|Sweden', 5, 'Algorithms|Amino Acid Sequence|Nuclear Magnetic Resonance, Biomolecular|Protein Structure, Secondary|Proteins|Software', 'Journal Article', '10.1371/journal.pcbi.1004022', '25569628', 'The process of resonance assignment is fundamental to most NMR studies of protein structure and dynamics. Unfortunately, the manual assignment of residues is tedious and time-consuming, and can represent a significant bottleneck for further characterization. Furthermore, while automated approaches have been developed, they are often limited in their accuracy, particularly for larger proteins. Here, we address this by introducing the software COMPASS, which, by combining automated resonance assignment with manual intervention, is able to achieve accuracy approaching that from manual assignments at greatly accelerated speeds. Moreover, by including the option to compensate for isotope shift effects in deuterated proteins, COMPASS is far more accurate for larger proteins than existing automated methods. COMPASS is an open-source project licensed under GNU General Public License and is available for download from http://www.liu.se/forskning/foass/tidigare-foass/patrik-lundstrom/software?l=en. Source code and binaries for Linux, Mac OS X and Microsoft Windows are available. '),
(86959, 2015, 'plos', 'Modulation of elementary calcium release mediates a transition from puffs to waves in an IP3R cluster model', 'Rückl, Martin|Parker, Ian|Marchant, Jonathan S|Nagaiah, Chamakuri|Johenning, Friedrich W|Rüdiger, Sten', 'Institut für Physik, Humboldt-Universität zu Berlin, Berlin, Germany.|Departments of Neurobiology and Behavior, Physiology and Biophysics, University of California, Irvine, Irvine, California, United States of America.|Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, United States of America.|Johann Radon Institute for Computational and Applied Mathematics, Austrian Academy of Sciences, Linz, Austria.|Neuroscience Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Institut für Physik, Humboldt-Universität zu Berlin, Berlin, Germany.', 'Germany|United States|United States|Austria|Germany|Germany', 20, 'Calcium|Computational Biology|Computer Simulation|Inositol 1,4,5-Trisphosphate Receptors|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1003965', '25569772', 'The oscillating concentration of intracellular calcium is one of the most important examples for collective dynamics in cell biology. Localized releases of calcium through clusters of inositol 1,4,5-trisphosphate receptor channels constitute elementary signals called calcium puffs. Coupling by diffusing calcium leads to global releases and waves, but the exact mechanism of inter-cluster coupling and triggering of waves is unknown. To elucidate the relation of puffs and waves, we here model a cluster of IP3R channels using a gating scheme with variable non-equilibrium IP3 binding. Hybrid stochastic and deterministic simulations show that puffs are not stereotyped events of constant duration but are sensitive to stimulation strength and residual calcium. For increasing IP3 concentration, the release events become modulated at a timescale of minutes, with repetitive wave-like releases interspersed with several puffs. This modulation is consistent with experimental observations we present, including refractoriness and increase of puff frequency during the inter-wave interval. Our results suggest that waves are established by a random but time-modulated appearance of sustained release events, which have a high potential to trigger and synchronize activity throughout the cell. '),
(86960, 2015, 'plos', 'The thalidomide-binding domain of cereblon defines the CULT domain family and is a new member of the xcexb2-tent fold', 'Lupas, Andrei N|Zhu, Hongbo|Korycinski, Mateusz', 'Department of Protein Evolution, Max-Planck-Institute for Developmental Biology, Tuebingen, Germany.|Department of Protein Evolution, Max-Planck-Institute for Developmental Biology, Tuebingen, Germany.|Department of Protein Evolution, Max-Planck-Institute for Developmental Biology, Tuebingen, Germany.', 'Germany|Germany|Germany', 0, 'Amino Acid Sequence|Animals|Binding Sites|Carrier Proteins|Drosophila|Drosophila Proteins|Models, Molecular|Molecular Sequence Data|Peptide Hydrolases|Protein Binding|Protein Structure, Secondary|Protein Structure, Tertiary|Sequence Alignment|Thalidomide', 'Journal Article', '10.1371/journal.pcbi.1004023', '25569776', 'Despite having caused one of the greatest medical catastrophies of the last century through its teratogenic side-effects, thalidomide continues to be an important agent in the treatment of leprosy and cancer. The protein cereblon, which forms an E3 ubiquitin ligase compex together with damaged DNA-binding protein 1 (DDB1) and cullin 4A, has been recently indentified as a primary target of thalidomide and its C-terminal part as responsible for binding thalidomide within a domain carrying several invariant cysteine and tryptophan residues. This domain, which we name CULT (cereblon domain of unknown activity, binding cellular ligands and thalidomide), is also found in a family of secreted proteins from animals and in a family of bacterial proteins occurring primarily in xcexb4-proteobacteria. Its nearest relatives are yippee, a highly conserved eukaryotic protein of unknown function, and Mis18, a protein involved in the priming of centromeres for recruitment of CENP-A. Searches for distant homologs point to an evolutionary relationship of CULT, yippee, and Mis18 to proteins sharing a common fold, which consists of two four-stranded xcexb2-meanders packing at a roughly right angle and coordinating a zinc ion at their apex. A xcexb2-hairpin inserted into the first xcexb2-meander extends across the bottom of the structure towards the C-terminal edge of the second xcexb2-meander, with which it forms a cradle-shaped binding site that is topologically conserved in all members of this fold. We name this the xcexb2-tent fold for the striking arrangement of its constituent xcexb2-sheets. The fold has internal pseudosymmetry, raising the possibility that it arose by duplication of a subdomain-sized fragment. '),
(86961, 2015, 'plos', 'Simulating the complex cell design of Trypanosoma brucei and its motility', 'Alizadehrad, Davod|Krüger, Timothy|Engstler, Markus|Stark, Holger', 'Institute of Theoretical Physics, Technische Universität Berlin, Berlin, Germany.|Department of Cell and Developmental Biology, Biocenter, University of Würzburg, Würzburg, Germany.|Department of Cell and Developmental Biology, Biocenter, University of Würzburg, Würzburg, Germany.|Institute of Theoretical Physics, Technische Universität Berlin, Berlin, Germany.', 'Germany|Germany|Germany|Germany', 0, 'Cell Movement|Computational Biology|Computer Simulation|Models, Biological|Trypanosoma brucei brucei', 'Journal Article', '10.1371/journal.pcbi.1003967', '25569823', 'The flagellate Trypanosoma brucei, which causes the sleeping sickness when infecting a mammalian host, goes through an intricate life cycle. It has a rather complex propulsion mechanism and swims in diverse microenvironments. These continuously exert selective pressure, to which the trypanosome adjusts with its architecture and behavior. As a result, the trypanosome assumes a diversity of complex morphotypes during its life cycle. However, although cell biology has detailed form and function of most of them, experimental data on the dynamic behavior and development of most morphotypes is lacking. Here we show that simulation science can predict intermediate cell designs by conducting specific and controlled modifications of an accurate, nature-inspired cell model, which we developed using information from live cell analyses. The cell models account for several important characteristics of the real trypanosomal morphotypes, such as the geometry and elastic properties of the cell body, and their swimming mechanism using an eukaryotic flagellum. We introduce an elastic network model for the cell body, including bending rigidity and simulate swimming in a fluid environment, using the mesoscale simulation technique called multi-particle collision dynamics. The in silico trypanosome of the bloodstream form displays the characteristic in vivo rotational and translational motility pattern that is crucial for survival and virulence in the vertebrate host. Moreover, our model accurately simulates the trypanosomes tumbling and backward motion. We show that the distinctive course of the attached flagellum around the cell body is one important aspect to produce the observed swimming behavior in a viscous fluid, and also required to reach the maximal swimming velocity. Changing details of the flagellar attachment generates less efficient swimmers. We also simulate different morphotypes that occur during the parasites development in the tsetse fly, and predict a flagellar course we have not been able to measure in experiments so far. '),
(86962, 2015, 'plos', 'Bayesian history matching of complex infectious disease models using emulation: a tutorial and a case study on HIV in Uganda', 'Andrianakis, Ioannis|Vernon, Ian R|McCreesh, Nicky|McKinley, Trevelyan J|Oakley, Jeremy E|Nsubuga, Rebecca N|Goldstein, Michael|White, Richard G', 'Dept. of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom.|Dept. of Mathematical Sciences, Durham University, Durham, United Kingdom.|School of Medicine, Pharmacy and Health, Durham University, Durham, United Kingdom.|Dept. of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.|School of Mathematics and Statistics, University of Sheffield, Sheffield, United Kingdom.|Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda.|Dept. of Mathematical Sciences, Durham University, Durham, United Kingdom.|Dept. of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|Uganda|United Kingdom|Uni', 45, 'Algorithms|Bayes Theorem|Computational Biology|Computer Simulation|Female|HIV Infections|Humans|Male|Models, Biological|Uganda', 'Journal Article', '10.1371/journal.pcbi.1003968', '25569850', 'Advances in scientific computing have allowed the development of complex models that are being routinely applied to problems in disease epidemiology, public health and decision making. The utility of these models depends in part on how well they can reproduce empirical data. However, fitting such models to real world data is greatly hindered both by large numbers of input and output parameters, and by long run times, such that many modelling studies lack a formal calibration methodology. We present a novel method that has the potential to improve the calibration of complex infectious disease models (hereafter called simulators). We present this in the form of a tutorial and a case study where we history match a dynamic, event-driven, individual-based stochastic HIV simulator, using extensive demographic, behavioural and epidemiological data available from Uganda. The tutorial describes history matching and emulation. History matching is an iterative procedure that reduces the simulators input space by identifying and discarding areas that are unlikely to provide a good match to the empirical data. History matching relies on the computational efficiency of a Bayesian representation of the simulator, known as an emulator. Emulators mimic the simulators behaviour, but are often several orders of magnitude faster to evaluate. In the case study, we use a 22 input simulator, fitting its 18 outputs simultaneously. After 9 iterations of history matching, a non-implausible region of the simulator input space was identified that was 10(11) times smaller than the original input space. Simulator evaluations made within this region were found to have a 65% probability of fitting all 18 outputs. History matching and emulation are useful additions to the toolbox of infectious disease modellers. Further research is required to explicitly address the stochastic nature of the simulator as well as to account for correlations between outputs.'),
(86963, 2015, 'plos', 'Inference of quantitative models of bacterial promoters from time-series reporter gene data', 'Stefan, Diana|Pinel, Corinne|Pinhal, Stéphane|Cinquemani, Eugenio|Geiselmann, Johannes|de Jong, Hidde', 'INRIA Grenoble - Rhône-Alpes, Grenoble, France, Laboratoire Interdisciplinaire de Physique (LIPhy, CNRS UMR 5588), Université Joseph Fourier, Grenoble, France.|INRIA Grenoble - Rhône-Alpes, Grenoble, France, Laboratoire Interdisciplinaire de Physique (LIPhy, CNRS UMR 5588), Université Joseph Fourier, Grenoble, France.|INRIA Grenoble - Rhône-Alpes, Grenoble, France, Laboratoire Interdisciplinaire de Physique (LIPhy, CNRS UMR 5588), Université Joseph Fourier, Grenoble, France.|INRIA Grenoble - Rhône-Alpes, Grenoble, France.|INRIA Grenoble - Rhône-Alpes, Grenoble, France, Laboratoire Interdisciplinaire de Physique (LIPhy, CNRS UMR 5588), Université Joseph Fourier, Grenoble, France.|INRIA Grenoble - Rhône-Alpes, Grenoble, France.', 'France|France|France|France|France|France', 0, 'Bacterial Proteins|Escherichia coli|Gene Expression Regulation, Bacterial|Genes, Reporter|Green Fluorescent Proteins|Models, Genetic|Promoter Regions, Genetic|RNA, Messenger|Sigma Factor|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1004028', '25590141', 'The inference of regulatory interactions and quantitative models of gene regulation from time-series transcriptomics data has been extensively studied and applied to a range of problems in drug discovery, cancer research, and biotechnology. The application of existing methods is commonly based on implicit assumptions on the biological processes under study. First, the measurements of mRNA abundance obtained in transcriptomics experiments are taken to be representative of protein concentrations. Second, the observed changes in gene expression are assumed to be solely due to transcription factors and other specific regulators, while changes in the activity of the gene expression machinery and other global physiological effects are neglected. While convenient in practice, these assumptions are often not valid and bias the reverse engineering process. Here we systematically investigate, using a combination of models and experiments, the importance of this bias and possible corrections. We measure in real time and in vivo the activity of genes involved in the FliA-FlgM module of the E. coli motility network. From these data, we estimate protein concentrations and global physiological effects by means of kinetic models of gene expression. Our results indicate that correcting for the bias of commonly-made assumptions improves the quality of the models inferred from the data. Moreover, we show by simulation that these improvements are expected to be even stronger for systems in which protein concentrations have longer half-lives and the activity of the gene expression machinery varies more strongly across conditions than in the FliA-FlgM module. The approach proposed in this study is broadly applicable when using time-series transcriptome data to learn about the structure and dynamics of regulatory networks. In the case of the FliA-FlgM module, our results demonstrate the importance of global physiological effects and the active regulation of FliA and FlgM half-lives for the dynamics of FliA-dependent promoters. '),
(86964, 2015, 'plos', 'The formation of multi-synaptic connections by the interaction of synaptic and structural plasticity and their functional consequences', 'Fauth, Michael|Wörgötter, Florentin|Tetzlaff, Christian', 'Georg-August University Göttingen, Third Institute of Physics, Bernstein Center for Computational Neuroscience, Göttingen, Germany.|Georg-August University Göttingen, Third Institute of Physics, Bernstein Center for Computational Neuroscience, Göttingen, Germany.|Georg-August University Göttingen, Third Institute of Physics, Bernstein Center for Computational Neuroscience, Göttingen, Germany.', 'Germany|Germany|Germany', 27, 'Animals|Cerebral Cortex|Models, Neurological|Neuronal Plasticity|Neurons|Rats|Synapses', 'Journal Article', '10.1371/journal.pcbi.1004031', '25590330', 'Cortical connectivity emerges from the permanent interaction between neuronal activity and synaptic as well as structural plasticity. An important experimentally observed feature of this connectivity is the distribution of the number of synapses from one neuron to another, which has been measured in several cortical layers. All of these distributions are bimodal with one peak at zero and a second one at a small number (3-8) of synapses. In this study, using a probabilistic model of structural plasticity, which depends on the synaptic weights, we explore how these distributions can emerge and which functional consequences they have. We find that bimodal distributions arise generically from the interaction of structural plasticity with synaptic plasticity rules that fulfill the following biological realistic constraints: First, the synaptic weights have to grow with the postsynaptic activity. Second, this growth curve and/or the input-output relation of the postsynaptic neuron have to change sub-linearly (negative curvature). As most neurons show such input-output-relations, these constraints can be fulfilled by many biological reasonable systems. Given such a system, we show that the different activities, which can explain the layer-specific distributions, correspond to experimentally observed activities. Considering these activities as working point of the system and varying the pre- or postsynaptic stimulation reveals a hysteresis in the number of synapses. As a consequence of this, the connectivity between two neurons can be controlled by activity but is also safeguarded against overly fast changes. These results indicate that the complex dynamics between activity and plasticity will, already between a pair of neurons, induce a variety of possible stable synaptic distributions, which could support memory mechanisms. '),
(86965, 2015, 'plos', 'Synaptic plasticity enables adaptive self-tuning critical networks', 'Stepp, Nigel|Plenz, Dietmar|Srinivasa, Narayan', 'Center for Neural and Emergent Systems, Information and System Sciences Lab, HRL Laboratories LLC, Malibu, California, United States of America.|Section on Critical Brain Dynamics, Laboratory of Systems Neuroscience, National Institutes of Mental Health, Bethesda, Maryland, United States of America.|Center for Neural and Emergent Systems, Information and System Sciences Lab, HRL Laboratories LLC, Malibu, California, United States of America.', 'Mali|United States|Mali', 27, 'Action Potentials|Animals|Computational Biology|Mammals|Models, Neurological|Neuronal Plasticity|Neurons', 'Journal Article', '10.1371/journal.pcbi.1004043', '25590427', 'During rest, the mammalian cortex displays spontaneous neural activity. Spiking of single neurons during rest has been described as irregular and asynchronous. In contrast, recent in vivo and in vitro population measures of spontaneous activity, using the LFP, EEG, MEG or fMRI suggest that the default state of the cortex is critical, manifested by spontaneous, scale-invariant, cascades of activity known as neuronal avalanches. Criticality keeps a network poised for optimal information processing, but this view seems to be difficult to reconcile with apparently irregular single neuron spiking. Here, we simulate a 10,000 neuron, deterministic, plastic network of spiking neurons. We show that a combination of short- and long-term synaptic plasticity enables these networks to exhibit criticality in the face of intrinsic, i.e. self-sustained, asynchronous spiking. Brief external perturbations lead to adaptive, long-term modification of intrinsic network connectivity through long-term excitatory plasticity, whereas long-term inhibitory plasticity enables rapid self-tuning of the network back to a critical state. The critical state is characterized by a branching parameter oscillating around unity, a critical exponent close to -3/2 and a long tail distribution of a self-similarity parameter between 0.5 and 1. '),
(86966, 2015, 'plos', 'System model network for adipose tissue signatures related to weight changes in response to calorie restriction and subsequent weight maintenance', 'Montastier, Emilie|Villa-Vialaneix, Nathalie|Caspar-Bauguil, Sylvie|Hlavaty, Petr|Tvrzicka, Eva|Gonzalez, Ignacio|Saris, Wim H M|Langin, Dominique|Kunesova, Marie|Viguerie, Nathalie', 'Institut National de la Santé et de la Recherche Médicale (INSERM), UMR1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases (I2MC), Toulouse, France, University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France, Toulouse University Hospitals, Departments of Clinical Biochemistry and Nutrition, Toulouse, France.|INRA, UR875 MIAT, Castanet Tolosan, France, Statistique, Analyse, Modélisation Multidisciplinaire (SAMM), Université Paris 1, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases (I2MC), Toulouse, France, University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France, Toulouse University Hospitals, Departments of Clinical Biochemistry and Nutrition, Toulouse, France.|Institute of Endocrinology, Obesity Management Centre, Prague, Czech Republic.|Fourth Department of Internal Medicine, 1st Medical School, Charles University, Prague, Czech Republic.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases (I2MC), Toulouse, France, University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France.|Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases (I2MC), Toulouse, France, University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France, Toulouse University Hospitals, Departments of Clinical Biochemistry and Nutrition, Toulouse, France.|Institute of Endocrinology, Obesity Management Centre, Prague, Czech Republic.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases (I2MC), Toulouse, France, University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France.', 'France|France|France|-|-|France|Netherlands|France|-|France', 0, 'Adipose Tissue|Adult|Caloric Restriction|Female|Gene Expression Profiling|Gene Regulatory Networks|Humans|Middle Aged|Obesity|Weight Loss|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1004047', '25590576', 'Nutrigenomics investigates relationships between nutrients and all genome-encoded molecular entities. This holistic approach requires systems biology to scrutinize the effects of diet on tissue biology. To decipher the adipose tissue (AT) response to diet induced weight changes we focused on key molecular (lipids and transcripts) AT species during a longitudinal dietary intervention. To obtain a systems model, a network approach was used to combine all sets of variables (bio-clinical, fatty acids and mRNA levels) and get an overview of their interactions. AT fatty acids and mRNA levels were quantified in 135 obese women at baseline, after an 8-week low calorie diet (LCD) and after 6 months of ad libitum weight maintenance diet (WMD). After LCD, individuals were stratified a posteriori according to weight change during WMD. A 3 steps approach was used to infer a global model involving the 3 sets of variables. It consisted in inferring intra-omic networks with sparse partial correlations and inter-omic networks with regularized canonical correlation analysis and finally combining the obtained omic-specific network in a single global model. The resulting networks were analyzed using node clustering, systematic important node extraction and cluster comparisons. Overall, AT showed both constant and phase-specific biological signatures in response to dietary intervention. AT from women regaining weight displayed growth factors, angiogenesis and proliferation signaling signatures, suggesting unfavorable tissue hyperplasia. By contrast, after LCD a strong positive relationship between AT myristoleic acid (a fatty acid with low AT level) content and de novo lipogenesis mRNAs was found. This relationship was also observed, after WMD, in the group of women that continued to lose weight. This original system biology approach provides novel insight in the AT response to weight control by highlighting the central role of myristoleic acid that may account for the beneficial effects of weight loss. '),
(86967, 2015, 'plos', 'The interaction between seasonality and pulsed interventions against malaria in their effects on the reproduction number', 'Griffin, Jamie T', 'MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College London, London, United Kingdom.', 'United Kingdom', 0, 'Africa|Animals|Anopheles|Humans|Insect Vectors|Malaria, Falciparum|Models, Biological|Plasmodium falciparum|Reproduction|Seasons', 'Journal Article', '10.1371/journal.pcbi.1004057', '25590612', 'The basic reproduction number (R0) is an important quantity summarising the dynamics of an infectious disease, as it quantifies how much effort is needed to control transmission. The relative change in R0 due to an intervention is referred to as the effect size. However malaria and other diseases are often highly seasonal and some interventions have time-varying effects, meaning that simple reproduction number formulae cannot be used. Methods have recently been developed for calculating R0 for diseases with seasonally varying transmission. I extend those methods to calculate the effect size of repeated rounds of mass drug administration, indoor residual spraying and other interventions against Plasmodium falciparum malaria in seasonal settings in Africa. I show that if an intervention reduces transmission from one host to another by a constant factor, then its effect size is the same in a seasonal as in a non-seasonal setting. The optimal time of year for drug administration is in the low season, whereas the best time for indoor residual spraying or a vaccine which reduces infection rates is just before the high season. In general, the impact of time-varying interventions increases with increasing seasonality, if carried out at the optimal time of year. The effect of combinations of interventions that act at different stages of the transmission cycle is roughly the product of the separate effects. However for individual time-varying interventions, it is necessary to use methods such as those developed here rather than inserting the average efficacy into a simple formula. '),
(86968, 2015, 'plos', 'A probabilistic palimpsest model of visual short-term memory', 'Matthey, Loic|Bays, Paul M|Dayan, Peter', 'Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom.|Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, United Kingdom, Institute of Cognitive and Brain Sciences, University of California, Berkeley, Berkeley, California, United States of America.|Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 23, 'Humans|Memory, Short-Term|Mental Recall|Models, Neurological|Models, Statistical|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1004003', '25611204', 'Working memory plays a key role in cognition, and yet its mechanisms remain much debated. Human performance on memory tasks is severely limited, however, the two major classes of theory explaining the limits leave open questions about key issues such as how multiple simultaneously-represented items can be distinguished. We propose a palimpsest model, with the occurrent activity of a single population of neurons coding for several multi-featured items. Using a probabilistic approach to storage and recall, we show how this model can account for many qualitative aspects of existing experimental data. In our account, the underlying nature of a memory item depends entirely on the characteristics of the population representation, and we provide analytical and numerical insights into critical issues such as multiplicity and binding. We consider representations in which information about individual feature values is partially separate from the information about binding that creates single items out of multiple features. An appropriate balance between these two types of information is required to capture fully the different types of error seen in human experimental data. Our model provides the first principled account of misbinding errors. We also suggest a specific set of stimuli designed to elucidate the representations that subjects actually employ. '),
(86969, 2015, 'plos', 'A new algorithm to diagnose atrial ectopic origin from multi lead ECG systems--insights from 3D virtual human atria and torso', 'Alday, Erick A Perez|Colman, Michael A|Langley, Philip|Butters, Timothy D|Higham, Jonathan|Workman, Antony J|Hancox, Jules C|Zhang, Henggui', 'Biological Physics Group, Department of Physics and Astronomy, University of Manchester, Manchester, United Kingdom.|Biological Physics Group, Department of Physics and Astronomy, University of Manchester, Manchester, United Kingdom.|School of Engineering, University of Hull, Hull, United Kingdom.|Biological Physics Group, Department of Physics and Astronomy, University of Manchester, Manchester, United Kingdom.|Biological Physics Group, Department of Physics and Astronomy, University of Manchester, Manchester, United Kingdom.|Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.|Biological Physics Group, Department of Physics and Astronomy, University of Manchester, Manchester, United Kingdom, School of Physiology and Pharmacology, and Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, Bristol, United Kingdom.|Biological Physics Group, Department of Physics and Astronomy, University of Manchester, Manchester, United Kingdom, School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Algorithms|Atrial Fibrillation|Body Surface Potential Mapping|Computer Simulation|Electrocardiography|Female|Heart Atria|Humans|Male|Models, Biological|Torso', 'Journal Article', '10.1371/journal.pcbi.1004026', '25611350', 'Rapid atrial arrhythmias such as atrial fibrillation (AF) predispose to ventricular arrhythmias, sudden cardiac death and stroke. Identifying the origin of atrial ectopic activity from the electrocardiogram (ECG) can help to diagnose the early onset of AF in a cost-effective manner. The complex and rapid atrial electrical activity during AF makes it difficult to obtain detailed information on atrial activation using the standard 12-lead ECG alone. Compared to conventional 12-lead ECG, more detailed ECG lead configurations may provide further information about spatio-temporal dynamics of the body surface potential (BSP) during atrial excitation. We apply a recently developed 3D human atrial model to simulate electrical activity during normal sinus rhythm and ectopic pacing. The atrial model is placed into a newly developed torso model which considers the presence of the lungs, liver and spinal cord. A boundary element method is used to compute the BSP resulting from atrial excitation. Elements of the torso mesh corresponding to the locations of the placement of the electrodes in the standard 12-lead and a more detailed 64-lead ECG configuration were selected. The ectopic focal activity was simulated at various origins across all the different regions of the atria. Simulated BSP maps during normal atrial excitation (i.e. sinoatrial node excitation) were compared to those observed experimentally (obtained from the 64-lead ECG system), showing a strong agreement between the evolution in time of the simulated and experimental data in the P-wave morphology of the ECG and dipole evolution. An algorithm to obtain the location of the stimulus from a 64-lead ECG system was developed. The algorithm presented had a success rate of 93%, meaning that it correctly identified the origin of atrial focus in 75/80 simulations, and involved a general approach relevant to any multi-lead ECG system. This represents a significant improvement over previously developed algorithms. ');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(86970, 2015, 'plos', 'A computational approach to identifying gene-microRNA modules in cancer', 'Jin, Daeyong|Lee, Hyunju', 'School of Information and Communications, Gwangju Institute of Science and Technology, Gwangju, South Korea.|School of Information and Communications, Gwangju Institute of Science and Technology, Gwangju, South Korea.', '-|-', 24, 'Bayes Theorem|Computational Biology|Gene Expression Profiling|Gene Regulatory Networks|Humans|MicroRNAs|Neoplasms', 'Journal Article', '10.1371/journal.pcbi.1004042', '25611546', 'MicroRNAs (miRNAs) play key roles in the initiation and progression of various cancers by regulating genes. Regulatory interactions between genes and miRNAs are complex, as multiple miRNAs can regulate multiple genes. In addtion, these interactions vary from patient to patient and even among patients with the same cancer type, as cancer development is a heterogeneous process. These relationships are more complicated because transcription factors and other regulatory molecules can also regulate miRNAs and genes. Hence, it is important to identify the complex relationships between genes and miRNAs in cancer. In this study, we propose a computational approach to constructing modules that represent these relationships by integrating the expression data of genes and miRNAs with gene-gene interaction data. First, we used a biclustering algorithm to construct modules consisting of a subset of genes and a subset of samples to incorporate the heterogeneity of cancer cells. Second, we combined gene-gene interactions to include genes that play important roles in cancer-related pathways. Then, we selected miRNAs that are closely associated with genes in the modules based on a Gaussian Bayesian network and Bayesian Information Criteria. When we applied our approach to ovarian cancer and glioblastoma (GBM) data sets, 33 and 54 modules were constructed, respectively. In these modules, 91% and 94% of ovarian cancer and GBM modules, respectively, were explained either by direct regulation between genes and miRNAs or by indirect relationships via transcription factors. In addition, 48.4% and 74.0% of modules from ovarian cancer and GBM, respectively, were enriched with cancer-related pathways, and 51.7% and 71.7% of miRNAs in modules were ovarian cancer-related miRNAs and GBM-related miRNAs, respectively. Finally, we extensively analyzed significant modules and showed that most genes in these modules were related to ovarian cancer and GBM. '),
(86971, 2015, 'plos', 'Modulation of calmodulin lobes by different targets: an allosteric model with hemiconcerted conformational transitions', 'Lai, Massimo|Brun, Denis|Edelstein, Stuart J|Le Novère, Nicolas', 'Babraham Institute, Cambridge, United Kingdom.|EMBL-EBI, Hinxton, United Kingdom, Amadeus IT Group, Sophia Antipolis, France.|Babraham Institute, Cambridge, United Kingdom.|Babraham Institute, Cambridge, United Kingdom, EMBL-EBI, Hinxton, United Kingdom.', 'United Kingdom|France|United Kingdom|United Kingdom', 11, 'Allosteric Regulation|Amino Acid Sequence|Calcium|Calmodulin|Models, Molecular|Molecular Sequence Data|Protein Conformation|Sequence Alignment|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1004063', '25611683', 'Calmodulin is a calcium-binding protein ubiquitous in eukaryotic cells, involved in numerous calcium-regulated biological phenomena, such as synaptic plasticity, muscle contraction, cell cycle, and circadian rhythms. It exibits a characteristic dumbell shape, with two globular domains (N- and C-terminal lobe) joined by a linker region. Each lobe can take alternative conformations, affected by the binding of calcium and target proteins. Calmodulin displays considerable functional flexibility due to its capability to bind different targets, often in a tissue-specific fashion. In various specific physiological environments (e.g. skeletal muscle, neuron dendritic spines) several targets compete for the same calmodulin pool, regulating its availability and affinity for calcium. In this work, we sought to understand the general principles underlying calmodulin modulation by different target proteins, and to account for simultaneous effects of multiple competing targets, thus enabling a more realistic simulation of calmodulin-dependent pathways. We built a mechanistic allosteric model of calmodulin, based on an hemiconcerted framework: each calmodulin lobe can exist in two conformations in thermodynamic equilibrium, with different affinities for calcium and different affinities for each target. Each lobe was allowed to switch conformation on its own. The model was parameterised and validated against experimental data from the literature. In spite of its simplicity, a two-state allosteric model was able to satisfactorily represent several sets of experiments, in particular the binding of calcium on intact and truncated calmodulin and the effect of different skMLCK peptides on calmodulins saturation curve. The model can also be readily extended to include multiple targets. We show that some targets stabilise the low calcium affinity T state while others stabilise the high affinity R state. Most of the effects produced by calmodulin targets can be explained as modulation of a pre-existing dynamic equilibrium between different conformations of calmodulins lobes, in agreement with linkage theory and MWC-type models. '),
(86972, 2015, 'plos', 'Laminar and dorsoventral molecular organization of the medial entorhinal cortex revealed by large-scale anatomical analysis of gene expression', 'Ramsden, Helen L|Sxc3xbcrmeli, Gxc3xbclxc5x9fen|McDonagh, Steven G|Nolan, Matthew F', 'Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom, Neuroinformatics Doctoral Training Centre, School of Informatics, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.|Institute of Perception, Action and Behaviour, School of Informatics, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom, Centre for Brain Development and Repair, inStem, Bangalore, India.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 21, 'Animals|Entorhinal Cortex|Gene Expression Profiling|Image Processing, Computer-Assisted|Male|Mice|Mice, Inbred C57BL|Molecular Imaging|Organ Specificity', 'Journal Article', '10.1371/journal.pcbi.1004032', '25615592', 'Neural circuits in the medial entorhinal cortex (MEC) encode an animals position and orientation in space. Within the MEC spatial representations, including grid and directional firing fields, have a laminar and dorsoventral organization that corresponds to a similar topography of neuronal connectivity and cellular properties. Yet, in part due to the challenges of integrating anatomical data at the resolution of cortical layers and borders, we know little about the molecular components underlying this organization. To address this we develop a new computational pipeline for high-throughput analysis and comparison of in situ hybridization (ISH) images at laminar resolution. We apply this pipeline to ISH data for over 16,000 genes in the Allen Brain Atlas and validate our analysis with RNA sequencing of MEC tissue from adult mice. We find that differential gene expression delineates the borders of the MEC with neighboring brain structures and reveals its laminar and dorsoventral organization. We propose a new molecular basis for distinguishing the deep layers of the MEC and show that their similarity to corresponding layers of neocortex is greater than that of superficial layers. Our analysis identifies ion channel-, cell adhesion- and synapse-related genes as candidates for functional differentiation of MEC layers and for encoding of spatial information at different scales along the dorsoventral axis of the MEC. We also reveal laminar organization of genes related to disease pathology and suggest that a high metabolic demand predisposes layer II to neurodegenerative pathology. In principle, our computational pipeline can be applied to high-throughput analysis of many forms of neuroanatomical data. Our results support the hypothesis that differences in gene expression contribute to functional specialization of superficial layers of the MEC and dorsoventral organization of the scale of spatial representations. '),
(86973, 2015, 'plos', 'Computation in dynamically bounded asymmetric systems', 'Rutishauser, Ueli|Slotine, Jean-Jacques|Douglas, Rodney', 'Computation and Neural Systems, California Institute of Technology, Pasadena, California, United States of America, Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, United States of America, Departments of Neurosurgery, Neurology and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.|Nonlinear Systems Laboratory, Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Institute of Neuroinformatics, University and ETH Zurich, Zurich, Switzerland.', 'United States|United States|Switzerland', 0, 'Computational Biology|Computer Simulation|Feedback, Physiological|Models, Neurological|Models, Statistical|Nerve Net|Neurons', 'Journal Article', '10.1371/journal.pcbi.1004039', '25617645', 'Previous explanations of computations performed by recurrent networks have focused on symmetrically connected saturating neurons and their convergence toward attractors. Here we analyze the behavior of asymmetrical connected networks of linear threshold neurons, whose positive response is unbounded. We show that, for a wide range of parameters, this asymmetry brings interesting and computationally useful dynamical properties. When driven by input, the network explores potential solutions through highly unstable expansion dynamics. This expansion is steered and constrained by negative divergence of the dynamics, which ensures that the dimensionality of the solution space continues to reduce until an acceptable solution manifold is reached. Then the system contracts stably on this manifold towards its final solution trajectory. The unstable positive feedback and cross inhibition that underlie expansion and divergence are common motifs in molecular and neuronal networks. Therefore we propose that very simple organizational constraints that combine these motifs can lead to spontaneous computation and so to the spontaneous modification of entropy that is characteristic of living systems. '),
(86974, 2015, 'plos', 'Ten simple rules for organizing an unconference', 'Budd, Aidan|Dinkel, Holger|Corpas, Manuel|Fuller, Jonathan C|Rubinat, Laura|Devos, Damien P|Khoueiry, Pierre H|Förstner, Konrad U|Georgatos, Fotis|Rowland, Francis|Sharan, Malvika|Binder, Janos X|Grace, Tom|Traphagen, Karyn|Gristwood, Adam|Wood, Natasha T', 'Structural and Computational Biology (SCB) Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.|Structural and Computational Biology (SCB) Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.|The Genome Analysis Centre (TGAC), Norwich Research Park, Norwich, United Kingdom.|Heidelberg Institute for Theoretical Studies (HITS) gGmbH, Heidelberg, Germany.|Structural and Computational Biology (SCB) Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany, Molecular Microbial Ecology Group, Institute of Aquatic Ecology, Universitat de Girona, Girona, Spain.|Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide, Sevilla, Spain.|Genome Biology (GB) Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.|Core Unit Systems Medicine, University of Würzburg, Würzburg, Germany.|Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg.|European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom.|Institute for Molecular Infection Biology, Universität Würzburg, Würzburg, Germany.|Structural and Computational Biology (SCB) Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany, Bioinformatics Core Facility, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Walferdange, Luxembourg.|Typeface & Lettering Design, Heidelberg, Germany.|ScienceOnline, Durham, North Carolina, United States of America.|Office of Information and Public Affairs, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.|South African National Bioinformatics Institute (SANBI), South African Medical Research Council Bioinformatics Unit, University of the Western Cape, Cape Town, South Africa.', 'Germany|Germany|United Kingdom|Germany|Germany|Spain|Germany|Germany|Luxembourg|United Kingdom|Germa', 21, 'Communication|Computational Biology|Congresses as Topic|Crowdsourcing|Humans', 'Editorial', '10.1371/journal.pcbi.1003905', '25633715', '-'),
(86975, 2015, 'plos', 'GenomicScape: an easy-to-use web tool for gene expression data analysis Application to investigate the molecular events in the differentiation of B cells into plasma cells', 'Kassambara, Alboukadel|Rème, Thierry|Jourdan, Michel|Fest, Thierry|Hose, Dirk|Tarte, Karin|Klein, Bernard', 'U1040, INSERM, Montpellier, France, Department of Biological Hematology, CHU Montpellier, Montpellier, France.|U1040, INSERM, Montpellier, France, Department of Biological Hematology, CHU Montpellier, Montpellier, France.|U1040, INSERM, Montpellier, France.|U917, INSERM, Rennes, France.|Medizinische Klinik V, Universitätsklinikum Heidelberg and Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany.|U917, INSERM, Rennes, France.|U1040, INSERM, Montpellier, France, Department of Biological Hematology, CHU Montpellier, Montpellier, France, UFR Médecine, Université MONTPELLIER 1, Montpellier, France.', 'France|France|France|France|Germany|France|France', 47, 'B-Lymphocytes|Cell Differentiation|Cluster Analysis|Data Mining|Databases, Genetic|Gene Expression Profiling|Genomics|Humans|Internet|Plasma Cells|Principal Component Analysis|Software', 'Journal Article', '10.1371/journal.pcbi.1004077', '25633866', 'DNA microarrays have considerably helped to improve the understanding of biological processes and diseases. Large amounts of publicly available microarray data are accumulating, but are poorly exploited due to a lack of easy-to-use bioinformatics resources. The aim of this study is to build a free and convenient data-mining web site (www.genomicscape.com). GenomicScape allows mining dataset from various microarray platforms, identifying genes differentially expressed between populations, clustering populations, visualizing expression profiles of large sets of genes, and exporting results and figures. We show how easily GenomicScape makes it possible to construct a molecular atlas of the B cell differentiation using publicly available transcriptome data of naïve B cells, centroblasts, centrocytes, memory B cells, preplasmablasts, plasmablasts, early plasma cells and bone marrow plasma cells. Genes overexpressed in each population and the pathways encoded by these genes are provided as well as how the populations cluster together. All the analyses, tables and figures can be easily done and exported using GenomicScape and this B cell to plasma cell atlas is freely available online. Beyond this B cell to plasma cell atlas, the molecular characteristics of any biological process can be easily and freely investigated by uploading the corresponding transcriptome files into GenomicScape. '),
(86976, 2015, 'plos', 'Comprehensive sieve analysis of breakthrough HIV-1 sequences in the RV144 vaccine efficacy trial', 'Edlefsen, Paul T|Rolland, Morgane|Hertz, Tomer|Tovanabutra, Sodsai|Gartland, Andrew J|deCamp, Allan C|Magaret, Craig A|Ahmed, Hasan|Gottardo, Raphael|Juraska, Michal|McCoy, Connor|Larsen, Brendan B|Sanders-Buell, Eric|Carrico, Chris|Menis, Sergey|Kijak, Gustavo H|Bose, Meera|RV144 Sequencing Team|Arroyo, Miguel A|OConnell, Robert J|Nitayaphan, Sorachai|Pitisuttithum, Punnee|Kaewkungwal, Jaranit|Rerks-Ngarm, Supachai|Robb, Merlin L|Kirys, Tatsiana|Georgiev, Ivelin S|Kwong, Peter D|Scheffler, Konrad|Pond, Sergei L Kosakovsky|Carlson, Jonathan M|Michael, Nelson L|Schief, William R|Mullins, James I|Kim, Jerome H|Gilbert, Peter B', 'Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|US Military HIV Research Program, Silver Spring, Maryland, United States of America.|Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America, The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences, and The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|US Military HIV Research Program, Silver Spring, Maryland, United States of America.|Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Department of Microbiology, University of Washington, Seattle, Washington, United States of America.|US Military HIV Research Program, Silver Spring, Maryland, United States of America.|Department of Biochemistry, University of Washington, Seattle, Washington, United States of America, IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Biochemistry, University of Washington, Seattle, Washington, United States of America, IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, United States of America.|US Military HIV Research Program, Silver Spring, Maryland, United States of America.|US Military HIV Research Program, Silver Spring, Maryland, United States of America.|US Military HIV Research Program, Silver Spring, Maryland, United States of America.|Royal Thai Army Component, AFRIMS, Bangkok, Thailand.|US Army Component, AFRIMS, Bangkok, Thailand.|Royal Thai Army Component, AFRIMS, Bangkok, Thailand.|Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Royal Thai Army Component, AFRIMS, Bangkok, Thailand.|CDC Department, Thai Ministry of Public Health, Nonthaburi, Thailand.|US Military HIV Research Program, Silver Spring, Maryland, United States of America.|Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.|Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.|Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.|Department of Medicine, University of California, San Diego, La Jolla, California, United States of America.|Department of Medicine, University of California, San Diego, La Jolla, California, United States of America.|eSience Research Group, Microsoft Research, Redmond, Washington, United States of America.|US Military HIV Research Program, Silver Spring, Maryland, United States of America.|Department of Biochemistry, University of Washington, Seattle, Washington, United States of America, IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, United States of America, Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.|Department of Microbiology, University of Washington, Seattle, Washington, United States of America.|US Military HIV Research Program, Silver Spring, Maryland, United States of America.|Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.', 'United States|United States|Israel|United States|United States|United States|United States|United St', 0, 'AIDS Vaccines|Binding Sites|Genome, Viral|HIV Infections|HIV-1|Human Immunodeficiency Virus Proteins|Humans|Models, Molecular|Molecular Sequence Data|Sequence Alignment|Sequence Analysis, Protein', 'Clinical Trial, Phase III', '10.1371/journal.pcbi.1003973', '25646817', 'The RV144 clinical trial showed the partial efficacy of a vaccine regimen with an estimated vaccine efficacy (VE) of 31% for protecting low-risk Thai volunteers against acquisition of HIV-1. The impact of vaccine-induced immune responses can be investigated through sieve analysis of HIV-1 breakthrough infections (infected vaccine and placebo recipients). A V1/V2-targeted comparison of the genomes of HIV-1 breakthrough viruses identified two V2 amino acid sites that differed between the vaccine and placebo groups. Here we extended the V1/V2 analysis to the entire HIV-1 genome using an array of methods based on individual sites, k-mers and genes/proteins. We identified 56 amino acid sites or signatures and 119 k-mers that differed between the vaccine and placebo groups. Of those, 19 sites and 38 k-mers were located in the regions comprising the RV144 vaccine (Env-gp120, Gag, and Pro). The nine signature sites in Env-gp120 were significantly enriched for known antibody-associated sites (p = 0.0021). In particular, site 317 in the third variable loop (V3) overlapped with a hotspot of antibody recognition, and sites 369 and 424 were linked to CD4 binding site neutralization. The identified signature sites significantly covaried with other sites across the genome (mean = 32.1) more than did non-signature sites (mean = 0.9) (p < 0.0001), suggesting functional and/or structural relevance of the signature sites. Since signature sites were not preferentially restricted to the vaccine immunogens and because most of the associations were insignificant following correction for multiple testing, we predict that few of the genetic differences are strongly linked to the RV144 vaccine-induced immune pressure. In addition to presenting results of the first complete-genome analysis of the breakthrough infections in the RV144 trial, this work describes a set of statistical methods and tools applicable to analysis of breakthrough infection genomes in general vaccine efficacy trials for diverse pathogens. '),
(86977, 2015, 'plos', 'When less is more: non-monotonic spike sequence processing in neurons', 'Arnoldt, Hinrich|Chang, Shuwen|Jahnke, Sven|Urmersbach, Birk|Taschenberger, Holger|Timme, Marc', 'Network Dynamics, Max Planck Institute for Dynamics and Self-Organization (MPIDS), Göttingen, Germany, Institute for Nonlinear Dynamics, Faculty of Physics, Georg August University Göttingen, Göttingen, Germany.|Department of Membrane Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.|Network Dynamics, Max Planck Institute for Dynamics and Self-Organization (MPIDS), Göttingen, Germany, Institute for Nonlinear Dynamics, Faculty of Physics, Georg August University Göttingen, Göttingen, Germany, Bernstein Center for Computational Neuroscience (BCCN) Göttingen, Göttingen, Germany.|Network Dynamics, Max Planck Institute for Dynamics and Self-Organization (MPIDS), Göttingen, Germany.|Department of Membrane Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.|Network Dynamics, Max Planck Institute for Dynamics and Self-Organization (MPIDS), Göttingen, Germany, Institute for Nonlinear Dynamics, Faculty of Physics, Georg August University Göttingen, Göttingen, Germany, Bernstein Center for Computational Neuroscience (BCCN) Göttingen, Göttingen, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany', 3, 'Action Potentials|Animals|Cells, Cultured|Computer Simulation|Models, Neurological|Neurons|Patch-Clamp Techniques|Rats|Rats, Wistar|Trapezoid Body', 'Journal Article', '10.1371/journal.pcbi.1004002', '25646860', 'Fundamental response properties of neurons centrally underly the computational capabilities of both individual nerve cells and neural networks. Most studies on neuronal input-output relations have focused on continuous-time inputs such as constant or noisy sinusoidal currents. Yet, most neurons communicate via exchanging action potentials (spikes) at discrete times. Here, we systematically analyze the stationary spiking response to regular spiking inputs and reveal that it is generically non-monotonic. Our theoretical analysis shows that the underlying mechanism relies solely on a combination of the discrete nature of the communication by spikes, the capability of locking output to input spikes and limited resources required for spike processing. Numerical simulations of mathematically idealized and biophysically detailed models, as well as neurophysiological experiments confirm and illustrate our theoretical predictions. '),
(86978, 2015, 'plos', 'Exploring bacterial organelle interactomes: a model of the protein-protein interaction network in the Pdu microcompartment', 'Jorda, Julien|Liu, Yu|Bobik, Thomas A|Yeates, Todd O', 'UCLA-DOE Institute for Genomics and Proteomics, Los Angeles, California, United States of America.|Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa, United States of America.|Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa, United States of America.|UCLA-DOE Institute for Genomics and Proteomics, Los Angeles, California, United States of America, Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, United States of America, Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California, United States of America.', 'United States|United States|United States|United States', 14, 'Bacteria|Bacterial Proteins|Computational Biology|Models, Biological|Models, Molecular|Organelles|Protein Interaction Maps', 'Journal Article', '10.1371/journal.pcbi.1004067', '25646976', 'Bacterial microcompartments (MCPs) are protein-bound organelles that carry out diverse metabolic pathways in a wide range of bacteria. These supramolecular assemblies consist of a thin outer protein shell, reminiscent of a viral capsid, which encapsulates sequentially acting enzymes. The most complex MCP elucidated so far is the propanediol utilizing (Pdu) microcompartment. It contains the reactions for degrading 1,2-propanediol. While several experimental studies on the Pdu system have provided hints about its organization, a clear picture of how all the individual components interact has not emerged yet. Here we use co-evolution-based methods, involving pairwise comparisons of protein phylogenetic trees, to predict the protein-protein interaction (PPI) network governing the assembly of the Pdu MCP. We propose a model of the Pdu interactome, from which selected PPIs are further inspected via computational docking simulations. We find that shell protein PduA is able to serve as a universal hub for targeting an array of enzymes presenting special N-terminal extensions, namely PduC, D, E, L and P. The varied N-terminal peptides are predicted to bind in the same cleft on the presumptive luminal face of the PduA hexamer. We also propose that PduV, a protein of unknown function with remote homology to the Ras-like GTPase superfamily, is likely to localize outside the MCP, interacting with the protruding xcexb2-barrel of the hexameric PduU shell protein. Preliminary experiments involving a bacterial two-hybrid assay are presented that corroborate the existence of a PduU-PduV interaction. This first systematic computational study aimed at characterizing the interactome of a bacterial microcompartment provides fresh insight into the organization of the Pdu MCP. '),
(86979, 2015, 'plos', 'A quick guide for building a successful bioinformatics community', 'Budd, Aidan|Corpas, Manuel|Brazas, Michelle D|Fuller, Jonathan C|Goecks, Jeremy|Mulder, Nicola J|Michaut, Magali|Ouellette, B F Francis|Pawlik, Aleksandra|Blomberg, Niklas', 'Structural and Computational Biology (SCB) Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.|The Genome Analysis Centre (TGAC), Norwich Research Park, Norwich, United Kingdom.|Ontario Institute for Cancer Research, MaRS Centre, West Tower, Toronto, Ontario, Canada.|Heidelberg Institute for Theoretical Studies (HITS) gGmbH, Heidelberg, Germany.|The Computational Biology Institute, George Washington University, Innovation Hall, Virginia, United States of America.|Computational Biology Group, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town Faculty of Health Sciences, Cape Town, South Africa.|Computational Cancer Biology, Netherlands Cancer Institute, Amsterdam, the Netherlands.|Ontario Institute for Cancer Research, MaRS Centre, West Tower, Toronto, Ontario, Canada, Department of Cell and Systems Biology, University of Toronto, Toronto, Canada.|The Software Sustainability Institute, School of Computer Science, University of Manchester, Manchester, United Kingdom.|ELIXIR Hub, Wellcome Trust Genome Campus, Cambridge, United Kingdom.', 'Germany|United Kingdom|Canada|Germany|United States|South Africa|Netherlands|Canada|United Kingdom|U', 0, 'Communication|Computational Biology|Humans|Internet|Social Media', 'Journal Article', '10.1371/journal.pcbi.1003972', '25654371', 'Scientific community refers to a group of people collaborating together on scientific-research-related activities who also share common goals, interests, and values. Such communities play a key role in many bioinformatics activities. Communities may be linked to a specific location or institute, or involve people working at many different institutions and locations. Education and training is typically an important component of these communities, providing a valuable context in which to develop skills and expertise, while also strengthening links and relationships within the community. Scientific communities facilitate: (i) the exchange and development of ideas and expertise, (ii) career development, (iii) coordinated funding activities, (iv) interactions and engagement with professionals from other fields, and (v) other activities beneficial to individual participants, communities, and the scientific field as a whole. It is thus beneficial at many different levels to understand the general features of successful, high-impact bioinformatics communities, how individual participants can contribute to the success of these communities, and the role of education and training within these communities. We present here a quick guide to building and maintaining a successful, high-impact bioinformatics community, along with an overview of the general benefits of participating in such communities. This article grew out of contributions made by organizers, presenters, panelists, and other participants of the ISMB/ECCB 2013 workshop The How To Guide for Establishing a Successful Bioinformatics Network at the 21st Annual International Conference on Intelligent Systems for Molecular Biology (ISMB) and the 12th European Conference on Computational Biology (ECCB). '),
(86980, 2015, 'plos', 'HIV competition dynamics over sexual networks: first comer advantage conserves founder effects', 'Ferdinandy, Bence|Mones, Enys|Vicsek, Tamás|Müller, Viktor', 'Department of Biological Physics, Eötvös Loránd University, Budapest, Hungary.|Department of Biological Physics, Eötvös Loránd University, Budapest, Hungary.|Department of Biological Physics, Eötvös Loránd University, Budapest, Hungary, MTA-ELTE Statistical and Biological Physics Research Group, Eötvös Loránd University and the Hungarian Academy of Sciences, Budapest, Hungary.|MTA-ELTE Theoretical Biology and Evolutionary Ecology Research Group, Eötvös Loránd University and the Hungarian Academy of Sciences, Budapest, Hungary, Parmenides Center for the Conceptual Foundations of Science, Pullach/Munich, Germany.', 'Hungary|Hungary|Hungary|Germany', 5, 'Contact Tracing|Epidemics|Female|Founder Effect|HIV Infections|HIV-1|Humans|Male|Models, Biological|Prevalence|Sexual Behavior|Statistics, Nonparametric|Uganda', 'Journal Article', '10.1371/journal.pcbi.1004093', '25654450', 'Outside Africa, the global phylogeography of HIV is characterized by compartmentalized local epidemics that are typically dominated by a single subtype, which indicates strong founder effects. We hypothesized that the competition of viral strains at the epidemic level may involve an advantage of the resident strain that was the first to colonize a population. Such an effect would slow down the invasion of new strains, and thus also the diversification of the epidemic. We developed a stochastic modelling framework to simulate HIV epidemics over dynamic contact networks. We simulated epidemics in which the second strain was introduced into a population where the first strain had established a steady-state epidemic, and assessed whether, and on what time scale, the second strain was able to spread in the population. Simulations were parameterized based on empirical data, we tested scenarios with varying levels of overall prevalence. The spread of the second strain occurred on a much slower time scale compared with the initial expansion of the first strain. With strains of equal transmission efficiency, the second strain was unable to invade on a time scale relevant for the history of the HIV pandemic. To become dominant over a time scale of decades, the second strain needed considerable (>25%) advantage in transmission efficiency over the resident strain. The inhibition effect was weaker if the second strain was introduced while the first strain was still in its growth phase. We also tested how possible mechanisms of interference (inhibition of superinfection, depletion of highly connected hubs in the network, one-time acute peak of infectiousness) contribute to the inhibition effect. Our simulations confirmed a strong first comer advantage in the competition dynamics of HIV at the population level, which may explain the global phylogeography of the virus and may influence the future evolution of the pandemic. '),
(86981, 2015, 'plos', 'Embryonic stem cell specific master replication origins at the heart of the loss of pluripotency', 'Julienne, Hanna|Audit, Benjamin|Arneodo, Alain', 'Universitxc3xa9 de Lyon, Lyon, France, Laboratoire de Physique, CNRS UMR 5672, Ecole Normale Supxc3xa9rieure de Lyon, Lyon, France.|Universitxc3xa9 de Lyon, Lyon, France, Laboratoire de Physique, CNRS UMR 5672, Ecole Normale Supxc3xa9rieure de Lyon, Lyon, France.|Universitxc3xa9 de Lyon, Lyon, France, Laboratoire de Physique, CNRS UMR 5672, Ecole Normale Supxc3xa9rieure de Lyon, Lyon, France.', 'France|France|France', 13, 'Cell Differentiation|Cell Line|Chromatin|Cluster Analysis|Computational Biology|Embryonic Stem Cells|Epigenesis, Genetic|Histones|Humans|Replication Origin', 'Journal Article', '10.1371/journal.pcbi.1003969', '25658386', 'Epigenetic regulation of the replication program during mammalian cell differentiation remains poorly understood. We performed an integrative analysis of eleven genome-wide epigenetic profiles at 100 kb resolution of Mean Replication Timing (MRT) data in six human cell lines. Compared to the organization in four chromatin states shared by the five somatic cell lines, embryonic stem cell (ESC) line H1 displays (i) a gene-poor but highly dynamic chromatin state (EC4) associated to histone variant H2AZ rather than a HP1-associated heterochromatin state (C4) and (ii) a mid-S accessible chromatin state with bivalent gene marks instead of a polycomb-repressed heterochromatin state. Plastic MRT regions (xe2x89xb2 20% of the genome) are predominantly localized at the borders of U-shaped timing domains. Whereas somatic-specific U-domain borders are gene-dense GC-rich regions, 31.6% of H1-specific U-domain borders are early EC4 regions enriched in pluripotency transcription factors NANOG and OCT4 despite being GC poor and gene deserts. Silencing of these ESC-specific master replication initiation zones during differentiation corresponds to a loss of H2AZ and an enrichment in H3K9me3 mark characteristic of late replicating C4 heterochromatin. These results shed a new light on the epigenetically regulated global chromatin reorganization that underlies the loss of pluripotency and lineage commitment. '),
(86982, 2015, 'plos', 'Cell cycle control by a minimal Cdk network', 'Gérard, Claude|Tyson, John J|Coudreuse, Damien|Novák, Béla', 'Oxford Centre for Integrative Systems Biology, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.|Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, United States of America.|Institut de Génétique et Développement de Rennes, CNRS UMR 6290, Rennes, France.|Oxford Centre for Integrative Systems Biology, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.', 'United Kingdom|United States|France|United Kingdom', 31, 'Cell Cycle Checkpoints|Computational Biology|Cyclin-Dependent Kinases|Models, Biological|Phosphorylation|Schizosaccharomyces', 'Journal Article', '10.1371/journal.pcbi.1004056', '25658582', 'In present-day eukaryotes, the cell division cycle is controlled by a complex network of interacting proteins, including members of the cyclin and cyclin-dependent protein kinase (Cdk) families, and the Anaphase Promoting Complex (APC). Successful progression through the cell cycle depends on precise, temporally ordered regulation of the functions of these proteins. In light of this complexity, it is surprising that in fission yeast, a minimal Cdk network consisting of a single cyclin-Cdk fusion protein can control DNA synthesis and mitosis in a manner that is indistinguishable from wild type. To improve our understanding of the cell cycle regulatory network, we built and analysed a mathematical model of the molecular interactions controlling the G1/S and G2/M transitions in these minimal cells. The model accounts for all observed properties of yeast strains operating with the fusion protein. Importantly, coupling the models predictions with experimental analysis of alternative minimal cells, we uncover an explanation for the unexpected fact that elimination of inhibitory phosphorylation of Cdk is benign in these strains while it strongly affects normal cells. Furthermore, in the strain without inhibitory phosphorylation of the fusion protein, the distribution of cell size at division is unusually broad, an observation that is accounted for by stochastic simulations of the model. Our approach provides novel insights into the organization and quantitative regulation of wild type cell cycle progression. In particular, it leads us to propose a new mechanistic model for the phenomenon of mitotic catastrophe, relying on a combination of unregulated, multi-cyclin-dependent Cdk activities. '),
(86983, 2015, 'plos', 'Ethical challenges of big data in public health', 'Vayena, Effy|Salathé, Marcel|Madoff, Lawrence C|Brownstein, John S', 'Institute of Biomedical Ethics, University of Zurich, Zurich, Switzerland.|Center for Infectious Disease Dynamics, Department of Biology, Penn State University, University Park, Pennsylvania, United States of America.|ProMED (Program for Monitoring Emerging Diseases), International Society for Infectious Diseases and University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.|Childrens Hospital Informatics Program, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.', 'Switzerland|United States|United States|United States', 125, 'Biomedical Research|Confidentiality|Electronic Health Records|Epidemiology|Humans|Public Health', 'Editorial', '10.1371/journal.pcbi.1003904', '25664461', '-'),
(86984, 2015, 'plos', 'Communication over the network of binary switches regulates the activation of A2A adenosine receptor', 'Lee, Yoonji|Choi, Sun|Hyeon, Changbong', 'National Leading Research Laboratory (NLRL) of Molecular Modeling and Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Korea.|National Leading Research Laboratory (NLRL) of Molecular Modeling and Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Korea.|School of Computational Sciences, Korea Institute for Advanced Study, Seoul 130-722, Korea.', '-|-|-', 19, 'Adenosine A2 Receptor Agonists|Adenosine A2 Receptor Antagonists|Hydrogen Bonding|Molecular Dynamics Simulation|Protein Subunits|Receptor, Adenosine A2A', 'Journal Article', '10.1371/journal.pcbi.1004044', '25664580', 'Dynamics and functions of G-protein coupled receptors (GPCRs) are accurately regulated by the type of ligands that bind to the orthosteric or allosteric binding sites. To glean the structural and dynamical origin of ligand-dependent modulation of GPCR activity, we performed total ~ 5 xcexbcsec molecular dynamics simulations of A2A adenosine receptor (A2AAR) in its apo, antagonist-bound, and agonist-bound forms in an explicit water and membrane environment, and examined the corresponding dynamics and correlation between the 10 key structural motifs that serve as the allosteric hotspots in intramolecular signaling network. We dubbed these 10 structural motifs binary switches as they display molecular interactions that switch between two distinct states. By projecting the receptor dynamics on these binary switches that yield 2(10) microstates, we show that (i) the receptors in apo, antagonist-bound, and agonist-bound states explore vastly different conformational space, (ii) among the three receptor states the apo state explores the broadest range of microstates, (iii) in the presence of the agonist, the active conformation is maintained through coherent couplings among the binary switches, and (iv) to be most specific, our analysis shows that W246, located deep inside the binding cleft, can serve as both an agonist sensor and actuator of ensuing intramolecular signaling for the receptor activation. Finally, our analysis of multiple trajectories generated by inserting an agonist to the apo state underscores that the transition of the receptor from inactive to active form requires the disruption of ionic-lock in the DRY motif.'),
(86985, 2015, 'plos', 'Confronting the ethical challenges of big data in public health', 'Bourne, Philip E', 'Office of the Director, National Institutes of Health, Bethesda, Maryland, United States of America.', 'United States', 5, 'Confidentiality|Electronic Health Records|Humans|Public Health', 'Editorial', '10.1371/journal.pcbi.1004073', '25664660', '-'),
(86986, 2015, 'plos', 'Developing a molecular roadmap of drug-food interactions', 'Jensen, Kasper|Ni, Yueqiong|Panagiotou, Gianni|Kouskoumvekaki, Irene', 'Department of Systems Biology, Technical University of Denmark, Kgs. Lyngby, Denmark.|School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong.|School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong.|Department of Systems Biology, Technical University of Denmark, Kgs. Lyngby, Denmark.', 'Denmark|Hong Kong|Hong Kong|Denmark', 13, 'Animals|Computational Biology|Databases, Factual|Diet|Disease|Food-Drug Interactions|Gene Expression Profiling|Humans|Mice|Models, Molecular|Phytochemicals', 'Journal Article', '10.1371/journal.pcbi.1004048', '25668218', 'Recent research has demonstrated that consumption of food -especially fruits and vegetables- can alter the effects of drugs by interfering either with their pharmacokinetic or pharmacodynamic processes. Despite the recognition of such drug-food associations as an important element for successful therapeutic interventions, a systematic approach for identifying, predicting and preventing potential interactions between food and marketed or novel drugs is not yet available. The overall objective of this work was to sketch a comprehensive picture of the interference of xe2x88xbc 4,000 dietary components present in xe2x88xbc1800 plant-based foods with the pharmacokinetics and pharmacodynamics processes of medicine, with the purpose of elucidating the molecular mechanisms involved. By employing a systems chemical biology approach that integrates data from the scientific literature and online databases, we gained a global view of the associations between diet and dietary molecules with drug targets, metabolic enzymes, drug transporters and carriers currently deposited in DrugBank. Moreover, we identified disease areas and drug targets that are most prone to the negative effects of drug-food interactions, showcasing a platform for making recommendations in relation to foods that should be avoided under certain medications. Lastly, by investigating the correlation of gene expression signatures of foods and drugs we were able to generate a completely novel drug-diet interactome map. '),
(86987, 2015, 'plos', 'Mesoscopic segregation of excitation and inhibition in a brain network model', 'Malagarriga, Daniel|Villa, Alessandro E P|Garcia-Ojalvo, Jordi|Pons, Antonio J', 'Departament de Física i Enginyeria Nuclear, Universitat Politècnica de Catalunya, Terrassa, Spain, Neuroheuristic Research Group, Faculty of Business and Economics, University of Lausanne, Lausanne, Switzerland.|Neuroheuristic Research Group, Faculty of Business and Economics, University of Lausanne, Lausanne, Switzerland.|Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.|Departament de Física i Enginyeria Nuclear, Universitat Politècnica de Catalunya, Terrassa, Spain.', 'Switzerland|Switzerland|Spain|Spain', 14, 'Action Potentials|Algorithms|Brain|Computational Biology|Models, Neurological|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.1004007', '25671573', 'Neurons in the brain are known to operate under a careful balance of excitation and inhibition, which maintains neural microcircuits within the proper operational range. How this balance is played out at the mesoscopic level of neuronal populations is, however, less clear. In order to address this issue, here we use a coupled neural mass model to study computationally the dynamics of a network of cortical macrocolumns operating in a partially synchronized, irregular regime. The topology of the network is heterogeneous, with a few of the nodes acting as connector hubs while the rest are relatively poorly connected. Our results show that in this type of mesoscopic network excitation and inhibition spontaneously segregate, with some columns acting mainly in an excitatory manner while some others have predominantly an inhibitory effect on their neighbors. We characterize the conditions under which this segregation arises, and relate the character of the different columns with their topological role within the network. In particular, we show that the connector hubs are preferentially inhibitory, the more so the larger the nodes connectivity. These results suggest a potential mesoscale organization of the excitation-inhibition balance in brain networks. ');
