INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85839, 2013, 'plos', 'Reward from punishment does not emerge at all costs', 'Vukov, Jeromos|Pinheiro, Flávio L|Santos, Francisco C|Pacheco, Jorge M', 'ATP-group, Centro de Matemática e Aplicações Fundamentais, Instituto para a Investigação Interdisciplinar da Universidade de Lisboa, Lisboa, Portugal. jvukov@cii.fc.ul.pt|ATP-group, Centro de Matemática e Aplicações Fundamentais, Instituto para a Investigação Interdisciplinar da Universidade de Lisboa, Lisboa, Portugal. jvukov@cii.fc.ul.pt|ATP-group, Centro de Matemática e Aplicações Fundamentais, Instituto para a Investigação Interdisciplinar da Universidade de Lisboa, Lisboa, Portugal. jvukov@cii.fc.ul.pt|ATP-group, Centro de Matemática e Aplicações Fundamentais, Instituto para a Investigação Interdisciplinar da Universidade de Lisboa, Lisboa, Portugal. jvukov@cii.fc.ul.pt', 'Portugal|Portugal|Portugal|Portugal', 17, 'Altruism|Conflict (Psychology)|Humans|Punishment|Reward', 'Journal Article', '10.1371/journal.pcbi.1002868', '23341764', 'The conundrum of cooperation has received increasing attention during the last decade. In this quest, the role of altruistic punishment has been identified as a mechanism promoting cooperation. Here we investigate the role of altruistic punishment on the emergence and maintenance of cooperation in structured populations exhibiting connectivity patterns recently identified as key elements of social networks. We do so in the framework of Evolutionary Game Theory, employing the Prisoners Dilemma and the Stag-Hunt metaphors to model the conflict between individual and collective interests regarding cooperation. We find that the impact of altruistic punishment strongly depends on the ratio q/p between the cost of punishing a defecting partner (q) and the actual punishment incurred by the partner (p). We show that whenever q/p<1, altruistic punishment turns out to be detrimental for cooperation for a wide range of payoff parameters, when compared to the scenario without punishment. The results imply that while locally, the introduction of peer punishment may seem to reduce the chances of free-riding, realistic population structure may drive the population towards the opposite scenario. Hence, structured populations effectively reduce the expected beneficial contribution of punishment to the emergence of cooperation which, if not carefully dosed, may in fact hinder the chances of widespread cooperation.'),
(85840, 2013, 'plos', 'Durable resistance to crop pathogens: an epidemiological framework to predict risk under uncertainty', 'Lo Iacono, Giovanni|van den Bosch, Frank|Gilligan, Chris A', 'Department of Veterinary Medicine, Disease Dynamics Unit, University of Cambridge, Cambridge, United Kingdom. gl334@cam.ac.uk|Department of Veterinary Medicine, Disease Dynamics Unit, University of Cambridge, Cambridge, United Kingdom. gl334@cam.ac.uk|Department of Veterinary Medicine, Disease Dynamics Unit, University of Cambridge, Cambridge, United Kingdom. gl334@cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 16, 'Crops, Agricultural|Models, Theoretical|Uncertainty', 'Journal Article', '10.1371/journal.pcbi.1002870', '23341765', 'Increasing the durability of crop resistance to plant pathogens is one of the key goals of virulence management. Despite the recognition of the importance of demographic and environmental stochasticity on the dynamics of an epidemic, their effects on the evolution of the pathogen and durability of resistance has not received attention. We formulated a stochastic epidemiological model, based on the Kramer-Moyal expansion of the Master Equation, to investigate how random fluctuations affect the dynamics of an epidemic and how these effects feed through to the evolution of the pathogen and durability of resistance. We focused on two hypotheses: firstly, a previous deterministic model has suggested that the effect of cropping ratio (the proportion of land area occupied by the resistant crop) on the durability of crop resistance is negligible. Increasing the cropping ratio increases the area of uninfected host, but the resistance is more rapidly broken, these two effects counteract each other. We tested the hypothesis that similar counteracting effects would occur when we take account of demographic stochasticity, but found that the durability does depend on the cropping ratio. Secondly, we tested whether a superimposed external source of stochasticity (for example due to environmental variation or to intermittent fungicide application) interacts with the intrinsic demographic fluctuations and how such interaction affects the durability of resistance. We show that in the pathosystem considered here, in general large stochastic fluctuations in epidemics enhance extinction of the pathogen. This is more likely to occur at large cropping ratios and for particular frequencies of the periodic external perturbation (stochastic resonance). The results suggest possible disease control practises by exploiting the natural sources of stochasticity.'),
(85841, 2013, 'plos', 'Saccadic momentum and facilitation of return saccades contribute to an optimal foraging strategy', 'Wilming, Niklas|Harst, Simon|Schmidt, Nico|König, Peter', 'Institute of Cognitive Science, University of Osnabrück, Osnabrück, Germany. nwilming@uni-osnabrueck.de|Institute of Cognitive Science, University of Osnabrück, Osnabrück, Germany. nwilming@uni-osnabrueck.de|Institute of Cognitive Science, University of Osnabrück, Osnabrück, Germany. nwilming@uni-osnabrueck.de|Institute of Cognitive Science, University of Osnabrück, Osnabrück, Germany. nwilming@uni-osnabrueck.de', 'Germany|Germany|Germany|Germany', 29, 'Food Supply|Humans|Models, Theoretical|Saccades', 'Journal Article', '10.1371/journal.pcbi.1002871', '23341766', 'The interest in saccadic IOR is funneled by the hypothesis that it serves a clear functional purpose in the selection of fixation points: the facilitation of foraging. In this study, we arrive at a different interpretation of saccadic IOR. First, we find that return saccades are performed much more often than expected from the statistical properties of saccades and saccade pairs. Second, we find that fixation durations before a saccade are modulated by the relative angle of the saccade, but return saccades show no sign of an additional temporal inhibition. Thus, we do not find temporal saccadic inhibition of return. Interestingly, we find that return locations are more salient, according to empirically measured saliency (locations that are fixated by many observers) as well as stimulus dependent saliency (defined by image features), than regular fixation locations. These results and the finding that return saccades increase the match of individual trajectories with a grand total priority map evidences the return saccades being part of a fixation selection strategy that trades off exploration and exploitation.'),
(85842, 2013, 'plos', 'An integrative model of ion regulation in yeast', 'Ke, Ruian|Ingram, Piers J|Haynes, Ken', 'Department of Mathematics, Imperial College London, London, United Kingdom. ruian@ucla.edu|Department of Mathematics, Imperial College London, London, United Kingdom. ruian@ucla.edu|Department of Mathematics, Imperial College London, London, United Kingdom. ruian@ucla.edu', 'United Kingdom|United Kingdom|United Kingdom', 21, 'Hydrogen-Ion Concentration|Ions|Membrane Potentials|Models, Theoretical|Phosphorylation|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Sodium Chloride|Stress, Physiological', 'Journal Article', '10.1371/journal.pcbi.1002879', '23341767', 'Yeast cells are able to tolerate and adapt to a variety of environmental stresses. An essential aspect of stress adaptation is the regulation of monovalent ion concentrations. Ion regulation determines many fundamental physiological parameters, such as cell volume, membrane potential, and intracellular pH. It is achieved through the concerted activities of multiple cellular components, including ion transporters and signaling molecules, on both short and long time scales. Although each component has been studied in detail previously, it remains unclear how the physiological parameters are maintained and regulated by the concerted action of all components under a diverse range of stress conditions. In this study, we have constructed an integrated mathematical model of ion regulation in Saccharomyces cerevisiae to understand this coordinated adaptation process. Using this model, we first predict that the interaction between phosphorylated Hog1p and Tok1p at the plasma membrane inhibits Tok1p activity and consequently reduces Na(+) influx under NaCl stress. We further characterize the impacts of NaCl, sorbitol, KCl and alkaline pH stresses on the cellular physiology and the differences between the cellular responses to these stresses. We predict that the calcineurin pathway is essential for maintaining a non-toxic level of intracellular Na(+) in the long-term adaptation to NaCl stress, but that its activation is not required for maintaining a low level of Na(+) under other stresses investigated. We provide evidence that, in addition to extrusion of toxic ions, Ena1p plays an important role, in some cases alongside Nha1p, in re-establishing membrane potential after stress perturbation. To conclude, this model serves as a powerful tool for both understanding the complex system-level properties of the highly coordinated adaptation process and generating further hypotheses for experimental investigation.'),
(85843, 2013, 'plos', 'Binding of nucleoid-associated protein fis to DNA is regulated by DNA breathing dynamics', 'Nowak-Lovato, Kristy|Alexandrov, Ludmil B|Banisadr, Afsheen|Bauer, Amy L|Bishop, Alan R|Usheva, Anny|Mu, Fangping|Hong-Geller, Elizabeth|Rasmussen, Kim Ø|Hlavacek, William S|Alexandrov, Boian S', 'Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.', 'Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico', 19, 'Binding Sites|DNA|DNA-Binding Proteins|Escherichia coli Proteins|Models, Molecular|Protein Binding', 'Journal Article', '10.1371/journal.pcbi.1002881', '23341768', 'Physicochemical properties of DNA, such as shape, affect protein-DNA recognition. However, the properties of DNA that are most relevant for predicting the binding sites of particular transcription factors (TFs) or classes of TFs have yet to be fully understood. Here, using a model that accurately captures the melting behavior and breathing dynamics (spontaneous local openings of the double helix) of double-stranded DNA, we simulated the dynamics of known binding sites of the TF and nucleoid-associated protein Fis in Escherichia coli. Our study involves simulations of breathing dynamics, analysis of large published in vitro and genomic datasets, and targeted experimental tests of our predictions. Our simulation results and available in vitro binding data indicate a strong correlation between DNA breathing dynamics and Fis binding. Indeed, we can define an average DNA breathing profile that is characteristic of Fis binding sites. This profile is significantly enriched among the identified in vivo E. coli Fis binding sites. To test our understanding of how Fis binding is influenced by DNA breathing dynamics, we designed base-pair substitutions, mismatch, and methylation modifications of DNA regions that are known to interact (or not interact) with Fis. The goal in each case was to make the local DNA breathing dynamics either closer to or farther from the breathing profile characteristic of a strong Fis binding site. For the modified DNA segments, we found that Fis-DNA binding, as assessed by gel-shift assay, changed in accordance with our expectations. We conclude that Fis binding is associated with DNA breathing dynamics, which in turn may be regulated by various nucleotide modifications.'),
(85844, 2013, 'plos', 'Redirector: designing cell factories by reconstructing the metabolic objective', 'Rockwell, Graham|Guido, Nicholas J|Church, George M', 'Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. grockwell@genetics.med.harvard.edu|Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. grockwell@genetics.med.harvard.edu|Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. grockwell@genetics.med.harvard.edu', 'United States|United States|United States', 18, 'Down-Regulation|Fatty Acids|Metabolic Networks and Pathways|Models, Biological|Up-Regulation', 'Journal Article', '10.1371/journal.pcbi.1002882', '23341769', 'Advances in computational metabolic optimization are required to realize the full potential of new in vivo metabolic engineering technologies by bridging the gap between computational design and strain development. We present Redirector, a new Flux Balance Analysis-based framework for identifying engineering targets to optimize metabolite production in complex pathways. Previous optimization frameworks have modeled metabolic alterations as directly controlling fluxes by setting particular flux bounds. Redirector develops a more biologically relevant approach, modeling metabolic alterations as changes in the balance of metabolic objectives in the system. This framework iteratively selects enzyme targets, adds the associated reaction fluxes to the metabolic objective, thereby incentivizing flux towards the production of a metabolite of interest. These adjustments to the objective act in competition with cellular growth and represent up-regulation and down-regulation of enzyme mediated reactions. Using the iAF1260 E. coli metabolic network model for optimization of fatty acid production as a test case, Redirector generates designs with as many as 39 simultaneous and 111 unique engineering targets. These designs discover proven in vivo targets, novel supporting pathways and relevant interdependencies, many of which cannot be predicted by other methods. Redirector is available as open and free software, scalable to computational resources, and powerful enough to find all known enzyme targets for fatty acid production.'),
(85845, 2013, 'plos', 'Oroxylin A inhibits hemolysis via hindering the self-assembly of xcexb1-hemolysin heptameric transmembrane pore', 'Dong, Jing|Qiu, Jiazhang|Zhang, Yu|Lu, Chongjian|Dai, Xiaohan|Wang, Jianfeng|Li, Hongen|Wang, Xin|Tan, Wei|Luo, Mingjing|Niu, Xiaodi|Deng, Xuming', 'Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.|Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.|Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.|Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.|Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.|Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.|Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.|Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.|Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.|Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.|Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.|Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.', 'China|China|China|China|China|China|China|China|China|China|China|China', 44, 'Binding Sites|Biopolymers|Cell Line|Coculture Techniques|Flavonoids|Hemolysin Proteins|Hemolysis|Humans|Models, Molecular|Molecular Dynamics Simulation|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1002869', '23349625', 'Alpha-hemolysin (xcexb1-HL) is a self-assembling, channel-forming toxin produced by most Staphylococcus aureus strains as a 33.2-kDa soluble monomer. Upon binding to a susceptible cell membrane, the monomer self-assembles to form a 232.4-kDa heptamer that ultimately causes host cell lysis and death. Consequently, xcexb1-HL plays a significant role in the pathogenesis of S. aureus infections, such as pneumonia, mastitis, keratitis and arthritis. In this paper, experimental studies show that oroxylin A (ORO), a natural compound without anti-S. aureus activity, can inhibit the hemolytic activity of xcexb1-HL. Molecular dynamics simulations, free energy calculations, and mutagenesis assays were performed to understand the formation of the xcexb1-HL-ORO complex. This combined approach revealed that the catalytic mechanism of inhibition involves the direct binding of ORO to xcexb1-HL, which blocks the conformational transition of the critical Loop region of the xcexb1-HL protein thereby inhibiting its hemolytic activity. This mechanism was confirmed by experimental data obtained from a deoxycholate-induced oligomerization assay. It was also found that, in a co-culture system with S. aureus and human alveolar epithelial (A549) cells, ORO could protect against xcexb1-HL-mediated injury. These findings indicate that ORO hinders the lytic activity of xcexb1-HL through a novel mechanism, which should facilitate the design of new and more effective antibacterial agents against S. aureus.'),
(85846, 2013, 'plos', 'Metallochaperones regulate intracellular copper levels', 'Pang, W Lee|Kaur, Amardeep|Ratushny, Alexander V|Cvetkovic, Aleksandar|Kumar, Sunil|Pan, Min|Arkin, Adam P|Aitchison, John D|Adams, Michael W W|Baliga, Nitin S', 'Institute for Systems Biology, Seattle, WA, USA.|Institute for Systems Biology, Seattle, WA, USA.|Institute for Systems Biology, Seattle, WA, USA.|Institute for Systems Biology, Seattle, WA, USA.|Institute for Systems Biology, Seattle, WA, USA.|Institute for Systems Biology, Seattle, WA, USA.|Institute for Systems Biology, Seattle, WA, USA.|Institute for Systems Biology, Seattle, WA, USA.|Institute for Systems Biology, Seattle, WA, USA.|Institute for Systems Biology, Seattle, WA, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States|United States|United States', 13, 'Copper|Flow Cytometry|Green Fluorescent Proteins|Halobacterium salinarum|Homeostasis|Ion Transport|Mass Spectrometry|Metallochaperones|Models, Theoretical|Oligonucleotide Array Sequence Analysis|RNA, Messenger|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002880', '23349626', 'Copper (Cu) is an important enzyme co-factor that is also extremely toxic at high intracellular concentrations, making active efflux mechanisms essential for preventing Cu accumulation. Here, we have investigated the mechanistic role of metallochaperones in regulating Cu efflux. We have constructed a computational model of Cu trafficking and efflux based on systems analysis of the Cu stress response of Halobacterium salinarum. We have validated several model predictions via assays of transcriptional dynamics and intracellular Cu levels, discovering a completely novel function for metallochaperones. We demonstrate that in addition to trafficking Cu ions, metallochaperones also function as buffers to modulate the transcriptional responsiveness and efficacy of Cu efflux. This buffering function of metallochaperones ultimately sets the upper limit for intracellular Cu levels and provides a mechanistic explanation for previously observed Cu metallochaperone mutation phenotypes.'),
(85847, 2013, 'plos', 'Positional bias of MHC class I restricted T-cell epitopes in viral antigens is likely due to a bias in conservation', 'Kim, Yohan|Yewdell, Jonathan W|Sette, Alessandro|Peters, Bjoern', 'La Jolla Institute for Allergy & Immunology, La Jolla, California, United States of America.|La Jolla Institute for Allergy & Immunology, La Jolla, California, United States of America.|La Jolla Institute for Allergy & Immunology, La Jolla, California, United States of America.|La Jolla Institute for Allergy & Immunology, La Jolla, California, United States of America.', 'United States|United States|United States|United States', 8, 'Antigens, Viral|Epitopes|Histocompatibility Antigens Class I|Humans|T-Lymphocytes', 'Journal Article', '10.1371/journal.pcbi.1002884', '23357871', 'The immune system rapidly responds to intracellular infections by detecting MHC class I restricted T-cell epitopes presented on infected cells. It was originally thought that viral peptides are liberated during constitutive protein turnover, but this conflicts with the observation that viral epitopes are detected within minutes of their synthesis even when their source proteins exhibit half-lives of days. The DRiPs hypothesis proposes that epitopes derive from Defective Ribosomal Products (DRiPs), rather than degradation of mature protein products. One potential source of DRiPs is premature translation termination. If this is a major source of DRiPs, this should be reflected in positional bias towards the N-terminus. By contrast, if downstream initiation is a major source of DRiPs, there should be positional bias towards the C-terminus. Here, we systematically assessed positional bias of epitopes in viral antigens, exploiting the large set of data available in the Immune Epitope Database and Analysis Resource. We show a statistically significant degree of positional skewing among epitopes, epitopes from both ends of antigens tend to be under-represented. Centric-skewing correlates with a bias towards class I binding peptides being over-represented in the middle, in parallel with a higher degree of evolutionary conservation.'),
(85848, 2013, 'plos', 'Divide and conquer: functional segregation of synaptic inputs by astrocytic microdomains could alleviate paroxysmal activity following brain trauma', 'Volman, Vladislav|Bazhenov, Maxim|Sejnowski, Terrence J', 'Howard Hughes Medical Institute, Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America. volman@salk.edu|Howard Hughes Medical Institute, Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America. volman@salk.edu|Howard Hughes Medical Institute, Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America. volman@salk.edu', 'United States|United States|United States', 8, 'Astrocytes|Brain Injuries|Humans|Models, Theoretical|N-Methylaspartate|Synapses|Tumor Necrosis Factor-alpha', 'Journal Article', '10.1371/journal.pcbi.1002856', '23357960', 'Traumatic brain injury often leads to epileptic seizures. Among other factors, homeostatic synaptic plasticity (HSP) mediates posttraumatic epileptogenesis through unbalanced synaptic scaling, partially compensating for the trauma-incurred loss of neural excitability. HSP is mediated in part by tumor necrosis factor alpha (TNFxcexb1), which is released locally from reactive astrocytes early after trauma in response to chronic neuronal inactivity. During this early period, TNFxcexb1 is likely to be constrained to its glial sources, however, the contribution of glia-mediated spatially localized HSP to post-traumatic epileptogenesis remains poorly understood. We used computational model to investigate the reorganization of collective neural activity early after trauma. Trauma and synaptic scaling transformed asynchronous spiking into paroxysmal discharges. The rate of paroxysms could be reduced by functional segregation of synaptic input into astrocytic microdomains. Thus, we propose that trauma-triggered reactive gliosis could exert both beneficial and deleterious effects on neural activity.'),
(85849, 2013, 'plos', 'How sensitive is the human visual system to the local statistics of natural images?', 'Gerhard, Holly E|Wichmann, Felix A|Bethge, Matthias', 'Computational Vision and Neuroscience Group, Max Planck Institute for Biological Cybernetics, Tübingen, Germany. holly.gerhard@bethgelab.org|Computational Vision and Neuroscience Group, Max Planck Institute for Biological Cybernetics, Tübingen, Germany. holly.gerhard@bethgelab.org|Computational Vision and Neuroscience Group, Max Planck Institute for Biological Cybernetics, Tübingen, Germany. holly.gerhard@bethgelab.org', 'Germany|Germany|Germany', 43, 'Humans|Models, Theoretical|Sensory Thresholds|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1002873', '23358106', 'A key hypothesis in sensory system neuroscience is that sensory representations are adapted to the statistical regularities in sensory signals and thereby incorporate knowledge about the outside world. Supporting this hypothesis, several probabilistic models of local natural image regularities have been proposed that reproduce neural response properties. Although many such physiological links have been made, these models have not been linked directly to visual sensitivity. Previous psychophysical studies of sensitivity to natural image regularities focus on global perception of large images, but much less is known about sensitivity to local natural image regularities. We present a new paradigm for controlled psychophysical studies of local natural image regularities and compare how well such models capture perceptually relevant image content. To produce stimuli with precise statistics, we start with a set of patches cut from natural images and alter their content to generate a matched set whose joint statistics are equally likely under a probabilistic natural image model. The task is forced choice to discriminate natural patches from model patches. The results show that human observers can learn to discriminate the higher-order regularities in natural images from those of model samples after very few exposures and that no current model is perfect for patches as small as 5 by 5 pixels or larger. Discrimination performance was accurately predicted by model likelihood, an information theoretic measure of model efficacy, indicating that the visual system possesses a surprisingly detailed knowledge of natural image higher-order correlations, much more so than current image models. We also perform three cue identification experiments to interpret how model features correspond to perceptually relevant image features.'),
(85850, 2013, 'plos', 'The human functional brain network demonstrates structural and dynamical resilience to targeted attack', 'Joyce, Karen E|Hayasaka, Satoru|Laurienti, Paul J', 'School of Biomedical Engineering and Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America. kajoyce@wakehealth.edu|School of Biomedical Engineering and Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America. kajoyce@wakehealth.edu|School of Biomedical Engineering and Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America. kajoyce@wakehealth.edu', 'United States|United States|United States', 36, 'Brain|Humans|Models, Anatomic|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.1002885', '23358557', 'In recent years, the field of network science has enabled researchers to represent the highly complex interactions in the brain in an approachable yet quantitative manner. One exciting finding since the advent of brain network research was that the brain network can withstand extensive damage, even to highly connected regions. However, these highly connected nodes may not be the most critical regions of the brain network, and it is unclear how the network dynamics are impacted by removal of these key nodes. This work seeks to further investigate the resilience of the human functional brain network. Network attack experiments were conducted on voxel-wise functional brain networks and region-of-interest (ROI) networks of 5 healthy volunteers. Networks were attacked at key nodes using several criteria for assessing node importance, and the impact on network structure and dynamics was evaluated. The findings presented here echo previous findings that the functional human brain network is highly resilient to targeted attacks, both in terms of network structure and dynamics.'),
(85851, 2013, 'plos', 'Important miRs of pathways in different tumor types', 'Wuchty, Stefan|Arjona, Dolores|Bauer, Peter O', 'National Center of Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America. wuchtys@ncbi.nlm.nih.gov|National Center of Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America. wuchtys@ncbi.nlm.nih.gov|National Center of Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America. wuchtys@ncbi.nlm.nih.gov', 'United States|United States|United States', 3, 'Humans|MicroRNAs|Neoplasms', 'Journal Article', '10.1371/journal.pcbi.1002883', '23358700', 'We computationally determined miRs that are significantly connected to molecular pathways by utilizing gene expression profiles in different cancer types such as glioblastomas, ovarian and breast cancers. Specifically, we assumed that the knowledge of physical interactions between miRs and genes indicated subsets of important miRs (IM) that significantly contributed to the regression of pathway-specific enrichment scores. Despite the different nature of the considered cancer types, we found strongly overlapping sets of IMs. Furthermore, IMs that were important for many pathways were enriched with literature-curated cancer and differentially expressed miRs. Such sets of IMs also coincided well with clusters of miRs that were experimentally indicated in numerous other cancer types. In particular, we focused on an overlapping set of 99 overall important miRs (OIM) that were found in glioblastomas, ovarian and breast cancers simultaneously. Notably, we observed that interactions between OIMs and leading edge genes of differentially expressed pathways were characterized by considerable changes in their expression correlations. Such gains/losses of miR and gene expression correlation indicated miR/gene pairs that may play a causal role in the underlying cancers.'),
(85852, 2013, 'plos', 'Dynamic finite size effects in spiking neural networks', 'Buice, Michael A|Chow, Carson C', 'Laboratory of Biological Modeling, NIDDK, NIH, Bethesda, Maryland, United States of America. mabuice@mail.clm.utexas.edu|Laboratory of Biological Modeling, NIDDK, NIH, Bethesda, Maryland, United States of America. mabuice@mail.clm.utexas.edu', 'United States|United States', 37, 'Action Potentials|Models, Theoretical|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.1002872', '23359258', 'We investigate the dynamics of a deterministic finite-sized network of synaptically coupled spiking neurons and present a formalism for computing the network statistics in a perturbative expansion. The small parameter for the expansion is the inverse number of neurons in the network. The network dynamics are fully characterized by a neuron population density that obeys a conservation law analogous to the Klimontovich equation in the kinetic theory of plasmas. The Klimontovich equation does not possess well-behaved solutions but can be recast in terms of a coupled system of well-behaved moment equations, known as a moment hierarchy. The moment hierarchy is impossible to solve but in the mean field limit of an infinite number of neurons, it reduces to a single well-behaved conservation law for the mean neuron density. For a large but finite system, the moment hierarchy can be truncated perturbatively with the inverse system size as a small parameter but the resulting set of reduced moment equations that are still very difficult to solve. However, the entire moment hierarchy can also be re-expressed in terms of a functional probability distribution of the neuron density. The moments can then be computed perturbatively using methods from statistical field theory. Here we derive the complete mean field theory and the lowest order second moment corrections for physiologically relevant quantities. Although we focus on finite-size corrections, our method can be used to compute perturbative expansions in any parameter.'),
(85853, 2013, 'plos', 'Assembly of the transmembrane domain of E coli PhoQ histidine kinase: implications for signal transduction from molecular simulations', 'Lemmin, Thomas|Soto, Cinque S|Clinthorne, Graham|DeGrado, William F|Dal Peraro, Matteo', 'Laboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Laboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Laboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Laboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Laboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 30, 'Escherichia coli|Histidine Kinase|Membrane Proteins|Models, Molecular|Molecular Dynamics Simulation|Protein Kinases|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002878', '23359663', 'The PhoQP two-component system is a signaling complex essential for bacterial virulence and cationic antimicrobial peptide resistance. PhoQ is the histidine kinase chemoreceptor of this tandem machine and assembles in a homodimer conformation spanning the bacterial inner membrane. Currently, a full understanding of the PhoQ signal transduction is hindered by the lack of a complete atomistic structure. In this study, an atomistic model of the key transmembrane (TM) domain is assembled by using molecular simulations, guided by experimental cross-linking data. The formation of a polar pocket involving Asn202 in the lumen of the tetrameric TM bundle is crucial for the assembly and solvation of the domain. Moreover, a concerted displacement of the TM helices at the periplasmic side is found to modulate a rotation at the cytoplasmic end, supporting the transduction of the chemical signal through a combination of scissoring and rotational movement of the TM helices.'),
(85854, 2013, 'plos', 'Significance analysis of prognostic signatures', 'Beck, Andrew H|Knoblauch, Nicholas W|Hefti, Marco M|Kaplan, Jennifer|Schnitt, Stuart J|Culhane, Aedin C|Schroeder, Markus S|Risch, Thomas|Quackenbush, John|Haibe-Kains, Benjamin', 'Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America. abeck2@bidmc.harvard.edu|Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America. abeck2@bidmc.harvard.edu|Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America. abeck2@bidmc.harvard.edu|Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America. abeck2@bidmc.harvard.edu|Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America. abeck2@bidmc.harvard.edu|Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America. abeck2@bidmc.harvard.edu|Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America. abeck2@bidmc.harvard.edu|Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America. abeck2@bidmc.harvard.edu|Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America. abeck2@bidmc.harvard.edu|Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America. abeck2@bidmc.harvard.edu', 'Israel|Israel|Israel|Israel|Israel|Israel|Israel|Israel|Israel|Israel', 22, 'Breast Neoplasms|Disease Progression|Female|Humans|Neoplasm Metastasis|Ovarian Neoplasms|Prognosis', 'Journal Article', '10.1371/journal.pcbi.1002875', '23365551', 'A major goal in translational cancer research is to identify biological signatures driving cancer progression and metastasis. A common technique applied in genomics research is to cluster patients using gene expression data from a candidate prognostic gene set, and if the resulting clusters show statistically significant outcome stratification, to associate the gene set with prognosis, suggesting its biological and clinical importance. Recent work has questioned the validity of this approach by showing in several breast cancer data sets that random gene sets tend to cluster patients into prognostically variable subgroups. This work suggests that new rigorous statistical methods are needed to identify biologically informative prognostic gene sets. To address this problem, we developed Significance Analysis of Prognostic Signatures (SAPS) which integrates standard prognostic tests with a new prognostic significance test based on stratifying patients into prognostic subtypes with random gene sets. SAPS ensures that a significant gene set is not only able to stratify patients into prognostically variable groups, but is also enriched for genes showing strong univariate associations with patient prognosis, and performs significantly better than random gene sets. We use SAPS to perform a large meta-analysis (the largest completed to date) of prognostic pathways in breast and ovarian cancer and their molecular subtypes. Our analyses show that only a small subset of the gene sets found statistically significant using standard measures achieve significance by SAPS. We identify new prognostic signatures in breast and ovarian cancer and their corresponding molecular subtypes, and we show that prognostic signatures in ER negative breast cancer are more similar to prognostic signatures in ovarian cancer than to prognostic signatures in ER positive breast cancer. SAPS is a powerful new method for deriving robust prognostic biological signatures from clinically annotated genomic datasets.'),
(85855, 2013, 'plos', 'Ribosome traffic on mRNAs maps to gene ontology: genome-wide quantification of translation initiation rates and polysome size regulation', 'Ciandrini, Luca|Stansfield, Ian|Romano, M Carmen', 'SUPA, Institute for Complex Systems and Mathematical Biology, Kings College, University of Aberdeen, Aberdeen, United Kingdom. l.ciandrini@abdn.ac.uk|SUPA, Institute for Complex Systems and Mathematical Biology, Kings College, University of Aberdeen, Aberdeen, United Kingdom. l.ciandrini@abdn.ac.uk|SUPA, Institute for Complex Systems and Mathematical Biology, Kings College, University of Aberdeen, Aberdeen, United Kingdom. l.ciandrini@abdn.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 64, 'Codon|Genome|Models, Theoretical|Polyribosomes|Protein Biosynthesis|RNA, Messenger|Ribosomes|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002866', '23382661', 'To understand the complex relationship governing transcript abundance and the level of the encoded protein, we integrate genome-wide experimental data of ribosomal density on mRNAs with a novel stochastic model describing ribosome traffic dynamics during translation elongation. This analysis reveals that codon arrangement, rather than simply codon bias, has a key role in determining translational efficiency. It also reveals that translation output is governed both by initiation efficiency and elongation dynamics. By integrating genome-wide experimental data sets with simulation of ribosome traffic on all Saccharomyces cerevisiae ORFs, mRNA-specific translation initiation rates are for the first time estimated across the entire transcriptome. Our analysis identifies different classes of mRNAs characterised by their initiation rates, their ribosome traffic dynamics, and by their response to ribosome availability. Strikingly, this classification based on translational dynamics maps onto key gene ontological classifications, revealing evolutionary optimisation of translation responses to be strongly influenced by gene function.'),
(85856, 2013, 'plos', 'Integrating phylodynamics and epidemiology to estimate transmission diversity in viral epidemics', 'Magiorkinis, Gkikas|Sypsa, Vana|Magiorkinis, Emmanouil|Paraskevis, Dimitrios|Katsoulidou, Antigoni|Belshaw, Robert|Fraser, Christophe|Pybus, Oliver George|Hatzakis, Angelos', 'Department of Hygiene, Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece. gkikas.magiorkinis@zoo.ox.ac.uk|Department of Hygiene, Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece. gkikas.magiorkinis@zoo.ox.ac.uk|Department of Hygiene, Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece. gkikas.magiorkinis@zoo.ox.ac.uk|Department of Hygiene, Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece. gkikas.magiorkinis@zoo.ox.ac.uk|Department of Hygiene, Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece. gkikas.magiorkinis@zoo.ox.ac.uk|Department of Hygiene, Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece. gkikas.magiorkinis@zoo.ox.ac.uk|Department of Hygiene, Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece. gkikas.magiorkinis@zoo.ox.ac.uk|Department of Hygiene, Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece. gkikas.magiorkinis@zoo.ox.ac.uk|Department of Hygiene, Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece. gkikas.magiorkinis@zoo.ox.ac.uk', 'Greece|Greece|Greece|Greece|Greece|Greece|Greece|Greece|Greece', 40, 'Epidemiologic Studies|HIV Infections|Hepatitis C|Humans|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1002876', '23382662', 'The epidemiology of chronic viral infections, such as those caused by Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV), is affected by the risk group structure of the infected population. Risk groups are defined by each of their members having acquired infection through a specific behavior. However, risk group definitions say little about the transmission potential of each infected individual. Variation in the number of secondary infections is extremely difficult to estimate for HCV and HIV but crucial in the design of efficient control interventions. Here we describe a novel method that combines epidemiological and population genetic approaches to estimate the variation in transmissibility of rapidly-evolving viral epidemics. We evaluate this method using a nationwide HCV epidemic and for the first time co-estimate viral generation times and superspreading events from a combination of molecular and epidemiological data. We anticipate that this integrated approach will form the basis of powerful tools for describing the transmission dynamics of chronic viral diseases, and for evaluating control strategies directed against them.'),
(85857, 2013, 'plos', 'Maximizing the information content of experiments in systems biology', 'Liepe, Juliane|Filippi, Sarah|Komorowski, Michaxc5x82|Stumpf, Michael P H', 'Centre for Integrative Systems Biology and Bioinformatics, Imperial College London, London, United Kingdom.|Centre for Integrative Systems Biology and Bioinformatics, Imperial College London, London, United Kingdom.|Centre for Integrative Systems Biology and Bioinformatics, Imperial College London, London, United Kingdom.|Centre for Integrative Systems Biology and Bioinformatics, Imperial College London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 94, 'Bayes Theorem|Models, Theoretical|Systems Biology|Uncertainty', 'Journal Article', '10.1371/journal.pcbi.1002888', '23382663', 'Our understanding of most biological systems is in its infancy. Learning their structure and intricacies is fraught with challenges, and often side-stepped in favour of studying the function of different gene products in isolation from their physiological context. Constructing and inferring global mathematical models from experimental data is, however, central to systems biology. Different experimental setups provide different insights into such systems. Here we show how we can combine concepts from Bayesian inference and information theory in order to identify experiments that maximize the information content of the resulting data. This approach allows us to incorporate preliminary information, it is global and not constrained to some local neighbourhood in parameter space and it readily yields information on parameter robustness and confidence. Here we develop the theoretical framework and apply it to a range of exemplary problems that highlight how we can improve experimental investigations into the structure and dynamics of biological systems and their behavior.'),
(85858, 2013, 'plos', 'Temporal adaptation enhances efficient contrast gain control on natural images', 'Sinz, Fabian|Bethge, Matthias', 'Department for Neuroethology, University Tübingen, Tübingen, Germany. fabian.sinz@bethgelab.org|Department for Neuroethology, University Tübingen, Tübingen, Germany. fabian.sinz@bethgelab.org', 'Germany|Germany', 14, 'Adaptation, Physiological|Contrast Sensitivity|Humans|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1002889', '23382664', 'Divisive normalization in primary visual cortex has been linked to adaptation to natural image statistics in accordance to Barlows redundancy reduction hypothesis. Using recent advances in natural image modeling, we show that the previously studied static model of divisive normalization is rather inefficient in reducing local contrast correlations, but that a simple temporal contrast adaptation mechanism of the half-saturation constant can substantially increase its efficiency. Our findings reveal the experimentally observed temporal dynamics of divisive normalization to be critical for redundancy reduction.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85859, 2013, 'plos', 'Membrane sculpting by F-BAR domains studied by molecular dynamics simulations', 'Yu, Hang|Schulten, Klaus', 'Beckman Institute, University of Illinois, Urbana, Illinois, United States of America.|Beckman Institute, University of Illinois, Urbana, Illinois, United States of America.', 'United States|United States', 76, 'Cell Membrane|Dimerization|Membrane Proteins|Molecular Dynamics Simulation|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1002892', '23382665', 'Interplay between cellular membranes and their peripheral proteins drives many processes in eukaryotic cells. Proteins of the Bin/Amphiphysin/Rvs (BAR) domain family, in particular, play a role in cellular morphogenesis, for example curving planar membranes into tubular membranes. However, it is still unclear how F-BAR domain proteins act on membranes. Electron microscopy revealed that, in vitro, F-BAR proteins form regular lattices on cylindrically deformed membrane surfaces. Using all-atom and coarse-grained (CG) molecular dynamics simulations, we show that such lattices, indeed, induce tubes of observed radii. A 250 ns all-atom simulation reveals that F-BAR domain curves membranes via the so-called scaffolding mechanism. Plasticity of the F-BAR domain permits conformational change in response to membrane interaction, via partial unwinding of the domains 3-helix bundle structure. A CG simulation covering more than 350 µs provides a dynamic picture of membrane tubulation by lattices of F-BAR domains. A series of CG simulations identified the optimal lattice type for membrane sculpting, which matches closely the lattices seen through cryo-electron microscopy.'),
(85860, 2013, 'plos', 'Bayesian inference of spatial organizations of chromosomes', 'Hu, Ming|Deng, Ke|Qin, Zhaohui|Dixon, Jesse|Selvaraj, Siddarth|Fang, Jennifer|Ren, Bing|Liu, Jun S', 'Department of Statistics, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Statistics, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Statistics, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Statistics, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Statistics, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Statistics, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Statistics, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Statistics, Harvard University, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 123, 'Algorithms|Animals|Bayes Theorem|Chromosomes|Embryonic Stem Cells|Epigenesis, Genetic|Genomics|Mice|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1002893', '23382666', 'Knowledge of spatial chromosomal organizations is critical for the study of transcriptional regulation and other nuclear processes in the cell. Recently, chromosome conformation capture (3C) based technologies, such as Hi-C and TCC, have been developed to provide a genome-wide, three-dimensional (3D) view of chromatin organization. Appropriate methods for analyzing these data and fully characterizing the 3D chromosomal structure and its structural variations are still under development. Here we describe a novel Bayesian probabilistic approach, denoted as Bayesian 3D constructor for Hi-C data (BACH), to infer the consensus 3D chromosomal structure. In addition, we describe a variant algorithm BACH-MIX to study the structural variations of chromatin in a cell population. Applying BACH and BACH-MIX to a high resolution Hi-C dataset generated from mouse embryonic stem cells, we found that most local genomic regions exhibit homogeneous 3D chromosomal structures. We further constructed a model for the spatial arrangement of chromatin, which reveals structural properties associated with euchromatic and heterochromatic regions in the genome. We observed strong associations between structural properties and several genomic and epigenetic features of the chromosome. Using BACH-MIX, we further found that the structural variations of chromatin are correlated with these genomic and epigenetic features. Our results demonstrate that BACH and BACH-MIX have the potential to provide new insights into the chromosomal architecture of mammalian cells.'),
(85861, 2013, 'plos', 'Starling flock networks manage uncertainty in consensus at low cost', 'Young, George F|Scardovi, Luca|Cavagna, Andrea|Giardina, Irene|Leonard, Naomi E', 'Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, New Jersey, United States of America.|Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, New Jersey, United States of America.|Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, New Jersey, United States of America.|Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, New Jersey, United States of America.|Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, New Jersey, United States of America.', 'Jersey|Jersey|Jersey|Jersey|Jersey', 57, 'Animals|Behavior, Animal|Starlings|Uncertainty', 'Journal Article', '10.1371/journal.pcbi.1002894', '23382667', 'Flocks of starlings exhibit a remarkable ability to maintain cohesion as a group in highly uncertain environments and with limited, noisy information. Recent work demonstrated that individual starlings within large flocks respond to a fixed number of nearest neighbors, but until now it was not understood why this number is seven. We analyze robustness to uncertainty of consensus in empirical data from multiple starling flocks and show that the flock interaction networks with six or seven neighbors optimize the trade-off between group cohesion and individual effort. We can distinguish these numbers of neighbors from fewer or greater numbers using our systems-theoretic approach to measuring robustness of interaction networks as a function of the network structure, i.e., who is sensing whom. The metric quantifies the disagreement within the network due to disturbances and noise during consensus behavior and can be evaluated over a parameterized family of hypothesized sensing strategies (here the parameter is number of neighbors). We use this approach to further show that for the range of flocks studied the optimal number of neighbors does not depend on the number of birds within a flock, rather, it depends on the shape, notably the thickness, of the flock. The results suggest that robustness to uncertainty may have been a factor in the evolution of flocking for starlings. More generally, our results elucidate the role of the interaction network on uncertainty management in collective behavior, and motivate the application of our approach to other biological networks.'),
(85862, 2013, 'plos', 'Using steered molecular dynamics to predict and assess Hsp70 substrate-binding domain mutants that alter prion propagation', 'Xu, Linan|Hasin, Naushaba|Shen, Manli|He, Jianwei|Xue, Youlin|Zhou, Xiaohong|Perrett, Sarah|Song, Youtao|Jones, Gary W', 'Province Key Laboratory of Animal Resource and Epidemic Disease Prevention, Liaoning University, Shenyang, China.|Province Key Laboratory of Animal Resource and Epidemic Disease Prevention, Liaoning University, Shenyang, China.|Province Key Laboratory of Animal Resource and Epidemic Disease Prevention, Liaoning University, Shenyang, China.|Province Key Laboratory of Animal Resource and Epidemic Disease Prevention, Liaoning University, Shenyang, China.|Province Key Laboratory of Animal Resource and Epidemic Disease Prevention, Liaoning University, Shenyang, China.|Province Key Laboratory of Animal Resource and Epidemic Disease Prevention, Liaoning University, Shenyang, China.|Province Key Laboratory of Animal Resource and Epidemic Disease Prevention, Liaoning University, Shenyang, China.|Province Key Laboratory of Animal Resource and Epidemic Disease Prevention, Liaoning University, Shenyang, China.|Province Key Laboratory of Animal Resource and Epidemic Disease Prevention, Liaoning University, Shenyang, China.', 'China|China|China|China|China|China|China|China|China', 22, 'HSP70 Heat-Shock Proteins|Hydrogen Bonding|Models, Molecular|Molecular Dynamics Simulation|Mutation|Prions|Protein Binding', 'Journal Article', '10.1371/journal.pcbi.1002896', '23382668', 'Genetic screens using Saccharomyces cerevisiae have identified an array of cytosolic Hsp70 mutants that are impaired in the ability to propagate the yeast [PSI(+)] prion. The best characterized of these mutants is the Ssa1 L483W mutant (so-called SSA1-21), which is located in the substrate-binding domain of the protein. However, biochemical analysis of some of these Hsp70 mutants has so far failed to provide major insight into the specific functional changes in Hsp70 that cause prion impairment. In order to gain a better understanding of the mechanism of Hsp70 impairment of prions we have taken an in silico approach and focused on the Escherichia coli Hsp70 ortholog DnaK. Using steered molecular dynamics simulations (SMD) we demonstrate that DnaK variant L484W (analogous to SSA1-21) is predicted to bind substrate more avidly than wild-type DnaK due to an increase in numbers of hydrogen bonds and hydrophobic interactions between chaperone and peptide. Additionally the presence of the larger tryptophan side chain is predicted to cause a conformational change in the peptide-binding domain that physically impairs substrate dissociation. The DnaK L484W variant in combination with some SSA1-21 phenotypic second-site suppressor mutations exhibits chaperone-substrate interactions that are similar to wild-type protein and this provides a rationale for the phenotypic suppression that is observed. Our computational analysis fits well with previous yeast genetics studies regarding the functionality of the Ssa1-21 protein and provides further evidence suggesting that manipulation of the Hsp70 ATPase cycle to favor the ADP/substrate-bound form impairs prion propagation. Furthermore, we demonstrate how SMD can be used as a computational tool for predicting Hsp70 peptide-binding domain mutants that impair prion propagation.'),
(85863, 2013, 'plos', 'Activity in inferior parietal and medial prefrontal cortex signals the accumulation of evidence in a probability learning task', 'dAcremont, Mathieu|Fornari, Eleonora|Bossaerts, Peter', 'Computation and Neural Systems, California Institute of Technology, Pasadena, CA, USA. dacremon@hss.caltech.edu|Computation and Neural Systems, California Institute of Technology, Pasadena, CA, USA. dacremon@hss.caltech.edu|Computation and Neural Systems, California Institute of Technology, Pasadena, CA, USA. dacremon@hss.caltech.edu', 'United States|United States|United States', 19, 'Frontal Lobe|Humans|Learning|Magnetic Resonance Imaging|Parietal Lobe|Probability', 'Journal Article', '10.1371/journal.pcbi.1002895', '23401673', 'In an uncertain environment, probabilities are key to predicting future events and making adaptive choices. However, little is known about how humans learn such probabilities and where and how they are encoded in the brain, especially when they concern more than two outcomes. During functional magnetic resonance imaging (fMRI), young adults learned the probabilities of uncertain stimuli through repetitive sampling. Stimuli represented payoffs and participants had to predict their occurrence to maximize their earnings. Choices indicated loss and risk aversion but unbiased estimation of probabilities. BOLD response in medial prefrontal cortex and angular gyri increased linearly with the probability of the currently observed stimulus, untainted by its value. Connectivity analyses during rest and task revealed that these regions belonged to the default mode network. The activation of past outcomes in memory is evoked as a possible mechanism to explain the engagement of the default mode network in probability learning. A BOLD response relating to value was detected only at decision time, mainly in striatum. It is concluded that activity in inferior parietal and medial prefrontal cortex reflects the amount of evidence accumulated in favor of competing and uncertain outcomes.'),
(85864, 2013, 'plos', 'Getting more out of biomedical documents with GATEs full lifecycle open source text analytics', 'Cunningham, Hamish|Tablan, Valentin|Roberts, Angus|Bontcheva, Kalina', 'Department of Computer Science, University of Sheffield, Sheffield, UK. hamish@gate.ac.uk|Department of Computer Science, University of Sheffield, Sheffield, UK. hamish@gate.ac.uk|Department of Computer Science, University of Sheffield, Sheffield, UK. hamish@gate.ac.uk|Department of Computer Science, University of Sheffield, Sheffield, UK. hamish@gate.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 173, 'Biomedical Research|Computational Biology|Data Mining|Database Management Systems|Genome-Wide Association Study|Humans|Natural Language Processing|Software|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1002854', '23408875', 'This software article describes the GATE family of open source text analysis tools and processes. GATE is one of the most widely used systems of its type with yearly download rates of tens of thousands and many active users in both academic and industrial contexts. In this paper we report three examples of GATE-based systems operating in the life sciences and in medicine. First, in genome-wide association studies which have contributed to discovery of a head and neck cancer mutation association. Second, medical records analysis which has significantly increased the statistical power of treatment/outcome models in the UKs largest psychiatric patient cohort. Third, richer constructs in drug-related searching. We also explore the ways in which the GATE family supports the various stages of the lifecycle present in our examples. We conclude that the deployment of text mining for document abstraction or rich search and navigation is best thought of as a process, and that with the right computational tools and data collection strategies this process can be made defined and repeatable. The GATE research programme is now 20 years old and has grown from its roots as a specialist development tool for text processing to become a rather comprehensive ecosystem, bringing together software developers, language engineers and research staff from diverse fields. GATE now has a strong claim to cover a uniquely wide range of the lifecycle of text analysis systems. It forms a focal point for the integration and reuse of advances that have been made by many people (the majority outside of the authors own group) who work in text processing for biomedicine and other areas. GATE is available online <1> under GNU open source licences and runs on all major operating systems. Support is available from an active user and developer community and also on a commercial basis.'),
(85865, 2013, 'plos', 'Linking proteomic and transcriptional data through the interactome and epigenome reveals a map of oncogene-induced signaling', 'Huang, Shao-shan Carol|Clarke, David C|Gosline, Sara J C|Labadorf, Adam|Chouinard, Candace R|Gordon, William|Lauffenburger, Douglas A|Fraenkel, Ernest', 'Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States', 39, 'Cell Line, Tumor|Cell Survival|Computational Biology|Drug Discovery|Gene Expression Profiling|Glioblastoma|Humans|Oncogenes|Protein Interaction Maps|Reproducibility of Results|Signal Transduction|Transcriptome', 'Journal Article', '10.1371/journal.pcbi.1002887', '23408876', 'Cellular signal transduction generally involves cascades of post-translational protein modifications that rapidly catalyze changes in protein-DNA interactions and gene expression. High-throughput measurements are improving our ability to study each of these stages individually, but do not capture the connections between them. Here we present an approach for building a network of physical links among these data that can be used to prioritize targets for pharmacological intervention. Our method recovers the critical missing links between proteomic and transcriptional data by relating changes in chromatin accessibility to changes in expression and then uses these links to connect proteomic and transcriptome data. We applied our approach to integrate epigenomic, phosphoproteomic and transcriptome changes induced by the variant III mutation of the epidermal growth factor receptor (EGFRvIII) in a cell line model of glioblastoma multiforme (GBM). To test the relevance of the network, we used small molecules to target highly connected nodes implicated by the network model that were not detected by the experimental data in isolation and we found that a large fraction of these agents alter cell viability. Among these are two compounds, ICG-001, targeting CREB binding protein (CREBBP), and PKF118-310, targeting xcexb2-catenin (CTNNB1), which have not been tested previously for effectiveness against GBM. At the level of transcriptional regulation, we used chromatin immunoprecipitation sequencing (ChIP-Seq) to experimentally determine the genome-wide binding locations of p300, a transcriptional co-regulator highly connected in the network. Analysis of p300 target genes suggested its role in tumorigenesis. We propose that this general method, in which experimental measurements are used as constraints for building regulatory networks from the interactome while taking into account noise and missing data, should be applicable to a wide range of high-throughput datasets.'),
(85866, 2013, 'plos', 'Connecting a connectome to behavior: an ensemble of neuroanatomical models of C elegans klinotaxis', 'Izquierdo, Eduardo J|Beer, Randall D', 'Cognitive Science Program, Indiana University, Bloomington, Indiana, USA. edizquie@indiana.edu|Cognitive Science Program, Indiana University, Bloomington, Indiana, USA. edizquie@indiana.edu', 'India|India', 38, 'Algorithms|Animals|Behavior, Animal|Caenorhabditis elegans|Chemotaxis|Computational Biology|Connectome|Models, Neurological|Motor Neurons|Sensory Receptor Cells', 'Journal Article', '10.1371/journal.pcbi.1002890', '23408877', 'Increased efforts in the assembly and analysis of connectome data are providing new insights into the principles underlying the connectivity of neural circuits. However, despite these considerable advances in connectomics, neuroanatomical data must be integrated with neurophysiological and behavioral data in order to obtain a complete picture of neural function. Due to its nearly complete wiring diagram and large behavioral repertoire, the nematode worm Caenorhaditis elegans is an ideal organism in which to explore in detail this link between neural connectivity and behavior. In this paper, we develop a neuroanatomically-grounded model of salt klinotaxis, a form of chemotaxis in which changes in orientation are directed towards the source through gradual continual adjustments. We identify a minimal klinotaxis circuit by systematically searching the C. elegans connectome for pathways linking chemosensory neurons to neck motor neurons, and prune the resulting network based on both experimental considerations and several simplifying assumptions. We then use an evolutionary algorithm to find possible values for the unknown electrophsyiological parameters in the network such that the behavioral performance of the entire model is optimized to match that of the animal. Multiple runs of the evolutionary algorithm produce an ensemble of such models. We analyze in some detail the mechanisms by which one of the best evolved circuits operates and characterize the similarities and differences between this mechanism and other solutions in the ensemble. Finally, we propose a series of experiments to determine which of these alternatives the worm may be using.'),
(85867, 2013, 'plos', 'Delay selection by spike-timing-dependent plasticity in recurrent networks of spiking neurons receiving oscillatory inputs', 'Kerr, Robert R|Burkitt, Anthony N|Thomas, Doreen A|Gilson, Matthieu|Grayden, David B', 'NeuroEngineering Laboratory, Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Victoria, Australia.|NeuroEngineering Laboratory, Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Victoria, Australia.|NeuroEngineering Laboratory, Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Victoria, Australia.|NeuroEngineering Laboratory, Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Victoria, Australia.|NeuroEngineering Laboratory, Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Victoria, Australia.', 'Australia|Australia|Australia|Australia|Australia', 12, 'Action Potentials|Animals|Axons|Brain|Computer Simulation|Dendrites|Models, Neurological|Neuronal Plasticity|Neurons|Poisson Distribution|Strigiformes', 'Journal Article', '10.1371/journal.pcbi.1002897', '23408878', 'Learning rules, such as spike-timing-dependent plasticity (STDP), change the structure of networks of neurons based on the firing activity. A network level understanding of these mechanisms can help infer how the brain learns patterns and processes information. Previous studies have shown that STDP selectively potentiates feed-forward connections that have specific axonal delays, and that this underlies behavioral functions such as sound localization in the auditory brainstem of the barn owl. In this study, we investigate how STDP leads to the selective potentiation of recurrent connections with different axonal and dendritic delays during oscillatory activity. We develop analytical models of learning with additive STDP in recurrent networks driven by oscillatory inputs, and support the results using simulations with leaky integrate-and-fire neurons. Our results show selective potentiation of connections with specific axonal delays, which depended on the input frequency. In addition, we demonstrate how this can lead to a network becoming selective in the amplitude of its oscillatory response to this frequency. We extend this model of axonal delay selection within a single recurrent network in two ways. First, we show the selective potentiation of connections with a range of both axonal and dendritic delays. Second, we show axonal delay selection between multiple groups receiving out-of-phase, oscillatory inputs. We discuss the application of these models to the formation and activation of neuronal ensembles or cell assemblies in the cortex, and also to missing fundamental pitch perception in the auditory brainstem.'),
(85868, 2013, 'plos', 'Viral capsid proteins are segregated in structural fold space', 'Cheng, Shanshan|Brooks, Charles L', 'Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.', 'United States|United States', 28, 'Capsid Proteins|Cluster Analysis|Computational Biology|Databases, Protein|Models, Molecular|Protein Conformation|Protein Folding|Sequence Alignment|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1002905', '23408879', 'Viral capsid proteins assemble into large, symmetrical architectures that are not found in complexes formed by their cellular counterparts. Given the prevalence of the signature jelly-roll topology in viral capsid proteins, we are interested in whether these functionally unique capsid proteins are also structurally unique in terms of folds. To explore this question, we applied a structure-alignment based clustering of all protein chains in VIPERdb filtered at 40% sequence identity to identify distinct capsid folds, and compared the cluster medoids with a non-redundant subset of protein domains in the SCOP database, not including the viral capsid entries. This comparison, using Template Modeling (TM)-score, identified 2078 structural relatives of capsid proteins from the non-capsid set, covering altogether 210 folds following the definition in SCOP. The statistical significance of the 210 folds shared by two sets of the same sizes, estimated from 10,000 permutation tests, is less than 0.0001, which is an upper bound on the p-value. We thus conclude that viral capsid proteins are segregated in structural fold space. Our result provides novel insight on how structural folds of capsid proteins, as opposed to their surface chemistry, might be constrained during evolution by requirement of the assembled cage-like architecture. Also importantly, our work highlights a guiding principle for virus-based nanoplatform design in a wide range of biomedical applications and materials science.'),
(85869, 2013, 'plos', 'The timing and targeting of treatment in influenza pandemics influences the emergence of resistance in structured populations', 'Althouse, Benjamin M|Patterson-Lomba, Oscar|Goerg, Georg M|Hébert-Dufresne, Laurent', 'Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. balthous@jhsph.edu|Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. balthous@jhsph.edu|Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. balthous@jhsph.edu|Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. balthous@jhsph.edu', 'United States|United States|United States|United States', 10, 'Antiviral Agents|Drug Resistance, Viral|Humans|Influenza, Human|Models, Biological|Pandemics|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002912', '23408880', 'Antiviral resistance in influenza is rampant and has the possibility of causing major morbidity and mortality. Previous models have identified treatment regimes to minimize total infections and keep resistance low. However, the bulk of these studies have ignored stochasticity and heterogeneous contact structures. Here we develop a network model of influenza transmission with treatment and resistance, and present both standard mean-field approximations as well as simulated dynamics. We find differences in the final epidemic sizes for identical transmission parameters (bistability) leading to different optimal treatment timing depending on the number initially infected. We also find, contrary to previous results, that treatment targeted by number of contacts per individual (node degree) gives rise to more resistance at lower levels of treatment than non-targeted treatment. Finally we highlight important differences between the two methods of analysis (mean-field versus stochastic simulations), and show where traditional mean-field approximations fail. Our results have important implications not only for the timing and distribution of influenza chemotherapy, but also for mathematical epidemiological modeling in general. Antiviral resistance in influenza may carry large consequences for pandemic mitigation efforts, and models ignoring contact heterogeneity and stochasticity may provide misleading policy recommendations.'),
(85870, 2013, 'plos', 'Cost and effects of different admission screening strategies to control the spread of methicillin-resistant Staphylococcus aureus', 'Gurieva, Tanya|Bootsma, Martin C J|Bonten, Marc J M', 'Julius Center for Health Research & Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. t.guryeva@gmail.com|Julius Center for Health Research & Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. t.guryeva@gmail.com|Julius Center for Health Research & Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. t.guryeva@gmail.com', 'Netherlands|Netherlands|Netherlands', 15, 'Analysis of Variance|Computational Biology|Computer Simulation|Cross Infection|Hospitalization|Humans|Infection Control|Intensive Care Units|Length of Stay|Mass Screening|Methicillin-Resistant Staphylococcus aureus|Models, Statistical|Patient Isolation|Prevalence|Staphylococcal Infections|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002874', '23436984', 'Nosocomial infection rates due to antibiotic-resistant bacteriae, e.g., methicillin-resistant Staphylococcus aureus (MRSA) remain high in most countries. Screening for MRSA carriage followed by barrier precautions for documented carriers (so-called screen and isolate (S&I)) has been successful in some, but not all settings. Moreover, different strategies have been proposed, but comparative studies determining their relative effects and costs are not available. We, therefore, used a mathematical model to evaluate the effect and costs of different S&I strategies and to identify the critical parameters for this outcome. The dynamic stochastic simulation model consists of 3 hospitals with general wards and intensive care units (ICUs) and incorporates readmission of carriers of MRSA. Patient flow between ICUs and wards was based on real observations. Baseline prevalence of MRSA was set at 20% in ICUs and hospital-wide at 5%, ranges of costs and infection rates were based on published data. Four S&I strategies were compared to a do-nothing scenario: S&I of previously documented carriers (flagged patients), S&I of flagged patients and ICU admissions, S&I of flagged and group of frequent patients, S&I of all hospital admissions (universal screening). Evaluated levels of efficacy of S&I were 10%, 25%, 50% and 100%. Our model predicts that S&I of flagged and S&I of flagged and ICU patients are the most cost-saving strategies with fastest return of investment. For low isolation efficacy universal screening and S&I of flagged and frequent patients may never become cost-saving. Universal screening is predicted to prevent hardly more infections than S&I of flagged and frequent patients, albeit at higher costs. Whether an intervention becomes cost-saving within 10 years critically depends on costs per infection in ICU, costs of screening and isolation efficacy.'),
(85871, 2013, 'plos', 'Significantly improved HIV inhibitor efficacy prediction employing proteochemometric models generated from antivirogram data', 'van Westen, Gerard J P|Hendriks, Alwin|Wegner, Jörg K|Ijzerman, Adriaan P|van Vlijmen, Herman W T|Bender, Andreas', 'Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.|Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.|Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.|Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.|Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.|Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 37, 'Anti-HIV Agents|Artificial Intelligence|Computational Biology|Databases, Genetic|Drug Discovery|HIV|Models, Biological|Mutation|Phenotype|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1002899', '23436985', 'Infection with HIV cannot currently be cured, however it can be controlled by combination treatment with multiple anti-retroviral drugs. Given different viral genotypes for virtually each individual patient, the question now arises which drug combination to use to achieve effective treatment. With the availability of viral genotypic data and clinical phenotypic data, it has become possible to create computational models able to predict an optimal treatment regimen for an individual patient. Current models are based only on sequence data derived from viral genotyping, chemical similarity of drugs is not considered. To explore the added value of chemical similarity inclusion we applied proteochemometric models, combining chemical and protein target properties in a single bioactivity model. Our dataset was a large scale clinical database of genotypic and phenotypic information (in total ca. 300,000 drug-mutant bioactivity data points, 4 (NNRTI), 8 (NRTI) or 9 (PI) drugs, and 10,700 (NNRTI) 10,500 (NRTI) or 27,000 (PI) mutants). Our models achieved a prediction error below 0.5 Log Fold Change. Moreover, when directly compared with previously published sequence data, derived models PCM performed better in resistance classification and prediction of Log Fold Change (0.76 log units versus 0.91). Furthermore, we were able to successfully confirm both known and identify previously unpublished, resistance-conferring mutations of HIV Reverse Transcriptase (e.g. K102Y, T216M) and HIV Protease (e.g. Q18N, N88G) from our dataset. Finally, we applied our models prospectively to the public HIV resistance database from Stanford University obtaining a correct resistance prediction rate of 84% on the full set (compared to 80% in previous work on a high quality subset). We conclude that proteochemometric models are able to accurately predict the phenotypic resistance based on genotypic data even for novel mutants and mixtures. Furthermore, we add an applicability domain to the prediction, informing the user about the reliability of predictions.'),
(85872, 2013, 'plos', 'Pairwise analysis can account for network structures arising from spike-timing dependent plasticity', 'Babadi, Baktash|Abbott, L F', 'Center for Theoretical Neuroscience, Department of Neuroscience, Columbia University, New York, New York, United States of America. bbabadi@fas.harvard.edu|Center for Theoretical Neuroscience, Department of Neuroscience, Columbia University, New York, New York, United States of America. bbabadi@fas.harvard.edu', 'United States|United States', 22, 'Action Potentials|Animals|Computer Simulation|Models, Neurological|Neuronal Plasticity|Neurons|Rats|Synapses', 'Journal Article', '10.1371/journal.pcbi.1002906', '23436986', 'Spike timing-dependent plasticity (STDP) modifies synaptic strengths based on timing information available locally at each synapse. Despite this, it induces global structures within a recurrently connected network. We study such structures both through simulations and by analyzing the effects of STDP on pair-wise interactions of neurons. We show how conventional STDP acts as a loop-eliminating mechanism and organizes neurons into in- and out-hubs. Loop-elimination increases when depression dominates and turns into loop-generation when potentiation dominates. STDP with a shifted temporal window such that coincident spikes cause depression enhances recurrent connections and functions as a strict buffering mechanism that maintains a roughly constant average firing rate. STDP with the opposite temporal shift functions as a loop eliminator at low rates and as a potent loop generator at higher rates. In general, studying pairwise interactions of neurons provides important insights about the structures that STDP can produce in large networks.'),
(85873, 2013, 'plos', 'Mutational analysis of the high-affinity zinc binding site validates a refined human dopamine transporter homology model', 'Stockner, Thomas|Montgomery, Therese R|Kudlacek, Oliver|Weissensteiner, Rene|Ecker, Gerhard F|Freissmuth, Michael|Sitte, Harald H', 'Center of Physiology and Pharmacology, Institute of Pharmacology, Medical University Vienna, Vienna, Austria.|Center of Physiology and Pharmacology, Institute of Pharmacology, Medical University Vienna, Vienna, Austria.|Center of Physiology and Pharmacology, Institute of Pharmacology, Medical University Vienna, Vienna, Austria.|Center of Physiology and Pharmacology, Institute of Pharmacology, Medical University Vienna, Vienna, Austria.|Center of Physiology and Pharmacology, Institute of Pharmacology, Medical University Vienna, Vienna, Austria.|Center of Physiology and Pharmacology, Institute of Pharmacology, Medical University Vienna, Vienna, Austria.|Center of Physiology and Pharmacology, Institute of Pharmacology, Medical University Vienna, Vienna, Austria.', 'Austria|Austria|Austria|Austria|Austria|Austria|Austria', 53, '1-Methyl-4-phenylpyridinium|Amino Acid Sequence|Binding Sites|DNA Mutational Analysis|Dopamine Plasma Membrane Transport Proteins|HEK293 Cells|Humans|Models, Molecular|Molecular Sequence Data|Protein Binding|Protein Conformation|Protein Structure, Tertiary|Sequence Alignment|Water|Zinc', 'Journal Article', '10.1371/journal.pcbi.1002909', '23436987', 'The high-resolution crystal structure of the leucine transporter (LeuT) is frequently used as a template for homology models of the dopamine transporter (DAT). Although similar in structure, DAT differs considerably from LeuT in a number of ways: (i) when compared to LeuT, DAT has very long intracellular amino and carboxyl termini, (ii) LeuT and DAT share a rather low overall sequence identity (22%) and (iii) the extracellular loop 2 (EL2) of DAT is substantially longer than that of LeuT. Extracellular zinc binds to DAT and restricts the transporters movement through the conformational cycle, thereby resulting in a decrease in substrate uptake. Residue H293 in EL2 praticipates in zinc binding and must be modelled correctly to allow for a full understanding of its effects. We exploited the high-affinity zinc binding site endogenously present in DAT to create a model of the complete transmemberane domain of DAT. The zinc binding site provided a DAT-specific molecular ruler for calibration of the model. Our DAT model places EL2 at the transporter lipid interface in the vicinity of the zinc binding site. Based on the model, D206 was predicted to represent a fourth co-ordinating residue, in addition to the three previously described zinc binding residues H193, H375 and E396. This prediction was confirmed by mutagenesis: substitution of D206 by lysine and cysteine affected the inhibitory potency of zinc and the maximum inhibition exerted by zinc, respectively. Conversely, the structural changes observed in the model allowed for rationalizing the zinc-dependent regulation of DAT: upon binding, zinc stabilizes the outward-facing state, because its first coordination shell can only be completed in this conformation. Thus, the model provides a validated solution to the long extracellular loop and may be useful to address other aspects of the transport cycle.'),
(85874, 2013, 'plos', 'From hub proteins to hub modules: the relationship between essentiality and centrality in the yeast interactome at different scales of organization', 'Song, Jimin|Singh, Mona', 'Department of Computer Science and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.|Department of Computer Science and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.', 'Jersey|Jersey', 0, 'Computational Biology|Databases, Protein|Fungal Proteins|Kinetochores|Protein Interaction Mapping|Protein Interaction Maps|Statistics, Nonparametric|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1002910', '23436988', 'Numerous studies have suggested that hub proteins in the S. cerevisiae physical interaction network are more likely to be essential than other proteins. The proposed reasons underlying this observed relationship between topology and functioning have been subject to some controversy, with recent work suggesting that it arises due to the participation of hub proteins in essential complexes and processes. However, do these essential modules themselves have distinct network characteristics, and how do their essential proteins differ in their topological properties from their non-essential proteins? We aimed to advance our understanding of protein essentiality by analyzing proteins, complexes and processes within their broader functional context and by considering physical interactions both within and across complexes and biological processes. In agreement with the view that essentiality is a modular property, we found that the number of intracomplex or intraprocess interactions that a protein has is a better indicator of its essentiality than its overall number of interactions. Moreover, we found that within an essential complex, its essential proteins have on average more interactions, especially intracomplex interactions, than its non-essential proteins. Finally, we built a module-level interaction network and found that essential complexes and processes tend to have higher interaction degrees in this network than non-essential complexes and processes, that is, they exhibit a larger amount of functional cross-talk than their non-essential counterparts.'),
(85875, 2013, 'plos', 'Modelling trial-by-trial changes in the mismatch negativity', 'Lieder, Falk|Daunizeau, Jean|Garrido, Marta I|Friston, Karl J|Stephan, Klaas E', 'Translational Neuromodeling Unit-TNU, Institute of Biomedical Engineering, University of Zurich & ETH Zurich, Zurich, Switzerland. falk.lieder@gmail.com|Translational Neuromodeling Unit-TNU, Institute of Biomedical Engineering, University of Zurich & ETH Zurich, Zurich, Switzerland. falk.lieder@gmail.com|Translational Neuromodeling Unit-TNU, Institute of Biomedical Engineering, University of Zurich & ETH Zurich, Zurich, Switzerland. falk.lieder@gmail.com|Translational Neuromodeling Unit-TNU, Institute of Biomedical Engineering, University of Zurich & ETH Zurich, Zurich, Switzerland. falk.lieder@gmail.com|Translational Neuromodeling Unit-TNU, Institute of Biomedical Engineering, University of Zurich & ETH Zurich, Zurich, Switzerland. falk.lieder@gmail.com', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 0, 'Acoustic Stimulation|Adult|Bayes Theorem|Electroencephalography|Evoked Potentials, Auditory|Female|Humans|Learning|Male|Models, Neurological|Models, Statistical|Neurons|Signal Processing, Computer-Assisted', 'Journal Article', '10.1371/journal.pcbi.1002911', '23436989', 'The mismatch negativity (MMN) is a differential brain response to violations of learned regularities. It has been used to demonstrate that the brain learns the statistical structure of its environment and predicts future sensory inputs. However, the algorithmic nature of these computations and the underlying neurobiological implementation remain controversial. This article introduces a mathematical framework with which competing ideas about the computational quantities indexed by MMN responses can be formalized and tested against single-trial EEG data. This framework was applied to five major theories of the MMN, comparing their ability to explain trial-by-trial changes in MMN amplitude. Three of these theories (predictive coding, model adjustment, and novelty detection) were formalized by linking the MMN to different manifestations of the same computational mechanism: approximate Bayesian inference according to the free-energy principle. We thereby propose a unifying view on three distinct theories of the MMN. The relative plausibility of each theory was assessed against empirical single-trial MMN amplitudes acquired from eight healthy volunteers in a roving oddball experiment. Models based on the free-energy principle provided more plausible explanations of trial-by-trial changes in MMN amplitude than models representing the two more traditional theories (change detection and adaptation). Our results suggest that the MMN reflects approximate Bayesian learning of sensory regularities, and that the MMN-generating process adjusts a probabilistic model of the environment according to prediction errors.'),
(85876, 2013, 'plos', 'Evidence for model-based computations in the human amygdala during Pavlovian conditioning', 'Prévost, Charlotte|McNamee, Daniel|Jessup, Ryan K|Bossaerts, Peter|ODoherty, John P', 'Trinity College Institute of Neuroscience and School of Psychology, Dublin, Ireland.|Trinity College Institute of Neuroscience and School of Psychology, Dublin, Ireland.|Trinity College Institute of Neuroscience and School of Psychology, Dublin, Ireland.|Trinity College Institute of Neuroscience and School of Psychology, Dublin, Ireland.|Trinity College Institute of Neuroscience and School of Psychology, Dublin, Ireland.', 'Ireland|Ireland|Ireland|Ireland|Ireland', 0, 'Algorithms|Amygdala|Blinking|Conditioning, Classical|Heart Rate|Humans|Magnetic Resonance Imaging|Male|Models, Neurological|Pupil|Respiratory Rate|Signal Processing, Computer-Assisted', 'Journal Article', '10.1371/journal.pcbi.1002918', '23436990', 'Contemporary computational accounts of instrumental conditioning have emphasized a role for a model-based system in which values are computed with reference to a rich model of the structure of the world, and a model-free system in which values are updated without encoding such structure. Much less studied is the possibility of a similar distinction operating at the level of Pavlovian conditioning. In the present study, we scanned human participants while they participated in a Pavlovian conditioning task with a simple structure while measuring activity in the human amygdala using a high-resolution fMRI protocol. After fitting a model-based algorithm and a variety of model-free algorithms to the fMRI data, we found evidence for the superiority of a model-based algorithm in accounting for activity in the amygdala compared to the model-free counterparts. These findings support an important role for model-based algorithms in describing the processes underpinning Pavlovian conditioning, as well as providing evidence of a role for the human amygdala in model-based inference.'),
(85877, 2013, 'plos', 'Optimal properties of analog perceptrons with excitatory weights', 'Clopath, Claudia|Brunel, Nicolas', 'Laboratory of Neurophysics and Physiology, CNRS and Université Paris Descartes, Paris, France. cc3450@columbia.edu|Laboratory of Neurophysics and Physiology, CNRS and Université Paris Descartes, Paris, France. cc3450@columbia.edu', 'France|France', 0, 'Animals|Computer Simulation|Mice|Models, Neurological|Nerve Fibers|Neural Networks (Computer)|Neuronal Plasticity|Purkinje Cells|Synapses', 'Journal Article', '10.1371/journal.pcbi.1002919', '23436991', 'The cerebellum is a brain structure which has been traditionally devoted to supervised learning. According to this theory, plasticity at the Parallel Fiber (PF) to Purkinje Cell (PC) synapses is guided by the Climbing fibers (CF), which encode an error signal. Purkinje cells have thus been modeled as perceptrons, learning input/output binary associations. At maximal capacity, a perceptron with excitatory weights expresses a large fraction of zero-weight synapses, in agreement with experimental findings. However, numerous experiments indicate that the firing rate of Purkinje cells varies in an analog, not binary, manner. In this paper, we study the perceptron with analog inputs and outputs. We show that the optimal input has a sparse binary distribution, in good agreement with the burst firing of the Granule cells. In addition, we show that the weight distribution consists of a large fraction of silent synapses, as in previously studied binary perceptron models, and as seen experimentally.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85878, 2013, 'plos', 'Structure-based molecular simulations reveal the enhancement of biased Brownian motions in single-headed kinesin', 'Kanada, Ryo|Kuwata, Takeshi|Kenzaki, Hiroo|Takada, Shoji', 'Department of Biophysics Graduate School of Science, Kyoto University, Kyoto, Japan.|Department of Biophysics Graduate School of Science, Kyoto University, Kyoto, Japan.|Department of Biophysics Graduate School of Science, Kyoto University, Kyoto, Japan.|Department of Biophysics Graduate School of Science, Kyoto University, Kyoto, Japan.', 'Japan|Japan|Japan|Japan', 0, 'Adenosine Triphosphate|Animals|Humans|Kinesin|Models, Biological|Molecular Dynamics Simulation', 'Journal Article', '10.1371/journal.pcbi.1002907', '23459019', 'Kinesin is a family of molecular motors that move unidirectionally along microtubules (MT) using ATP hydrolysis free energy. In the family, the conventional two-headed kinesin was experimentally characterized to move unidirectionally through walking in a hand-over-hand fashion by coordinated motions of the two heads. Interestingly a single-headed kinesin, a truncated KIF1A, still can generate a biased Brownian movement along MT, as observed by in vitro single molecule experiments. Thus, KIF1A must use a different mechanism from the conventional kinesin to achieve the unidirectional motions. Based on the energy landscape view of proteins, for the first time, we conducted a set of molecular simulations of the truncated KIF1A movements over an ATP hydrolysis cycle and found a mechanism exhibiting and enhancing stochastic forward-biased movements in a similar way to those in experiments. First, simulating stand-alone KIF1A, we did not find any biased movements, while we found that KIF1A with a large friction cargo-analog attached to the C-terminus can generate clearly biased Brownian movements upon an ATP hydrolysis cycle. The linked cargo-analog enhanced the detachment of the KIF1A from MT. Once detached, diffusion of the KIF1A head was restricted around the large cargo which was located in front of the head at the time of detachment, thus generating a forward bias of the diffusion. The cargo plays the role of a diffusional anchor, or cane, in KIF1A walking.'),
(85879, 2013, 'plos', 'Multi-population classical HLA type imputation', 'Dilthey, Alexander|Leslie, Stephen|Moutsianas, Loukas|Shen, Judong|Cox, Charles|Nelson, Matthew R|McVean, Gil', 'Department of Statistics, University of Oxford, Oxford, UK. dilthey@well.ox.ac.uk|Department of Statistics, University of Oxford, Oxford, UK. dilthey@well.ox.ac.uk|Department of Statistics, University of Oxford, Oxford, UK. dilthey@well.ox.ac.uk|Department of Statistics, University of Oxford, Oxford, UK. dilthey@well.ox.ac.uk|Department of Statistics, University of Oxford, Oxford, UK. dilthey@well.ox.ac.uk|Department of Statistics, University of Oxford, Oxford, UK. dilthey@well.ox.ac.uk|Department of Statistics, University of Oxford, Oxford, UK. dilthey@well.ox.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 94, 'Computational Biology|Continental Population Groups|Genetics, Population|HLA Antigens|Haplotypes|Humans|Models, Genetic|Models, Immunological|Polymorphism, Single Nucleotide|Principal Component Analysis|Reproducibility of Results|Software', 'Journal Article', '10.1371/journal.pcbi.1002877', '23459081', 'Statistical imputation of classical HLA alleles in case-control studies has become established as a valuable tool for identifying and fine-mapping signals of disease association in the MHC. Imputation into diverse populations has, however, remained challenging, mainly because of the additional haplotypic heterogeneity introduced by combining reference panels of different sources. We present an HLA type imputation model, HLA*IMP:02, designed to operate on a multi-population reference panel. HLA*IMP:02 is based on a graphical representation of haplotype structure. We present a probabilistic algorithm to build such models for the HLA region, accommodating genotyping error, haplotypic heterogeneity and the need for maximum accuracy at the HLA loci, generalizing the work of Browning and Browning (2007) and Ron et al. (1998). HLA*IMP:02 achieves an average 4-digit imputation accuracy on diverse European panels of 97% (call rate 97%). On non-European samples, 2-digit performance is over 90% for most loci and ethnicities where data available. HLA*IMP:02 supports imputation of HLA-DPB1 and HLA-DRB3-5, is highly tolerant of missing data in the imputation panel and works on standard genotype data from popular genotyping chips. It is publicly available in source code and as a user-friendly web service framework.'),
(85880, 2013, 'plos', 'Transformation of context-dependent sensory dynamics into motor behavior', 'Latorre, Roberto|Levi, Rafael|Varona, Pablo', 'Grupo de Neurocomputación Biológica, Dpto. de Ingeniería Informática, Escuela Politécnica Superior, Universidad Autónoma de Madrid, Madrid, Spain. roberto.latorre@uam.es|Grupo de Neurocomputación Biológica, Dpto. de Ingeniería Informática, Escuela Politécnica Superior, Universidad Autónoma de Madrid, Madrid, Spain. roberto.latorre@uam.es|Grupo de Neurocomputación Biológica, Dpto. de Ingeniería Informática, Escuela Politécnica Superior, Universidad Autónoma de Madrid, Madrid, Spain. roberto.latorre@uam.es', 'Spain|Spain|Spain', 0, 'Animals|Behavior, Animal|Clione|Computational Biology|Models, Neurological|Motor Neurons|Sensory Receptor Cells', 'Journal Article', '10.1371/journal.pcbi.1002908', '23459114', 'The intrinsic dynamics of sensory networks play an important role in the sensory-motor transformation. In this paper we use conductance based models and electrophysiological recordings to address the study of the dual role of a sensory network to organize two behavioral context-dependent motor programs in the mollusk Clione limacina. We show that: (i) a winner take-all dynamics in the gravimetric sensory network model drives the typical repetitive rhythm in the wing central pattern generator (CPG) during routine swimming, (ii) the winnerless competition dynamics of the same sensory network organizes the irregular pattern observed in the wing CPG during hunting behavior. Our model also shows that although the timing of the activity is irregular, the sequence of the switching among the sensory cells is preserved whenever the same set of neurons are activated in a given time window. These activation phase locks in the sensory signals are transformed into specific events in the motor activity. The activation phase locks can play an important role in motor coordination driven by the intrinsic dynamics of a multifunctional sensory organ.'),
(85881, 2013, 'plos', 'Transcranial electrical stimulation accelerates human sleep homeostasis', 'Reato, Davide|Gasca, Fernando|Datta, Abhishek|Bikson, Marom|Marshall, Lisa|Parra, Lucas C', 'Department of Biomedical Engineering, The City College of the City University of New York, New York, New York, USA. davide.reato@gmail.com|Department of Biomedical Engineering, The City College of the City University of New York, New York, New York, USA. davide.reato@gmail.com|Department of Biomedical Engineering, The City College of the City University of New York, New York, New York, USA. davide.reato@gmail.com|Department of Biomedical Engineering, The City College of the City University of New York, New York, New York, USA. davide.reato@gmail.com|Department of Biomedical Engineering, The City College of the City University of New York, New York, New York, USA. davide.reato@gmail.com|Department of Biomedical Engineering, The City College of the City University of New York, New York, New York, USA. davide.reato@gmail.com', 'United States|United States|United States|United States|United States|United States', 0, 'Adult|Computational Biology|Computer Simulation|Deep Brain Stimulation|Electroencephalography|Finite Element Analysis|Homeostasis|Humans|Male|Models, Neurological|Sleep', 'Journal Article', '10.1371/journal.pcbi.1002898', '23459152', 'The sleeping brain exhibits characteristic slow-wave activity which decays over the course of the night. This decay is thought to result from homeostatic synaptic downscaling. Transcranial electrical stimulation can entrain slow-wave oscillations (SWO) in the human electro-encephalogram (EEG). A computational model of the underlying mechanism predicts that firing rates are predominantly increased during stimulation. Assuming that synaptic homeostasis is driven by average firing rates, we expected an acceleration of synaptic downscaling during stimulation, which is compensated by a reduced drive after stimulation. We show that 25 minutes of transcranial electrical stimulation, as predicted, reduced the decay of SWO in the remainder of the night. Anatomically accurate simulations of the field intensities on human cortex precisely matched the effect size in different EEG electrodes. Together these results suggest a mechanistic link between electrical stimulation and accelerated synaptic homeostasis in human sleep.'),
(85882, 2013, 'plos', 'Passive dendrites enable single neurons to compute linearly non-separable functions', 'Cazé, Romain Daniel|Humphries, Mark|Gutkin, Boris', 'Group for Neural Theory, INSERM U960, Ecole Normale Superieure, Paris, France. romain.caze@ens.fr|Group for Neural Theory, INSERM U960, Ecole Normale Superieure, Paris, France. romain.caze@ens.fr|Group for Neural Theory, INSERM U960, Ecole Normale Superieure, Paris, France. romain.caze@ens.fr', 'France|France|France', 0, 'Action Potentials|Animals|Cerebellum|Computational Biology|Dendrites|Linear Models|Mice|Models, Neurological|Neurons', 'Journal Article', '10.1371/journal.pcbi.1002867', '23468600', 'Local supra-linear summation of excitatory inputs occurring in pyramidal cell dendrites, the so-called dendritic spikes, results in independent spiking dendritic sub-units, which turn pyramidal neurons into two-layer neural networks capable of computing linearly non-separable functions, such as the exclusive OR. Other neuron classes, such as interneurons, may possess only a few independent dendritic sub-units, or only passive dendrites where input summation is purely sub-linear, and where dendritic sub-units are only saturating. To determine if such neurons can also compute linearly non-separable functions, we enumerate, for a given parameter range, the Boolean functions implementable by a binary neuron model with a linear sub-unit and either a single spiking or a saturating dendritic sub-unit. We then analytically generalize these numerical results to an arbitrary number of non-linear sub-units. First, we show that a single non-linear dendritic sub-unit, in addition to the somatic non-linearity, is sufficient to compute linearly non-separable functions. Second, we analytically prove that, with a sufficient number of saturating dendritic sub-units, a neuron can compute all functions computable with purely excitatory inputs. Third, we show that these linearly non-separable functions can be implemented with at least two strategies: one where a dendritic sub-unit is sufficient to trigger a somatic spike, another where somatic spiking requires the cooperation of multiple dendritic sub-units. We formally prove that implementing the latter architecture is possible with both types of dendritic sub-units whereas the former is only possible with spiking dendrites. Finally, we show how linearly non-separable functions can be computed by a generic two-compartment biophysical model and a realistic neuron model of the cerebellar stellate cell interneuron. Taken together our results demonstrate that passive dendrites are sufficient to enable neurons to compute linearly non-separable functions.'),
(85883, 2013, 'plos', 'Discriminating external and internal causes for heading changes in freely flying Drosophila', 'Censi, Andrea|Straw, Andrew D|Sayaman, Rosalyn W|Murray, Richard M|Dickinson, Michael H', 'Control & Dynamical Systems, California Institute of Technology, Pasadena, California, United States of America.|Control & Dynamical Systems, California Institute of Technology, Pasadena, California, United States of America.|Control & Dynamical Systems, California Institute of Technology, Pasadena, California, United States of America.|Control & Dynamical Systems, California Institute of Technology, Pasadena, California, United States of America.|Control & Dynamical Systems, California Institute of Technology, Pasadena, California, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Algorithms|Animals|Behavior, Animal|Computational Biology|Decision Making|Drosophila melanogaster|Female|Flight, Animal|Models, Biological|Photic Stimulation|Saccades', 'Journal Article', '10.1371/journal.pcbi.1002891', '23468601', 'As animals move through the world in search of resources, they change course in reaction to both external sensory cues and internally-generated programs. Elucidating the functional logic of complex search algorithms is challenging because the observable actions of the animal cannot be unambiguously assigned to externally- or internally-triggered events. We present a technique that addresses this challenge by assessing quantitatively the contribution of external stimuli and internal processes. We apply this technique to the analysis of rapid turns (saccades) of freely flying Drosophila melanogaster. We show that a single scalar feature computed from the visual stimulus experienced by the animal is sufficient to explain a majority (93%) of the turning decisions. We automatically estimate this scalar value from the observable trajectory, without any assumption regarding the sensory processing. A posteriori, we show that the estimated feature field is consistent with previous results measured in other experimental conditions. The remaining turning decisions, not explained by this feature of the visual input, may be attributed to a combination of deterministic processes based on unobservable internal states and purely stochastic behavior. We cannot distinguish these contributions using external observations alone, but we are able to provide a quantitative bound of their relative importance with respect to stimulus-triggered decisions. Our results suggest that comparatively few saccades in free-flying conditions are a result of an intrinsic spontaneous process, contrary to previous suggestions. We discuss how this technique could be generalized for use in other systems and employed as a tool for classifying effects into sensory, decision, and motor categories when used to analyze data from genetic behavioral screens.'),
(85884, 2013, 'plos', 'Virus neutralisation: new insights from kinetic neutralisation curves', 'Magnus, Carsten', 'Institute for Emerging Infections, Department of Zoology, University of Oxford, Oxford, United Kingdom. carsten.magnus@zoo.ox.ac.uk', 'United Kingdom', 0, 'Animals|Antibodies, Neutralizing|Antibodies, Viral|Computational Biology|Epitopes|HIV|Humans|Immunoglobulin G|Kinetics|Mice|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002900', '23468602', 'Antibodies binding to the surface of virions can lead to virus neutralisation. Different theories have been proposed to determine the number of antibodies that must bind to a virion for neutralisation. Early models are based on chemical binding kinetics. Applying these models lead to very low estimates of the number of antibodies needed for neutralisation. In contrast, according to the more conceptual approach of stoichiometries in virology a much higher number of antibodies is required for virus neutralisation by antibodies. Here, we combine chemical binding kinetics with (virological) stoichiometries to better explain virus neutralisation by antibody binding. This framework is in agreement with published data on the neutralisation of the human immunodeficiency virus. Knowing antibody reaction constants, our model allows us to estimate stoichiometrical parameters from kinetic neutralisation curves. In addition, we can identify important parameters that will make further analysis of kinetic neutralisation curves more valuable in the context of estimating stoichiometries. Our model gives a more subtle explanation of kinetic neutralisation curves in terms of single-hit and multi-hit kinetics.'),
(85885, 2013, 'plos', 'The HAMP signal relay domain adopts multiple conformational states through collective piston and tilt motions', 'Zhu, Lizhe|Bolhuis, Peter G|Vreede, Jocelyne', 'Van t Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands.|Van t Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands.|Van t Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands.', 'Netherlands|Netherlands|Netherlands', 12, 'Archaeal Proteins|Archaeoglobus fulgidus|Molecular Dynamics Simulation|Protein Structure, Tertiary|Protein Unfolding|Signal Transduction|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002913', '23468603', 'The HAMP domain is a linker region in prokaryotic sensor proteins and relays input signals to the transmitter domain and vice versa. Functional as a dimer, the structure of HAMP shows a parallel coiled-coil motif comprising four helices. To date, it is unclear how HAMP can relay signals from one domain to another, although several models exist. In this work, we use molecular simulation to test the hypothesis that HAMP adopts different conformations, one of which represents an active, signal-relaying configuration, and another an inactive, resting state. We first performed molecular dynamics simulation on the prototype HAMP domain Af1503 from Archaeoglobus fulgidus. We explored its conformational space by taking the structure of the A291F mutant disabling HAMP activity as a starting point. These simulations revealed additional conformational states that differ in the tilt angles between the helices as well as the relative piston shifts of the helices relative to each other. By enhancing the sampling in a metadynamics set up, we investigated three mechanistic models for HAMP signal transduction. Our results indicate that HAMP can access additional conformational states characterized by piston motion. Furthermore, the piston motion of the N-terminal helix of one monomer is directly correlated with the opposite piston motion of the C-terminal helix of the other monomer. The change in piston motion is accompanied by a change in tilt angle between the monomers, thus revealing that HAMP exhibits a collective motion, i.e. a combination of changes in tilt angles and a piston-like displacement. Our results provide insights into the conformational changes that underlie the signaling mechanism involving HAMP.'),
(85886, 2013, 'plos', 'An entropic mechanism of generating selective ion binding in macromolecules', 'Thomas, Michael|Jayatilaka, Dylan|Corry, Ben', 'Research School of Biology, Australian National University, Canberra, Australia.|Research School of Biology, Australian National University, Canberra, Australia.|Research School of Biology, Australian National University, Canberra, Australia.', 'Australia|Australia|Australia', 0, 'Archaeal Proteins|Bacterial Proteins|Entropy|Ion Channels|Ions|Ligands|Models, Biological|Models, Molecular|Potassium|Sodium', 'Journal Article', '10.1371/journal.pcbi.1002914', '23468604', 'Several mechanisms have been proposed to explain how ion channels and transporters distinguish between similar ions, a process crucial for maintaining proper cell function. Of these, three can be broadly classed as mechanisms involving specific positional constraints on the ion coordinating ligands which arise through: a rigid cavity, a strained cavity and reduced ligand fluctuations. Each operates in subtly different ways yet can produce markedly different influences on ion selectivity. Here we expand upon preliminary investigations into the reduced ligand fluctuation mechanism of ion selectivity by simulating how a series of model systems respond to a decrease in ligand thermal fluctuations while simultaneously maintaining optimal ion-ligand binding distances. Simple abstract-ligand models, as well as simple models based upon the ion binding sites in two amino acid transporters, show that limiting ligand fluctuations can create ion selectivity between Li(+), Na(+) and K(+) even when there is no strain associated with the molecular framework accommodating the different ions. Reducing the fluctuations in the position of the coordinating ligands contributes to selectivity toward the smaller of two ions as a consequence of entropic differences.'),
(85887, 2013, 'plos', 'Collective states, multistability and transitional behavior in schooling fish', 'Tunstrøm, Kolbjørn|Katz, Yael|Ioannou, Christos C|Huepe, Cristián|Lutz, Matthew J|Couzin, Iain D', 'Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America. tunstrom@princeton.edu|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America. tunstrom@princeton.edu|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America. tunstrom@princeton.edu|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America. tunstrom@princeton.edu|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America. tunstrom@princeton.edu|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America. tunstrom@princeton.edu', 'Jersey|Jersey|Jersey|Jersey|Jersey|Jersey', 154, 'Animals|Behavior, Animal|Computer Simulation|Cyprinidae|Models, Biological|Swimming', 'Journal Article', '10.1371/journal.pcbi.1002915', '23468605', 'The spontaneous emergence of pattern formation is ubiquitous in nature, often arising as a collective phenomenon from interactions among a large number of individual constituents or sub-systems. Understanding, and controlling, collective behavior is dependent on determining the low-level dynamical principles from which spatial and temporal patterns emerge, a key question is whether different group-level patterns result from all components of a system responding to the same external factor, individual components changing behavior but in a distributed self-organized way, or whether multiple collective states co-exist for the same individual behaviors. Using schooling fish (golden shiners, in groups of 30 to 300 fish) as a model system, we demonstrate that collective motion can be effectively mapped onto a set of order parameters describing the macroscopic group structure, revealing the existence of at least three dynamically-stable collective states, swarm, milling and polarized groups. Swarms are characterized by slow individual motion and a relatively dense, disordered structure. Increasing swim speed is associated with a transition to one of two locally-ordered states, milling or highly-mobile polarized groups. The stability of the discrete collective behaviors exhibited by a group depends on the number of group members. Transitions between states are influenced by both external (boundary-driven) and internal (changing motion of group members) factors. Whereas transitions between locally-disordered and locally-ordered group states are speed dependent, analysis of local and global properties of groups suggests that, congruent with theory, milling and polarized states co-exist in a bistable regime with transitions largely driven by perturbations. Our study allows us to relate theoretical and empirical understanding of animal group behavior and emphasizes dynamic changes in the structure of such groups.'),
(85888, 2013, 'plos', 'Spartan: a comprehensive tool for understanding uncertainty in simulations of biological systems', 'Alden, Kieran|Read, Mark|Timmis, Jon|Andrews, Paul S|Veiga-Fernandes, Henrique|Coles, Mark', 'Centre for Systems Biology, School of Biosciences, University of Birmingham, Birmingham, United Kingdom. k.j.alden@bham.ac.uk|Centre for Systems Biology, School of Biosciences, University of Birmingham, Birmingham, United Kingdom. k.j.alden@bham.ac.uk|Centre for Systems Biology, School of Biosciences, University of Birmingham, Birmingham, United Kingdom. k.j.alden@bham.ac.uk|Centre for Systems Biology, School of Biosciences, University of Birmingham, Birmingham, United Kingdom. k.j.alden@bham.ac.uk|Centre for Systems Biology, School of Biosciences, University of Birmingham, Birmingham, United Kingdom. k.j.alden@bham.ac.uk|Centre for Systems Biology, School of Biosciences, University of Birmingham, Birmingham, United Kingdom. k.j.alden@bham.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 49, 'Cell Movement|Computer Simulation|Lymphoid Tissue|Models, Biological|Software', 'Journal Article', '10.1371/journal.pcbi.1002916', '23468606', 'Integrating computer simulation with conventional wet-lab research has proven to have much potential in furthering the understanding of biological systems. Success requires the relationship between simulation and the real-world system to be established: substantial aspects of the biological system are typically unknown, and the abstract nature of simulation can complicate interpretation of in silico results in terms of the biology. Here we present spartan (Simulation Parameter Analysis RToolkit ApplicatioN), a package of statistical techniques specifically designed to help researchers understand this relationship and provide novel biological insight. The tools comprising spartan help identify which simulation results can be attributed to the dynamics of the modelled biological system, rather than artefacts of biological uncertainty or parametrisation, or simulation stochasticity. Statistical analyses reveal the influence that pathways and components have on simulation behaviour, offering valuable biological insight into aspects of the system under study. We demonstrate the power of spartan in providing critical insight into aspects of lymphoid tissue development in the small intestine through simulation. Spartan is released under a GPLv2 license, implemented within the open source R statistical environment, and freely available from both the Comprehensive R Archive Network (CRAN) and http://www.cs.york.ac.uk/spartan. The techniques within the package can be applied to traditional ordinary or partial differential equation simulations as well as agent-based implementations. Manuals, comprehensive tutorials, and example simulation data upon which spartan can be applied are available from the website.'),
(85889, 2013, 'plos', 'The vast, conserved mammalian lincRNome', 'Managadze, David|Lobkovsky, Alexander E|Wolf, Yuri I|Shabalina, Svetlana A|Rogozin, Igor B|Koonin, Eugene V', 'National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America.|National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America.|National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America.|National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America.|National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America.|National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America.', 'United States|United States|United States|United States|United States|United States', 0, 'Animals|Databases, Genetic|Genome|Genome Size|Genomics|Humans|Mice|RNA, Long Noncoding', 'Journal Article', '10.1371/journal.pcbi.1002917', '23468607', 'We compare the sets of experimentally validated long intergenic non-coding (linc)RNAs from human and mouse and apply a maximum likelihood approach to estimate the total number of lincRNA genes as well as the size of the conserved part of the lincRNome. Under the assumption that the sets of experimentally validated lincRNAs are random samples of the lincRNomes of the corresponding species, we estimate the total lincRNome size at approximately 40,000 to 50,000 species, at least twice the number of protein-coding genes. We further estimate that the fraction of the human and mouse euchromatic genomes encoding lincRNAs is more than twofold greater than the fraction of protein-coding sequences. Although the sequences of most lincRNAs are much less strongly conserved than protein sequences, the extent of orthology between the lincRNomes is unexpectedly high, with 60 to 70% of the lincRNA genes shared between human and mouse. The orthologous mammalian lincRNAs can be predicted to perform equivalent functions, accordingly, it appears likely that thousands of evolutionarily conserved functional roles of lincRNAs remain to be characterized.'),
(85890, 2013, 'plos', 'Biomolecular events in cancer revealed by attractor metagenes', 'Cheng, Wei-Yi|Ou Yang, Tai-Hsien|Anastassiou, Dimitris', 'Center for Computational Biology and Bioinformatics and Department of Electrical Engineering, Columbia University, New York, New York, United States of America.|Center for Computational Biology and Bioinformatics and Department of Electrical Engineering, Columbia University, New York, New York, United States of America.|Center for Computational Biology and Bioinformatics and Department of Electrical Engineering, Columbia University, New York, New York, United States of America.', 'United States|United States|United States', 0, 'Algorithms|Computational Biology|Data Mining|Databases, Genetic|Epithelial-Mesenchymal Transition|Gene Expression Profiling|Genome|Humans|Kaplan-Meier Estimate|Kinetochores|Mitosis|Models, Biological|Neoplasms|Oncogenes|Phenotype|Prognosis', 'Journal Article', '10.1371/journal.pcbi.1002920', '23468608', 'Mining gene expression profiles has proven valuable for identifying signatures serving as surrogates of cancer phenotypes. However, the similarities of such signatures across different cancer types have not been strong enough to conclude that they represent a universal biological mechanism shared among multiple cancer types. Here we present a computational method for generating signatures using an iterative process that converges to one of several precise attractors defining signatures representing biomolecular events, such as cell transdifferentiation or the presence of an amplicon. By analyzing rich gene expression datasets from different cancer types, we identified several such biomolecular events, some of which are universally present in all tested cancer types in nearly identical form. Although the method is unsupervised, we show that it often leads to attractors with strong phenotypic associations. We present several such multi-cancer attractors, focusing on three that are prominent and sharply defined in all cases: a mesenchymal transition attractor strongly associated with tumor stage, a mitotic chromosomal instability attractor strongly associated with tumor grade, and a lymphocyte-specific attractor.'),
(85891, 2013, 'plos', 'Standard anatomical and visual space for the mouse retina: computational reconstruction and transformation of flattened retinae with the Retistruct package', 'Sterratt, David C|Lyngholm, Daniel|Willshaw, David J|Thompson, Ian D', 'Institute for Adaptive and Neural Computation, School of Informatics, University of Edinburgh, Edinburgh, Scotland, United Kingdom. david.c.sterratt@ed.ac.uk|Institute for Adaptive and Neural Computation, School of Informatics, University of Edinburgh, Edinburgh, Scotland, United Kingdom. david.c.sterratt@ed.ac.uk|Institute for Adaptive and Neural Computation, School of Informatics, University of Edinburgh, Edinburgh, Scotland, United Kingdom. david.c.sterratt@ed.ac.uk|Institute for Adaptive and Neural Computation, School of Informatics, University of Edinburgh, Edinburgh, Scotland, United Kingdom. david.c.sterratt@ed.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 36, 'Algorithms|Animals|Computational Biology|Fluorescent Dyes|Image Processing, Computer-Assisted|Mice|Oculomotor Muscles|Opsins|Reproducibility of Results|Retina', 'Journal Article', '10.1371/journal.pcbi.1002921', '23468609', 'The concept of topographic mapping is central to the understanding of the visual system at many levels, from the developmental to the computational. It is important to be able to relate different coordinate systems, e.g. maps of the visual field and maps of the retina. Retinal maps are frequently based on flat-mount preparations. These use dissection and relaxing cuts to render the quasi-spherical retina into a 2D preparation. The variable nature of relaxing cuts and associated tears limits quantitative cross-animal comparisons. We present an algorithm, Retistruct, that reconstructs retinal flat-mounts by mapping them into a standard, spherical retinal space. This is achieved by: stitching the marked-up cuts of the flat-mount outline, dividing the stitched outline into a mesh whose vertices then are mapped onto a curtailed sphere, and finally moving the vertices so as to minimise a physically-inspired deformation energy function. Our validation studies indicate that the algorithm can estimate the position of a point on the intact adult retina to within 8° of arc (3.6% of nasotemporal axis). The coordinates in reconstructed retinae can be transformed to visuotopic coordinates. Retistruct is used to investigate the organisation of the adult mouse visual system. We orient the retina relative to the nictitating membrane and compare this to eye muscle insertions. To align the retinotopic and visuotopic coordinate systems in the mouse, we utilised the geometry of binocular vision. In standard retinal space, the composite decussation line for the uncrossed retinal projection is located 64° away from the retinal pole. Projecting anatomically defined uncrossed retinal projections into visual space gives binocular congruence if the optical axis of the mouse eye is oriented at 64° azimuth and 22° elevation, in concordance with previous results. Moreover, using these coordinates, the dorsoventral boundary for S-opsin expressing cones closely matches the horizontal meridian.'),
(85892, 2013, 'plos', 'Functional connectivity in islets of Langerhans from mouse pancreas tissue slices', 'Stožer, Andraž|Gosak, Marko|Dolenšek, Jurij|Perc, Matjaž|Marhl, Marko|Rupnik, Marjan Slak|Korošak, Dean', 'Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia.|Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia.|Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia.|Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia.|Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia.|Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia.|Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia.', 'Slovenia|Slovenia|Slovenia|Slovenia|Slovenia|Slovenia|Slovenia', 70, 'Animals|Calcium|Calcium Signaling|Cluster Analysis|Computational Biology|Histocytochemistry|Islets of Langerhans|Mice|Microscopy, Confocal|Models, Biological|Systems Theory', 'Journal Article', '10.1371/journal.pcbi.1002923', '23468610', 'We propose a network representation of electrically coupled beta cells in islets of Langerhans. Beta cells are functionally connected on the basis of correlations between calcium dynamics of individual cells, obtained by means of confocal laser-scanning calcium imaging in islets from acute mouse pancreas tissue slices. Obtained functional networks are analyzed in the light of known structural and physiological properties of islets. Focusing on the temporal evolution of the network under stimulation with glucose, we show that the dynamics are more correlated under stimulation than under non-stimulated conditions and that the highest overall correlation, largely independent of Euclidean distances between cells, is observed in the activation and deactivation phases when cells are driven by the external stimulus. Moreover, we find that the range of interactions in networks during activity shows a clear dependence on the Euclidean distance, lending support to previous observations that beta cells are synchronized via calcium waves spreading throughout islets. Most interestingly, the functional connectivity patterns between beta cells exhibit small-world properties, suggesting that beta cells do not form a homogeneous geometric network but are connected in a functionally more efficient way. Presented results provide support for the existing knowledge of beta cell physiology from a network perspective and shed important new light on the functional organization of beta cell syncitia whose structural topology is probably not as trivial as believed so far.'),
(85893, 2013, 'plos', 'Enhancing human spermine synthase activity by engineered mutations', 'Zhang, Zhe|Zheng, Yueli|Petukh, Margo|Pegg, Anthony|Ikeguchi, Yoshihiko|Alexov, Emil', 'Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, South Carolina, United States of America.|Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, South Carolina, United States of America.|Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, South Carolina, United States of America.|Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, South Carolina, United States of America.|Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, South Carolina, United States of America.|Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, South Carolina, United States of America.', 'United States|United States|United States|United States|United States|United States', 0, 'Amino Acid Sequence|Amino Acid Substitution|Animals|Computer Simulation|Humans|Hydrogen Bonding|Mental Retardation, X-Linked|Models, Molecular|Molecular Sequence Data|Protein Conformation|Protein Stability|Sequence Alignment|Spermine Synthase|Static Electricity', 'Journal Article', '10.1371/journal.pcbi.1002924', '23468611', 'Spermine synthase (SMS) is an enzyme which function is to convert spermidine into spermine. It was shown that gene defects resulting in amino acid changes of the wild type SMS cause Snyder-Robinson syndrome, which is a mild-to-moderate mental disability associated with osteoporosis, facial asymmetry, thin habitus, hypotonia, and a nonspecific movement disorder. These disease-causing missense mutations were demonstrated, both in silico and in vitro, to affect the wild type function of SMS by either destabilizing the SMS dimer/monomer or directly affecting the hydrogen bond network of the active site of SMS. In contrast to these studies, here we report an artificial engineering of a more efficient SMS variant by transferring sequence information from another organism. It is confirmed experimentally that the variant, bearing four amino acid substitutions, is catalytically more active than the wild type. The increased functionality is attributed to enhanced monomer stability, lowering the pKa of proton donor catalytic residue, optimized spatial distribution of the electrostatic potential around the SMS with respect to substrates, and increase of the frequency of mechanical vibration of the clefts presumed to be the gates toward the active sites. The study demonstrates that wild type SMS is not particularly evolutionarily optimized with respect to the reaction spermidine xe2x86x92 spermine. Having in mind that currently there are no variations (non-synonymous single nucleotide polymorphism, nsSNP) detected in healthy individuals, it can be speculated that the human SMS function is precisely tuned toward its wild type and any deviation is unwanted and disease-causing.'),
(85894, 2013, 'plos', 'Dynamic modeling of cell migration and spreading behaviors on fibronectin coated planar substrates and micropatterned geometries', 'Kim, Min-Cheol|Neal, Devin M|Kamm, Roger D|Asada, H Harry', 'BioSystem & Micromechanics IRG, Singapore MIT Alliance Research Technology, Singapore. mincheol@mit.edu|BioSystem & Micromechanics IRG, Singapore MIT Alliance Research Technology, Singapore. mincheol@mit.edu|BioSystem & Micromechanics IRG, Singapore MIT Alliance Research Technology, Singapore. mincheol@mit.edu|BioSystem & Micromechanics IRG, Singapore MIT Alliance Research Technology, Singapore. mincheol@mit.edu', 'Singapore|Singapore|Singapore|Singapore', 0, 'Animals|Biomechanical Phenomena|CHO Cells|Cell Membrane|Cell Movement|Computer Simulation|Cricetinae|Cricetulus|Cytological Techniques|Fibronectins|Focal Adhesions|Models, Biological|Nuclear Envelope|Pseudopodia|Stress Fibers', 'Journal Article', '10.1371/journal.pcbi.1002926', '23468612', 'An integrative cell migration model incorporating focal adhesion (FA) dynamics, cytoskeleton and nucleus remodeling, actin motor activity, and lamellipodia protrusion is developed for predicting cell spreading and migration behaviors. This work is motivated by two experimental works: (1) cell migration on 2-D substrates under various fibronectin concentrations and (2) cell spreading on 2-D micropatterned geometries. These works suggest (1) cell migration speed takes a maximum at a particular ligand density (xe2x88xbc1140 molecules/xc2xb5m(2)) and (2) that strong traction forces at the corners of the patterns may exist due to combined effects exerted by actin stress fibers (SFs). The integrative model of this paper successfully reproduced these experimental results and indicates the mechanism of cell migration and spreading. In this paper, the mechanical structure of the cell is modeled as having two elastic membranes: an outer cell membrane and an inner nuclear membrane. The two elastic membranes are connected by SFs, which are extended from focal adhesions on the cortical surface to the nuclear membrane. In addition, the model also includes ventral SFs bridging two focal adhesions on the cell surface. The cell deforms and gains traction as transmembrane integrins distributed over the outer cell membrane bond to ligands on the ECM surface, activate SFs, and form focal adhesions. The relationship between the cell migration speed and fibronectin concentration agrees with existing experimental data for Chinese hamster ovary (CHO) cell migrations on fibronectin coated surfaces. In addition, the integrated model is validated by showing persistent high stress concentrations at sharp geometrically patterned edges. This model will be used as a predictive model to assist in design and data processing of upcoming microfluidic cell migration assays.'),
(85895, 2013, 'plos', 'No evidence for an item limit in change detection', 'Keshvari, Shaiyan|van den Berg, Ronald|Ma, Wei Ji', 'Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.', 'United States|United States|United States', 0, 'Adult|Bayes Theorem|Computational Biology|Female|Humans|Male|Memory, Short-Term|Models, Neurological|Photic Stimulation|Reproducibility of Results|Task Performance and Analysis', 'Journal Article', '10.1371/journal.pcbi.1002927', '23468613', 'Change detection is a classic paradigm that has been used for decades to argue that working memory can hold no more than a fixed number of items (item-limit models). Recent findings force us to consider the alternative view that working memory is limited by the precision in stimulus encoding, with mean precision decreasing with increasing set size (continuous-resource models). Most previous studies that used the change detection paradigm have ignored effects of limited encoding precision by using highly discriminable stimuli and only large changes. We conducted two change detection experiments (orientation and color) in which change magnitudes were drawn from a wide range, including small changes. In a rigorous comparison of five models, we found no evidence of an item limit. Instead, human change detection performance was best explained by a continuous-resource model in which encoding precision is variable across items and trials even at a given set size. This model accounts for comparison errors in a principled, probabilistic manner. Our findings sharply challenge the theoretical basis for most neural studies of working memory capacity.'),
(85896, 2013, 'plos', 'Extraction of sub-microscopic Ca fluxes from blurred and noisy fluorescent indicator images with a detailed model fitting approach', 'Kong, Cherrie H T|Laver, Derek R|Cannell, Mark B', 'Department of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom.|Department of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom.|Department of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Animals|Calcium|Calcium Signaling|Computer Simulation|Fluorescent Dyes|Intracellular Space|Male|Microscopy, Fluorescence|Models, Biological|Myocytes, Cardiac|Rats|Rats, Wistar|Sarcoplasmic Reticulum', 'Journal Article', '10.1371/journal.pcbi.1002931', '23468614', 'The release of Ca from intracellular stores is key to cardiac muscle function, however, the molecular control of intracellular Ca release remains unclear. Depletion of the intracellular Ca store (sarcoplasmic reticulum, SR) may play an important role, but the ability to measure local SR Ca with fluorescent Ca indicators is limited by the microscope optical resolution and properties of the indicator. This leads to an uncertain degree of spatio-temporal blurring, which is not easily corrected (by deconvolution methods) due to the low signal-to-noise ratio of the recorded signals. In this study, a 3D computer model was constructed to calculate local Ca fluxes and consequent dye signals, which were then blurred by a measured microscope point spread function. Parameter fitting was employed to adjust a release basis function until the model output fitted recorded (2D) Ca spark data. This forward method allowed us to obtain estimates of the time-course of Ca release flux and depletion within the sub-microscopic local SR associated with a number of Ca sparks. While variability in focal position relative to Ca spark sites causes more out-of-focus events to have smaller calculated fluxes (and less SR depletion), the average SR depletion was to 20±10% (s.d.) of the resting level. This focus problem implies that the actual SR depletion is likely to be larger and the five largest depletions analyzed were to 8±6% of the resting level. This profound depletion limits SR release flux during a Ca spark, which peaked at 8±3 pA and declined with a half time of 7±2 ms. By comparison, RyR open probability declined more slowly, suggesting release termination is dominated by neither SR Ca depletion nor intrinsic RyR gating, but results from an interaction of these processes.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85897, 2013, 'plos', 'A protein turnover signaling motif controls the stimulus-sensitivity of stress response pathways', 'Loriaux, Paul Michael|Hoffmann, Alexander', 'Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.|Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.', 'United States|United States', 0, 'Amino Acid Motifs|Animals|Cell Line|Computational Biology|Feedback, Physiological|Humans|Mice|Models, Biological|NF-kappa B|Signal Transduction|Tumor Necrosis Factor-alpha|Tumor Suppressor Protein p53', 'Journal Article', '10.1371/journal.pcbi.1002932', '23468615', 'Stimulus-induced perturbations from the steady state are a hallmark of signal transduction. In some signaling modules, the steady state is characterized by rapid synthesis and degradation of signaling proteins. Conspicuous among these are the p53 tumor suppressor, its negative regulator Mdm2, and the negative feedback regulator of NFxcexbaB, IxcexbaBxcexb1. We investigated the physiological importance of this turnover, or flux, using a computational method that allows flux to be systematically altered independently of the steady state protein abundances. Applying our method to a prototypical signaling module, we show that flux can precisely control the dynamic response to perturbation. Next, we applied our method to experimentally validated models of p53 and NFxcexbaB signaling. We find that high p53 flux is required for oscillations in response to a saturating dose of ionizing radiation (IR). In contrast, high flux of Mdm2 is not required for oscillations but preserves p53 sensitivity to sub-saturating doses of IR. In the NFxcexbaB system, degradation of NFxcexbaB-bound IxcexbaB by the IxcexbaB kinase (IKK) is required for activation in response to TNF, while high IKK-independent degradation prevents spurious activation in response to metabolic stress or low doses of TNF. Our work identifies flux pairs with opposing functional effects as a signaling motif that controls the stimulus-sensitivity of the p53 and NFxcexbaB stress-response pathways, and may constitute a general design principle in signaling pathways.'),
(85898, 2013, 'plos', 'Analysis of a gene regulatory cascade mediating circadian rhythm in zebrafish', 'Li, Ying|Li, Guang|Wang, Haifang|Du, Jiulin|Yan, Jun', 'CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.', 'China|China|China|China|China', 30, 'Animals|Circadian Rhythm|Circadian Rhythm Signaling Peptides and Proteins|Databases, Protein|Gene Regulatory Networks|Larva|Light|Melanins|Mice|Transcription Factors|Zebrafish|Zebrafish Proteins', 'Journal Article', '10.1371/journal.pcbi.1002940', '23468616', 'In the study of circadian rhythms, it has been a puzzle how a limited number of circadian clock genes can control diverse aspects of physiology. Here we investigate circadian gene expression genome-wide using larval zebrafish as a model system. We made use of a spatial gene expression atlas to investigate the expression of circadian genes in various tissues and cell types. Comparison of genome-wide circadian gene expression data between zebrafish and mouse revealed a nearly anti-phase relationship and allowed us to detect novel evolutionarily conserved circadian genes in vertebrates. We identified three groups of zebrafish genes with distinct responses to light entrainment: fast light-induced genes, slow light-induced genes, and dark-induced genes. Our computational analysis of the circadian gene regulatory network revealed several transcription factors (TFs) involved in diverse aspects of circadian physiology through transcriptional cascade. Of these, microphthalmia-associated transcription factor a (mitfa), a dark-induced TF, mediates a circadian rhythm of melanin synthesis, which may be involved in zebrafishs adaptation to daily light cycling. Our study describes a systematic method to discover previously unidentified TFs involved in circadian physiology in complex organisms.'),
(85899, 2013, 'plos', 'Interpretation of genomic variants using a unified biological network approach', 'Khurana, Ekta|Fu, Yao|Chen, Jieming|Gerstein, Mark', 'Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.', 'United States|United States|United States|United States', 0, 'Animals|Gene Regulatory Networks|Genomics|Humans|Logistic Models|Metabolic Networks and Pathways|Models, Genetic|Mutation|Pan troglodytes|Phosphorylation|Protein Interaction Maps|Reproducibility of Results|Sequence Analysis, DNA|Signal Transduction|Statistics, Nonparametric', 'Journal Article', '10.1371/journal.pcbi.1002886', '23505346', 'The decreasing cost of sequencing is leading to a growing repertoire of personal genomes. However, we are lagging behind in understanding the functional consequences of the millions of variants obtained from sequencing. Global system-wide effects of variants in coding genes are particularly poorly understood. It is known that while variants in some genes can lead to diseases, complete disruption of other genes, called loss-of-function tolerant, is possible with no obvious effect. Here, we build a systems-based classifier to quantitatively estimate the global perturbation caused by deleterious mutations in each gene. We first survey the degree to which gene centrality in various individual networks and a unified Multinet correlates with the tolerance to loss-of-function mutations and evolutionary conservation. We find that functionally significant and highly conserved genes tend to be more central in physical protein-protein and regulatory networks. However, this is not the case for metabolic pathways, where the highly central genes have more duplicated copies and are more tolerant to loss-of-function mutations. Integration of three-dimensional protein structures reveals that the correlation with centrality in the protein-protein interaction network is also seen in terms of the number of interaction interfaces used. Finally, combining all the network and evolutionary properties allows us to build a classifier distinguishing functionally essential and loss-of-function tolerant genes with higher accuracy (AUCxe2x80x8a=xe2x80x8a0.91) than any individual property. Application of the classifier to the whole genome shows its strong potential for interpretation of variants involved in mendelian diseases and in complex disorders probed by genome-wide association studies.'),
(85900, 2013, 'plos', 'Positively selected sites in cetacean myoglobins contribute to protein stability', 'Dasmeh, Pouria|Serohijos, Adrian W R|Kepp, Kasper P|Shakhnovich, Eugene I', 'Technical University of Denmark, DTU Chemistry, Kongens Lyngby, Denmark.|Technical University of Denmark, DTU Chemistry, Kongens Lyngby, Denmark.|Technical University of Denmark, DTU Chemistry, Kongens Lyngby, Denmark.|Technical University of Denmark, DTU Chemistry, Kongens Lyngby, Denmark.', 'Denmark|Denmark|Denmark|Denmark', 0, 'Adaptation, Biological|Animals|Bayes Theorem|Cetacea|Evolution, Molecular|Models, Genetic|Models, Molecular|Myoglobin|Phylogeny|Protein Folding|Protein Stability|Selection, Genetic|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.1002929', '23505347', 'Since divergence xe2x88xbc50 Ma ago from their terrestrial ancestors, cetaceans underwent a series of adaptations such as a xe2x88xbc10-20 fold increase in myoglobin (Mb) concentration in skeletal muscle, critical for increasing oxygen storage capacity and prolonging dive time. Whereas the O2-binding affinity of Mbs is not significantly different among mammals (with typical oxygenation constants of xe2x88xbc0.8-1.2 xc2xb5M(-1)), folding stabilities of cetacean Mbs are xe2x88xbc2-4 kcal/mol higher than for terrestrial Mbs. Using ancestral sequence reconstruction, maximum likelihood and bayesian tests to describe the evolution of cetacean Mbs, and experimentally calibrated computation of stability effects of mutations, we observe accelerated evolution in cetaceans and identify seven positively selected sites in Mb. Overall, these sites contribute to Mb stabilization with a conditional probability of 0.8. We observe a correlation between Mb folding stability and protein abundance, suggesting that a selection pressure for stability acts proportionally to higher expression. We also identify a major divergence event leading to the common ancestor of whales, during which major stabilization occurred. Most of the positively selected sites that occur later act against other destabilizing mutations to maintain stability across the clade, except for the shallow divers, where late stability relaxation occurs, probably due to the shorter aerobic dive limits of these species. The three main positively selected sites 66, 5, and 35 undergo changes that favor hydrophobic folding, structural integrity, and intra-helical hydrogen bonds.'),
(85901, 2013, 'plos', 'High prevalence of multistability of rest states and bursting in a database of a model neuron', 'Marin, Bóris|Barnett, William H|Doloc-Mihu, Anca|Calabrese, Ronald L|Cymbalyuk, Gennady S', 'Instituto de Física, Universidade de São Paulo, São Paulo, São Paulo, Brazil.|Instituto de Física, Universidade de São Paulo, São Paulo, São Paulo, Brazil.|Instituto de Física, Universidade de São Paulo, São Paulo, São Paulo, Brazil.|Instituto de Física, Universidade de São Paulo, São Paulo, São Paulo, Brazil.|Instituto de Física, Universidade de São Paulo, São Paulo, São Paulo, Brazil.', 'Brazil|Brazil|Brazil|Brazil|Brazil', 13, 'Action Potentials|Animals|Cell Survival|Computer Simulation|Databases, Factual|Heart|Interneurons|Leeches|Models, Neurological|Myocardium|Synapses', 'Journal Article', '10.1371/journal.pcbi.1002930', '23505348', 'Flexibility in neuronal circuits has its roots in the dynamical richness of their neurons. Depending on their membrane properties single neurons can produce a plethora of activity regimes including silence, spiking and bursting. What is less appreciated is that these regimes can coexist with each other so that a transient stimulus can cause persistent change in the activity of a given neuron. Such multistability of the neuronal dynamics has been shown in a variety of neurons under different modulatory conditions. It can play either a functional role or present a substrate for dynamical diseases. We considered a database of an isolated leech heart interneuron model that can display silent, tonic spiking and bursting regimes. We analyzed only the cases of endogenous bursters producing functional half-center oscillators (HCOs). Using a one parameter (the leak conductance (g(leak)) bifurcation analysis, we extended the database to include silent regimes (stationary states) and systematically classified cases for the coexistence of silent and bursting regimes. We showed that different cases could exhibit two stable depolarized stationary states and two hyperpolarized stationary states in addition to various spiking and bursting regimes. We analyzed all cases of endogenous bursters and found that 18% of the cases were multistable, exhibiting coexistences of stationary states and bursting. Moreover, 91% of the cases exhibited multistability in some range of g(leak). We also explored HCOs built of multistable neuron cases with coexisting stationary states and a bursting regime. In 96% of cases analyzed, the HCOs resumed normal alternating bursting after one of the neurons was reset to a stationary state, proving themselves robust against this perturbation.'),
(85902, 2013, 'plos', 'Dual coordination of post translational modifications in human protein networks', 'Woodsmith, Jonathan|Kamburov, Atanas|Stelzl, Ulrich', 'Otto-Warburg Laboratory, Max Planck Institute for Molecular Genetics (MPIMG), Berlin, Germany. woodsmit@molgen.mpg.de|Otto-Warburg Laboratory, Max Planck Institute for Molecular Genetics (MPIMG), Berlin, Germany. woodsmit@molgen.mpg.de|Otto-Warburg Laboratory, Max Planck Institute for Molecular Genetics (MPIMG), Berlin, Germany. woodsmit@molgen.mpg.de', 'Germany|Germany|Germany', 0, 'Databases, Protein|Humans|Multiprotein Complexes|Protein Interaction Maps|Protein Processing, Post-Translational|Protein Structure, Tertiary|Proteins|Proteomics', 'Journal Article', '10.1371/journal.pcbi.1002933', '23505349', 'Post-translational modifications (PTMs) regulate protein activity, stability and interaction profiles and are critical for cellular functioning. Further regulation is gained through PTM interplay whereby modifications modulate the occurrence of other PTMs or act in combination. Integration of global acetylation, ubiquitination and tyrosine or serine/threonine phosphorylation datasets with protein interaction data identified hundreds of protein complexes that selectively accumulate each PTM, indicating coordinated targeting of specific molecular functions. A second layer of PTM coordination exists in these complexes, mediated by PTM integration (PTMi) spots. PTMi spots represent very dense modification patterns in disordered protein regions and showed an equally high mutation rate as functional protein domains in cancer, inferring equivocal importance for cellular functioning. Systematic PTMi spot identification highlighted more than 300 candidate proteins for combinatorial PTM regulation. This study reveals two global PTM coordination mechanisms and emphasizes dataset integration as requisite in proteomic PTM studies to better predict modification impact on cellular signaling.'),
(85903, 2013, 'plos', 'Measurements of the impact of 3 end sequences on gene expression reveal wide range and sequence dependent effects', 'Shalem, Ophir|Carey, Lucas|Zeevi, Danny|Sharon, Eilon|Keren, Leeat|Weinberger, Adina|Dahan, Orna|Pilpel, Yitzhak|Segal, Eran', 'Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel|Israel|Israel|Israel|Israel|Israel|Israel|Israel', 19, '3 Untranslated Regions|Base Composition|Computational Biology|Gene Expression Regulation, Fungal|Genes, Fungal|Genes, Reporter|Poly A|Promoter Regions, Genetic|RNA, Messenger|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1002934', '23505350', 'A full understanding of gene regulation requires an understanding of the contributions that the various regulatory regions have on gene expression. Although it is well established that sequences downstream of the main promoter can affect expression, our understanding of the scale of this effect and how it is encoded in the DNA is limited. Here, to measure the effect of native S. cerevisiae 3 end sequences on expression, we constructed a library of 85 fluorescent reporter strains that differ only in their 3 end region. Notably, despite being driven by the same strong promoter, our library spans a continuous twelve-fold range of expression values. These measurements correlate with endogenous mRNA levels, suggesting that the 3 end contributes to constitutive differences in mRNA levels. We used deep sequencing to map the 3UTR ends of our strains and show that determination of polyadenylation sites is intrinsic to the local 3 end sequence. Polyadenylation mapping was followed by sequence analysis, we found that increased A/T content upstream of the main polyadenylation site correlates with higher expression, both in the library and genome-wide, suggesting that native genes differ by the encoded efficiency of 3 end processing. Finally, we use single cells fluorescence measurements, in different promoter activation levels, to show that 3 end sequences modulate protein expression dynamics differently than promoters, by predominantly affecting the size of protein production bursts as opposed to the frequency at which these bursts occur. Altogether, our results lead to a more complete understanding of gene regulation by demonstrating that 3 end regions have a unique and sequence dependent effect on gene expression.'),
(85904, 2013, 'plos', 'Comparative RNA-seq analysis in the unsequenced axolotl: the oncogene burst highlights early gene expression in the blastema', 'Stewart, Ron|Rascón, Cynthia Alexander|Tian, Shulan|Nie, Jeff|Barry, Chris|Chu, Li-Fang|Ardalani, Hamisha|Wagner, Ryan J|Probasco, Mitchell D|Bolin, Jennifer M|Leng, Ning|Sengupta, Srikumar|Volkmer, Michael|Habermann, Bianca|Tanaka, Elly M|Thomson, James A|Dewey, Colin N', 'Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org|Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org|Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org|Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org|Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org|Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org|Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org|Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org|Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org|Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org|Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org|Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org|Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org|Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org|Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org|Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org|Regenerative Biology, Morgridge Institute for Research, Madison, Wisconsin, United States of America. rstewart@morgridgeinstitute.org', 'United States|United States|United States|United States|United States|United States|United States|Un', 72, 'Ambystoma mexicanum|Amputation|Animals|Cluster Analysis|Extremities|Gene Expression Profiling|Gene Expression Regulation|Oncogenes|Regeneration|Sequence Analysis, RNA|Up-Regulation|Wound Healing', 'Journal Article', '10.1371/journal.pcbi.1002936', '23505351', 'The salamander has the remarkable ability to regenerate its limb after amputation. Cells at the site of amputation form a blastema and then proliferate and differentiate to regrow the limb. To better understand this process, we performed deep RNA sequencing of the blastema over a time course in the axolotl, a species whose genome has not been sequenced. Using a novel comparative approach to analyzing RNA-seq data, we characterized the transcriptional dynamics of the regenerating axolotl limb with respect to the human gene set. This approach involved de novo assembly of axolotl transcripts, RNA-seq transcript quantification without a reference genome, and transformation of abundances from axolotl contigs to human genes. We found a prominent burst in oncogene expression during the first day and blastemal/limb bud genes peaking at 7 to 14 days. In addition, we found that limb patterning genes, SALL genes, and genes involved in angiogenesis, wound healing, defense/immunity, and bone development are enriched during blastema formation and development. Finally, we identified a category of genes with no prior literature support for limb regeneration that are candidates for further evaluation based on their expression pattern during the regenerative process.'),
(85905, 2013, 'plos', 'Trade-off between multiple constraints enables simultaneous formation of modules and hubs in neural systems', 'Chen, Yuhan|Wang, Shengjun|Hilgetag, Claus C|Zhou, Changsong', 'Department of Physics, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.|Department of Physics, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.|Department of Physics, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.|Department of Physics, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.', 'China|China|China|China', 0, 'Animals|Brain|Caenorhabditis elegans|Cluster Analysis|Macaca|Models, Neurological|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.1002937', '23505352', 'The formation of the complex network architecture of neural systems is subject to multiple structural and functional constraints. Two obvious but apparently contradictory constraints are low wiring cost and high processing efficiency, characterized by short overall wiring length and a small average number of processing steps, respectively. Growing evidence shows that neural networks are results from a trade-off between physical cost and functional value of the topology. However, the relationship between these competing constraints and complex topology is not well understood quantitatively. We explored this relationship systematically by reconstructing two known neural networks, Macaque cortical connectivity and C. elegans neuronal connections, from combinatory optimization of wiring cost and processing efficiency constraints, using a control parameter xcexb1, and comparing the reconstructed networks to the real networks. We found that in both neural systems, the reconstructed networks derived from the two constraints can reveal some important relations between the spatial layout of nodes and the topological connectivity, and match several properties of the real networks. The reconstructed and real networks had a similar modular organization in a broad range of xcexb1, resulting from spatial clustering of network nodes. Hubs emerged due to the competition of the two constraints, and their positions were close to, and partly coincided, with the real hubs in a range of xcexb1 values. The degree of nodes was correlated with the density of nodes in their spatial neighborhood in both reconstructed and real networks. Generally, the rebuilt network matched a significant portion of real links, especially short-distant ones. These findings provide clear evidence to support the hypothesis of trade-off between multiple constraints on brain networks. The two constraints of wiring cost and processing efficiency, however, cannot explain all salient features in the real networks. The discrepancy suggests that there are further relevant factors that are not yet captured here.'),
(85906, 2013, 'plos', 'A simple iterative model accurately captures complex trapline formation by bumblebees across spatial scales and flower arrangements', 'Reynolds, Andrew M|Lihoreau, Mathieu|Chittka, Lars', 'Rothamsted Research, Harpenden, Hertfordshire, United Kingdom. andy.reynolds@rothamsted.ac.uk|Rothamsted Research, Harpenden, Hertfordshire, United Kingdom. andy.reynolds@rothamsted.ac.uk|Rothamsted Research, Harpenden, Hertfordshire, United Kingdom. andy.reynolds@rothamsted.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Animals|Appetitive Behavior|Bees|Computational Biology|Databases, Factual|Flight, Animal|Flowers|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002938', '23505353', 'Pollinating bees develop foraging circuits (traplines) to visit multiple flowers in a manner that minimizes overall travel distance, a task analogous to the travelling salesman problem. We report on an in-depth exploration of an iterative improvement heuristic model of bumblebee traplining previously found to accurately replicate the establishment of stable routes by bees between flowers distributed over several hectares. The critical test for a model is its predictive power for empirical data for which the model has not been specifically developed, and here the model is shown to be consistent with observations from different research groups made at several spatial scales and using multiple configurations of flowers. We refine the model to account for the spatial search strategy of bees exploring their environment, and test several previously unexplored predictions. We find that the model predicts accurately 1) the increasing propensity of bees to optimize their foraging routes with increasing spatial scale, 2) that bees cannot establish stable optimal traplines for all spatial configurations of rewarding flowers, 3) the observed trade-off between travel distance and prioritization of high-reward sites (with a slight modification of the model), 4) the temporal pattern with which bees acquire approximate solutions to travelling salesman-like problems over several dozen foraging bouts, 5) the instability of visitation schedules in some spatial configurations of flowers, 6) the observation that in some flower arrays, bees visitation schedules are highly individually different, 7) the searching behaviour that leads to efficient location of flowers and routes between them. Our model constitutes a robust theoretical platform to generate novel hypotheses and refine our understanding about how small-brained insects develop a representation of space and use it to navigate in complex and dynamic environments.'),
(85907, 2013, 'plos', 'Noise-invariant neurons in the avian auditory cortex: hearing the song in noise', 'Moore, R Channing|Lee, Tyler|Theunissen, Frédéric E', 'Biophysics Graduate Group, University of California, Berkeley, Berkeley, California, United States of America.|Biophysics Graduate Group, University of California, Berkeley, Berkeley, California, United States of America.|Biophysics Graduate Group, University of California, Berkeley, Berkeley, California, United States of America.', 'United States|United States|United States', 0, 'Acoustic Stimulation|Animals|Auditory Cortex|Auditory Perception|Computational Biology|Finches|Models, Neurological|Music|Noise|Signal Processing, Computer-Assisted|Signal-To-Noise Ratio', 'Journal Article', '10.1371/journal.pcbi.1002942', '23505354', 'Given the extraordinary ability of humans and animals to recognize communication signals over a background of noise, describing noise invariant neural responses is critical not only to pinpoint the brain regions that are mediating our robust perceptions but also to understand the neural computations that are performing these tasks and the underlying circuitry. Although invariant neural responses, such as rotation-invariant face cells, are well described in the visual system, high-level auditory neurons that can represent the same behaviorally relevant signal in a range of listening conditions have yet to be discovered. Here we found neurons in a secondary area of the avian auditory cortex that exhibit noise-invariant responses in the sense that they responded with similar spike patterns to song stimuli presented in silence and over a background of naturalistic noise. By characterizing the neurons tuning in terms of their responses to modulations in the temporal and spectral envelope of the sound, we then show that noise invariance is partly achieved by selectively responding to long sounds with sharp spectral structure. Finally, to demonstrate that such computations could explain noise invariance, we designed a biologically inspired noise-filtering algorithm that can be used to separate song or speech from noise. This novel noise-filtering method performs as well as other state-of-the-art de-noising algorithms and could be used in clinical or consumer oriented applications. Our biologically inspired model also shows how high-level noise-invariant responses could be created from neural responses typically found in primary auditory cortex.'),
(85908, 2013, 'plos', 'Embedding responses in spontaneous neural activity shaped through sequential learning', 'Kurikawa, Tomoki|Kaneko, Kunihiko', 'Graduate School of Arts and Sciences, University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo, Japan. kurikawa@complex.c.u-tokyo.ac.jp|Graduate School of Arts and Sciences, University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo, Japan. kurikawa@complex.c.u-tokyo.ac.jp', 'Japan|Japan', 8, 'Computational Biology|Learning|Memory|Models, Neurological|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.1002943', '23505355', 'Recent experimental measurements have demonstrated that spontaneous neural activity in the absence of explicit external stimuli has remarkable spatiotemporal structure. This spontaneous activity has also been shown to play a key role in the response to external stimuli. To better understand this role, we proposed a viewpoint, memories-as-bifurcations, that differs from the traditional memories-as-attractors viewpoint. Memory recall from the memories-as-bifurcations viewpoint occurs when the spontaneous neural activity is changed to an appropriate output activity upon application of an input, known as a bifurcation in dynamical systems theory, wherein the input modifies the flow structure of the neural dynamics. Learning, then, is a process that helps create neural dynamical systems such that a target output pattern is generated as an attractor upon a given input. Based on this novel viewpoint, we introduce in this paper an associative memory model with a sequential learning process. Using a simple hebbian-type learning, the model is able to memorize a large number of input/output mappings. The neural dynamics shaped through the learning exhibit different bifurcations to make the requested targets stable upon an increase in the input, and the neural activity in the absence of input shows chaotic dynamics with occasional approaches to the memorized target patterns. These results suggest that these dynamics facilitate the bifurcations to each target attractor upon application of the corresponding input, which thus increases the capacity for learning. This theoretical finding about the behavior of the spontaneous neural activity is consistent with recent experimental observations in which the neural activity without stimuli wanders among patterns evoked by previously applied signals. In addition, the neural networks shaped by learning properly reflect the correlations of input and target-output patterns in a similar manner to those designed in our previous study.'),
(85909, 2013, 'plos', 'Collective cell motion in an epithelial sheet can be quantitatively described by a stochastic interacting particle model', 'Sepúlveda, Néstor|Petitjean, Laurence|Cochet, Olivier|Grasland-Mongrain, Erwan|Silberzan, Pascal|Hakim, Vincent', 'Laboratoire de Physique Statistique, CNRS, Université P et M Curie, Ecole Normale Supérieure, Paris, France. nesepulv@gmail.com|Laboratoire de Physique Statistique, CNRS, Université P et M Curie, Ecole Normale Supérieure, Paris, France. nesepulv@gmail.com|Laboratoire de Physique Statistique, CNRS, Université P et M Curie, Ecole Normale Supérieure, Paris, France. nesepulv@gmail.com|Laboratoire de Physique Statistique, CNRS, Université P et M Curie, Ecole Normale Supérieure, Paris, France. nesepulv@gmail.com|Laboratoire de Physique Statistique, CNRS, Université P et M Curie, Ecole Normale Supérieure, Paris, France. nesepulv@gmail.com|Laboratoire de Physique Statistique, CNRS, Université P et M Curie, Ecole Normale Supérieure, Paris, France. nesepulv@gmail.com', 'France|France|France|France|France|France', 119, 'Animals|Cell Movement|Computer Simulation|Dogs|Epithelial Cells|Epithelium|Madin Darby Canine Kidney Cells|Models, Biological|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002944', '23505356', 'Modelling the displacement of thousands of cells that move in a collective way is required for the simulation and the theoretical analysis of various biological processes. Here, we tackle this question in the controlled setting where the motion of Madin-Darby Canine Kidney (MDCK) cells in a confluent epithelium is triggered by the unmasking of free surface. We develop a simple model in which cells are described as point particles with a dynamic based on the two premises that, first, cells move in a stochastic manner and, second, tend to adapt their motion to that of their neighbors. Detailed comparison to experimental data show that the model provides a quantitatively accurate description of cell motion in the epithelium bulk at early times. In addition, inclusion of model leader cells with modified characteristics, accounts for the digitated shape of the interface which develops over the subsequent hours, providing that leader cells invade free surface more easily than other cells and coordinate their motion with their followers. The previously-described progression of the epithelium border is reproduced by the model and quantitatively explained.'),
(85910, 2013, 'plos', 'Policy resistance undermines superspreader vaccination strategies for influenza', 'Wells, Chad R|Klein, Eili Y|Bauch, Chris T', 'Department of Mathematics and Statistics, University of Guelph, Guelph, Ontario, Canada. cwells01@uoguelph.ca|Department of Mathematics and Statistics, University of Guelph, Guelph, Ontario, Canada. cwells01@uoguelph.ca|Department of Mathematics and Statistics, University of Guelph, Guelph, Ontario, Canada. cwells01@uoguelph.ca', 'Canada|Canada|Canada', 0, 'Computational Biology|Computer Simulation|Disease Outbreaks|Health Behavior|Health Knowledge, Attitudes, Practice|Humans|Influenza Vaccines|Influenza, Human|Models, Theoretical|Patient Acceptance of Health Care|Vaccination', 'Journal Article', '10.1371/journal.pcbi.1002945', '23505357', 'Theoretical models of infection spread on networks predict that targeting vaccination at individuals with a very large number of contacts (superspreaders) can reduce infection incidence by a significant margin. These models generally assume that superspreaders will always agree to be vaccinated. Hence, they cannot capture unintended consequences such as policy resistance, where the behavioral response induced by a new vaccine policy tends to reduce the expected benefits of the policy. Here, we couple a model of influenza transmission on an empirically-based contact network with a psychologically structured model of influenza vaccinating behavior, where individual vaccinating decisions depend on social learning and past experiences of perceived infections, vaccine complications and vaccine failures. We find that policy resistance almost completely undermines the effectiveness of superspreader strategies: the most commonly explored approaches that target a randomly chosen neighbor of an individual, or that preferentially choose neighbors with many contacts, provide at best a 2% relative improvement over their non-targeted counterpart as compared to 12% when behavioral feedbacks are ignored. Increased vaccine coverage in super spreaders is offset by decreased coverage in non-superspreaders, and superspreaders also have a higher rate of perceived vaccine failures on account of being infected more often. Including incentives for vaccination provides modest improvements in outcomes. We conclude that the design of influenza vaccine strategies involving widespread incentive use and/or targeting of superspreaders should account for policy resistance, and mitigate it whenever possible.'),
(85911, 2013, 'plos', 'Split histidine kinases enable ultrasensitivity and bistability in two-component signaling networks', 'Amin, Munia|Porter, Steven L|Soyer, Orkun S', 'Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom|Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom|Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom', 'United Kingdom|United Kingdom|United Kingdom', 12, 'Bacterial Proteins|Enzyme Stability|Histidine Kinase|Models, Biological|Phosphoric Monoester Hydrolases|Phosphorylation|Protein Kinases|Recombinant Proteins|Rhodobacter sphaeroides|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002949', '23505358', 'Bacteria sense and respond to their environment through signaling cascades generally referred to as two-component signaling networks. These networks comprise histidine kinases and their cognate response regulators. Histidine kinases have a number of biochemical activities: ATP binding, autophosphorylation, the ability to act as a phosphodonor for their response regulators, and in many cases the ability to catalyze the hydrolytic dephosphorylation of their response regulator. Here, we explore the functional role of split kinases where the ATP binding and phosphotransfer activities of a conventional histidine kinase are split onto two distinct proteins that form a complex. We find that this unusual configuration can enable ultrasensitivity and bistability in the signal-response relationship of the resulting system. These dynamics are displayed under a wide parameter range but only when specific biochemical requirements are met. We experimentally show that one of these requirements, namely segregation of the phosphatase activity predominantly onto the free form of one of the proteins making up the split kinase, is met in Rhodobacter sphaeroides. These findings indicate split kinases as a bacterial alternative for enabling ultrasensitivity and bistability in signaling networks. Genomic analyses reveal that up 1.7% of all identified histidine kinases have the potential to be split and bifunctional.'),
(85912, 2013, 'plos', 'Lipid tail protrusion in simulations predicts fusogenic activity of influenza fusion peptide mutants and conformational models', 'Larsson, Per|Kasson, Peter M', 'Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, United States of America.|Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, United States of America.', 'United States|United States', 50, 'Hemagglutinin Glycoproteins, Influenza Virus|Lipid Bilayers|Molecular Dynamics Simulation|Mutation|Peptides|Protein Binding|Protein Conformation|Recombinant Proteins|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002950', '23505359', 'Fusion peptides from influenza hemagglutinin act on membranes to promote membrane fusion, but the mechanism by which they do so remains unknown. Recent theoretical work has suggested that contact of protruding lipid tails may be an important feature of the transition state for membrane fusion. If this is so, then influenza fusion peptides would be expected to promote tail protrusion in proportion to the ability of the corresponding full-length hemagglutinin to drive lipid mixing in fusion assays. We have performed molecular dynamics simulations of influenza fusion peptides in lipid bilayers, comparing the X-31 influenza strain against a series of N-terminal mutants. As hypothesized, the probability of lipid tail protrusion correlates well with the lipid mixing rate induced by each mutant. This supports the conclusion that tail protrusion is important to the transition state for fusion. Furthermore, it suggests that tail protrusion can be used to examine how fusion peptides might interact with membranes to promote fusion. Previous models for native influenza fusion peptide structure in membranes include a kinked helix, a straight helix, and a helical hairpin. Our simulations visit each of these conformations. Thus, the free energy differences between each are likely low enough that specifics of the membrane environment and peptide construct may be sufficient to modulate the equilibrium between them. However, the kinked helix promotes lipid tail protrusion in our simulations much more strongly than the other two structures. We therefore predict that the kinked helix is the most fusogenic of these three conformations.'),
(85913, 2013, 'plos', 'Druggable protein interaction sites are more predisposed to surface pocket formation than the rest of the protein surface', 'Johnson, David K|Karanicolas, John', 'Center for Bioinformatics, University of Kansas, Lawrence, Kansas, United States of America.|Center for Bioinformatics, University of Kansas, Lawrence, Kansas, United States of America.', 'United States|United States', 0, 'Binding Sites|Computational Biology|Computer Simulation|Drug Discovery|Inhibitor of Apoptosis Proteins|Models, Molecular|Protein Conformation|Protein Structure, Tertiary|Proteins|Structure-Activity Relationship|Surface Properties|bcl-X Protein', 'Journal Article', '10.1371/journal.pcbi.1002951', '23505360', 'Despite intense interest and considerable effort via high-throughput screening, there are few examples of small molecules that directly inhibit protein-protein interactions. This suggests that many protein interaction surfaces may not be intrinsically druggable by small molecules, and elevates in importance the few successful examples as model systems for improving our fundamental understanding of druggability. Here we describe an approach for exploring protein fluctuations enriched in conformations containing surface pockets suitable for small molecule binding. Starting from a set of seven unbound protein structures, we find that the presence of low-energy pocket-containing conformations is indeed a signature of druggable protein interaction sites and that analogous surface pockets are not formed elsewhere on the protein. We further find that ensembles of conformations generated with this biased approach structurally resemble known inhibitor-bound structures more closely than equivalent ensembles of unbiased conformations. Collectively these results suggest that druggability is a property encoded on a protein surface through its propensity to form pockets, and inspire a model in which the crude features of the predisposed pocket(s) restrict the range of complementary ligands, additional smaller conformational changes then respond to details of a particular ligand. We anticipate that the insights described here will prove useful in selecting protein targets for therapeutic intervention.'),
(85914, 2013, 'plos', 'Dissection of regulatory networks that are altered in disease via differential co-expression', 'Amar, David|Safer, Hershel|Shamir, Ron', 'Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.|Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.|Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.', 'Israel|Israel|Israel', 70, 'Algorithms|Cluster Analysis|Communicable Diseases|Computational Biology|Databases, Genetic|Gene Expression Profiling|Gene Regulatory Networks|Humans|Inflammatory Bowel Diseases|MicroRNAs|Models, Biological|Neoplasms|Neurodegenerative Diseases|Protein Interaction Maps', 'Journal Article', '10.1371/journal.pcbi.1002955', '23505361', 'Comparing the gene-expression profiles of sick and healthy individuals can help in understanding disease. Such differential expression analysis is a well-established way to find gene sets whose expression is altered in the disease. Recent approaches to gene-expression analysis go a step further and seek differential co-expression patterns, wherein the level of co-expression of a set of genes differs markedly between disease and control samples. Such patterns can arise from a disease-related change in the regulatory mechanism governing that set of genes, and pinpoint dysfunctional regulatory networks. Here we present DICER, a new method for detecting differentially co-expressed gene sets using a novel probabilistic score for differential correlation. DICER goes beyond standard differential co-expression and detects pairs of modules showing differential co-expression. The expression profiles of genes within each module of the pair are correlated across all samples. The correlation between the two modules, however, differs markedly between the disease and normal samples. We show that DICER outperforms the state of the art in terms of significance and interpretability of the detected gene sets. Moreover, the gene sets discovered by DICER manifest regulation by disease-specific microRNA families. In a case study on Alzheimers disease, DICER dissected biological processes and protein complexes into functional subunits that are differentially co-expressed, thereby revealing inner structures in disease regulatory networks.'),
(85915, 2013, 'plos', 'Integrative analysis using module-guided random forests reveals correlated genetic factors related to mouse weight', 'Chen, Zheng|Zhang, Weixiong', 'Department of Computer Science and Engineering, Washington University, St. Louis, Missouri, United States of America.|Department of Computer Science and Engineering, Washington University, St. Louis, Missouri, United States of America.', 'United States|United States', 18, 'Algorithms|Animals|Artificial Intelligence|Body Weight|Computational Biology|Decision Trees|Female|Mice|Models, Genetic|Obesity', 'Journal Article', '10.1371/journal.pcbi.1002956', '23505362', 'Complex traits such as obesity are manifestations of intricate interactions of multiple genetic factors. However, such relationships are difficult to identify. Thanks to the recent advance in high-throughput technology, a large amount of data has been collected for various complex traits, including obesity. These data often measure different biological aspects of the traits of interest, including genotypic variations at the DNA level and gene expression alterations at the RNA level. Integration of such heterogeneous data provides promising opportunities to understand the genetic components and possibly genetic architecture of complex traits. In this paper, we propose a machine learning based method, module-guided Random Forests (mgRF), to integrate genotypic and gene expression data to investigate genetic factors and molecular mechanism underlying complex traits. mgRF is an augmented Random Forests method enhanced by a network analysis for identifying multiple correlated variables of different types. We applied mgRF to genetic markers and gene expression data from a cohort of F2 female mouse intercross. mgRF outperformed several existing methods in our extensive comparison. Our new approach has an improved performance when combining both genotypic and gene expression data compared to using either one of the two types of data alone. The resulting predictive variables identified by mgRF provide information of perturbed pathways that are related to body weight. More importantly, the results uncovered intricate interactions among genetic markers and genes that have been overlooked if only one type of data was examined. Our results shed light on genetic mechanisms of obesity and our approach provides a promising complementary framework to the genetics of gene expression analysis for integrating genotypic and gene expression information for analyzing complex traits.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85916, 2013, 'plos', 'Characterizing the relationship between steady state and response using analytical expressions for the steady states of mass action models', 'Loriaux, Paul Michael|Tesler, Glenn|Hoffmann, Alexander', 'Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.|Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.|Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.', 'United States|United States|United States', 7, 'Antineoplastic Agents|Caspase 8|Cell Death|Computational Biology|HeLa Cells|Humans|Kinetics|Models, Biological|Signal Transduction|TNF-Related Apoptosis-Inducing Ligand', 'Journal Article', '10.1371/journal.pcbi.1002901', '23509437', 'The steady states of cells affect their response to perturbation. Indeed, diagnostic markers for predicting the response to therapeutic perturbation are often based on steady state measurements. In spite of this, no method exists to systematically characterize the relationship between steady state and response. Mathematical models are established tools for studying cellular responses, but characterizing their relationship to the steady state requires that it have a parametric, or analytical, expression. For some models, this expression can be derived by the King-Altman method. However, King-Altman requires that no substrate act as an enzyme, and is therefore not applicable to most models of signal transduction. For this reason we developed py-substitution, a simple but general method for deriving analytical expressions for the steady states of mass action models. Where the King-Altman method is applicable, we show that py-substitution yields an equivalent expression, and at comparable efficiency. We use py-substitution to study the relationship between steady state and sensitivity to the anti-cancer drug candidate, dulanermin (recombinant human TRAIL). First, we use py-substitution to derive an analytical expression for the steady state of a published model of TRAIL-induced apoptosis. Next, we show that the amount of TRAIL required for cell death is sensitive to the steady state concentrations of procaspase 8 and its negative regulator, Bar, but not the other procaspase molecules. This suggests that activation of caspase 8 is a critical point in the death decision process. Finally, we show that changes in the threshold at which TRAIL results in cell death is not always equivalent to changes in the time of death, as is commonly assumed. Our work demonstrates that an analytical expression is a powerful tool for identifying steady state determinants of the cellular response to perturbation. All code is available at http://signalingsystems.ucsd.edu/models-and-code/ or as supplementary material accompanying this paper.'),
(85917, 2013, 'plos', 'Stimulus-dependent maximum entropy models of neural population codes', 'Granot-Atedgi, Einat|Tkaxc4x8dik, Gaxc5xa1per|Segev, Ronen|Schneidman, Elad', 'Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.|Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.|Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.|Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel|Israel|Israel', 41, 'Action Potentials|Ambystoma|Animals|Cluster Analysis|Computational Biology|Electrophysiology|Entropy|Linear Models|Models, Neurological|Nonlinear Dynamics|Photic Stimulation|Retina|Retinal Ganglion Cells', 'Journal Article', '10.1371/journal.pcbi.1002922', '23516339', 'Neural populations encode information about their stimulus in a collective fashion, by joint activity patterns of spiking and silence. A full account of this mapping from stimulus to neural activity is given by the conditional probability distribution over neural codewords given the sensory input. For large populations, direct sampling of these distributions is impossible, and so we must rely on constructing appropriate models. We show here that in a population of 100 retinal ganglion cells in the salamander retina responding to temporal white-noise stimuli, dependencies between cells play an important encoding role. We introduce the stimulus-dependent maximum entropy (SDME) model-a minimal extension of the canonical linear-nonlinear model of a single neuron, to a pairwise-coupled neural population. We find that the SDME model gives a more accurate account of single cell responses and in particular significantly outperforms uncoupled models in reproducing the distributions of population codewords emitted in response to a stimulus. We show how the SDME model, in conjunction with static maximum entropy models of population vocabulary, can be used to estimate information-theoretic quantities like average surprise and information transmission in a neural population.'),
(85918, 2013, 'plos', 'Modelling the emergence and dynamics of perceptual organisation in auditory streaming', 'Mill, Robert W|Bxc5x91hm, Tamxc3xa1s M|Bendixen, Alexandra|Winkler, Istvxc3xa1n|Denham, Susan L', 'MRC Institute of Hearing Research, Nottingham, United Kingdom.|MRC Institute of Hearing Research, Nottingham, United Kingdom.|MRC Institute of Hearing Research, Nottingham, United Kingdom.|MRC Institute of Hearing Research, Nottingham, United Kingdom.|MRC Institute of Hearing Research, Nottingham, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 45, 'Acoustic Stimulation|Adolescent|Adult|Algorithms|Auditory Perception|Computer Simulation|Female|Humans|Male|Models, Neurological|Models, Statistical|Sound', 'Journal Article', '10.1371/journal.pcbi.1002925', '23516340', 'Many sound sources can only be recognised from the pattern of sounds they emit, and not from the individual sound events that make up their emission sequences. Auditory scene analysis addresses the difficult task of interpreting the sound world in terms of an unknown number of discrete sound sources (causes) with possibly overlapping signals, and therefore of associating each event with the appropriate source. There are potentially many different ways in which incoming events can be assigned to different causes, which means that the auditory system has to choose between them. This problem has been studied for many years using the auditory streaming paradigm, and recently it has become apparent that instead of making one fixed perceptual decision, given sufficient time, auditory perception switches back and forth between the alternatives-a phenomenon known as perceptual bi- or multi-stability. We propose a new model of auditory scene analysis at the core of which is a process that seeks to discover predictable patterns in the ongoing sound sequence. Representations of predictable fragments are created on the fly, and are maintained, strengthened or weakened on the basis of their predictive success, and conflict with other representations. Auditory perceptual organisation emerges spontaneously from the nature of the competition between these representations. We present detailed comparisons between the model simulations and data from an auditory streaming experiment, and show that the model accounts for many important findings, including: the emergence of, and switching between, alternative organisations, the influence of stimulus parameters on perceptual dominance, switching rate and perceptual phase durations, and the build-up of auditory streaming. The principal contribution of the model is to show that a two-stage process of pattern discovery and competition between incompatible patterns can account for both the contents (perceptual organisations) and the dynamics of human perception in auditory streaming.'),
(85919, 2013, 'plos', 'Detecting DNA modifications from SMRT sequencing data by modeling sequence context dependence of polymerase kinetic', 'Feng, Zhixing|Fang, Gang|Korlach, Jonas|Clark, Tyson|Luong, Khai|Zhang, Xuegong|Wong, Wing|Schadt, Eric', 'Tsinghua National Laboratory for Information Science and Technology, and Department of Automation, Tsinghua University, Beijing, China.|Tsinghua National Laboratory for Information Science and Technology, and Department of Automation, Tsinghua University, Beijing, China.|Tsinghua National Laboratory for Information Science and Technology, and Department of Automation, Tsinghua University, Beijing, China.|Tsinghua National Laboratory for Information Science and Technology, and Department of Automation, Tsinghua University, Beijing, China.|Tsinghua National Laboratory for Information Science and Technology, and Department of Automation, Tsinghua University, Beijing, China.|Tsinghua National Laboratory for Information Science and Technology, and Department of Automation, Tsinghua University, Beijing, China.|Tsinghua National Laboratory for Information Science and Technology, and Department of Automation, Tsinghua University, Beijing, China.|Tsinghua National Laboratory for Information Science and Technology, and Department of Automation, Tsinghua University, Beijing, China.', 'China|China|China|China|China|China|China|China', 30, 'Bayes Theorem|Computational Biology|DNA Methylation|DNA, Bacterial|DNA-Directed DNA Polymerase|Escherichia coli|Kinetics|Models, Genetic|Nucleic Acid Conformation|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1002935', '23516341', 'DNA modifications such as methylation and DNA damage can play critical regulatory roles in biological systems. Single molecule, real time (SMRT) sequencing technology generates DNA sequences as well as DNA polymerase kinetic information that can be used for the direct detection of DNA modifications. We demonstrate that local sequence context has a strong impact on DNA polymerase kinetics in the neighborhood of the incorporation site during the DNA synthesis reaction, allowing for the possibility of estimating the expected kinetic rate of the enzyme at the incorporation site using kinetic rate information collected from existing SMRT sequencing data (historical data) covering the same local sequence contexts of interest. We develop an Empirical Bayesian hierarchical model for incorporating historical data. Our results show that the model could greatly increase DNA modification detection accuracy, and reduce requirement of control data coverage. For some DNA modifications that have a strong signal, a control sample is not even needed by using historical data as alternative to control. Thus, sequencing costs can be greatly reduced by using the model. We implemented the model in a R package named seqPatch, which is available at https://github.com/zhixingfeng/seqPatch.'),
(85920, 2013, 'plos', 'A dynamical role for acetylcholine in synaptic renormalization', 'Fink, Christian G|Murphy, Geoffrey G|Zochowski, Michal|Booth, Victoria', 'Department of Physics, University of Michigan, Ann Arbor, Michigan, USA. cgfink@owu.edu|Department of Physics, University of Michigan, Ann Arbor, Michigan, USA. cgfink@owu.edu|Department of Physics, University of Michigan, Ann Arbor, Michigan, USA. cgfink@owu.edu|Department of Physics, University of Michigan, Ann Arbor, Michigan, USA. cgfink@owu.edu', 'United States|United States|United States|United States', 15, 'Acetylcholine|Animals|Cluster Analysis|Computational Biology|Computer Simulation|Mice|Models, Neurological|Sleep|Synapses|Visual Cortex|Wakefulness', 'Journal Article', '10.1371/journal.pcbi.1002939', '23516342', 'Although sleep is a fundamental behavior observed in virtually all animal species, its functions remain unclear. One leading proposal, known as the synaptic renormalization hypothesis, suggests that sleep is necessary to counteract a global strengthening of synapses that occurs during wakefulness. Evidence for sleep-dependent synaptic downscaling (or synaptic renormalization) has been observed experimentally, but the physiological mechanisms which generate this phenomenon are unknown. In this study, we propose that changes in neuronal membrane excitability induced by acetylcholine may provide a dynamical mechanism for both wake-dependent synaptic upscaling and sleep-dependent downscaling. We show in silico that cholinergically-induced changes in network firing patterns alter overall network synaptic potentiation when synaptic strengths evolve through spike-timing dependent plasticity mechanisms. Specifically, network synaptic potentiation increases dramatically with high cholinergic concentration and decreases dramatically with low levels of acetylcholine. We demonstrate that this phenomenon is robust across variation of many different network parameters.'),
(85921, 2013, 'plos', 'Restricted N-glycan conformational space in the PDB and its implication in glycan structure modeling', 'Jo, Sunhwan|Lee, Hui Sun|Skolnick, Jeffrey|Im, Wonpil', 'Department of Molecular Biosciences and Center for Bioinformatics, The University of Kansas, Lawrence, Kansas, USA.|Department of Molecular Biosciences and Center for Bioinformatics, The University of Kansas, Lawrence, Kansas, USA.|Department of Molecular Biosciences and Center for Bioinformatics, The University of Kansas, Lawrence, Kansas, USA.|Department of Molecular Biosciences and Center for Bioinformatics, The University of Kansas, Lawrence, Kansas, USA.', 'United States|United States|United States|United States', 19, 'Asparagine|Carbohydrate Sequence|Computational Biology|Databases, Protein|Glycoproteins|Models, Molecular|Polysaccharides|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1002946', '23516343', 'Understanding glycan structure and dynamics is central to understanding protein-carbohydrate recognition and its role in protein-protein interactions. Given the difficulties in obtaining the glycans crystal structure in glycoconjugates due to its flexibility and heterogeneity, computational modeling could play an important role in providing glycosylated protein structure models. To address if glycan structures available in the PDB can be used as templates or fragments for glycan modeling, we present a survey of the N-glycan structures of 35 different sequences in the PDB. Our statistical analysis shows that the N-glycan structures found on homologous glycoproteins are significantly conserved compared to the random background, suggesting that N-glycan chains can be confidently modeled with template glycan structures whose parent glycoproteins share sequence similarity. On the other hand, N-glycan structures found on non-homologous glycoproteins do not show significant global structural similarity. Nonetheless, the internal substructures of these N-glycans, particularly, the substructures that are closer to the protein, show significantly similar structures, suggesting that such substructures can be used as fragments in glycan modeling. Increased interactions with protein might be responsible for the restricted conformational space of N-glycan chains. Our results suggest that structure prediction/modeling of N-glycans of glycoconjugates using structure database could be effective and different modeling approaches would be needed depending on the availability of template structures.'),
(85922, 2013, 'plos', 'Localized lipid packing of transmembrane domains impedes integrin clustering', 'Mehrbod, Mehrdad|Mofrad, Mohammad R K', 'Molecular Cell Biomechanics Laboratory, Department of Bioengineering, University of California, Berkeley, California, USA.|Molecular Cell Biomechanics Laboratory, Department of Bioengineering, University of California, Berkeley, California, USA.', 'United States|United States', 27, 'Animals|CHO Cells|Cell Membrane|Cricetinae|Cricetulus|Humans|Integrins|Lipid Bilayers|Molecular Dynamics Simulation|Protein Multimerization|Protein Structure, Tertiary', 'Journal Article', '10.1371/journal.pcbi.1002948', '23516344', 'Integrin clustering plays a pivotal role in a host of cell functions. Hetero-dimeric integrin adhesion receptors regulate cell migration, survival, and differentiation by communicating signals bidirectionally across the plasma membrane. Thus far, crystallographic structures of integrin components are solved only separately, and for some integrin types. Also, the sequence of interactions that leads to signal transduction remains ambiguous. Particularly, it remains controversial whether the homo-dimerization of integrin transmembrane domains occurs following the integrin activation (i.e. when integrin ectodomain is stretched out) or if it regulates integrin clustering. This study employs molecular dynamics modeling approaches to address these questions in molecular details and sheds light on the crucial effect of the plasma membrane. Conducting a normal mode analysis of the intact xcexb1llbxcexb23 integrin, it is demonstrated that the ectodomain and transmembrane-cytoplasmic domains are connected via a membrane-proximal hinge region, thus merely transmembrane-cytoplasmic domains are modeled. By measuring the free energy change and force required to form integrin homo-oligomers, this study suggests that the xcexb2-subunit homo-oligomerization potentially regulates integrin clustering, as opposed to xcexb1-subunit, which appears to be a poor regulator for the clustering process. If xcexb1-subunits are to regulate the clustering they should overcome a high-energy barrier formed by a stable lipid pack around them. Finally, an outside-in activation-clustering scenario is speculated, explaining how further loading the already-active integrin affects its homo-oligomerization so that focal adhesions grow in size.'),
(85923, 2013, 'plos', 'Spatial pattern dynamics of 3D stem cell loss of pluripotency via rules-based computational modeling', 'White, Douglas E|Kinney, Melissa A|McDevitt, Todd C|Kemp, Melissa L', 'The Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, Georgia, USA.|The Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, Georgia, USA.|The Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, Georgia, USA.|The Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, Georgia, USA.', 'Georgia|Georgia|Georgia|Georgia', 25, 'Animals|Cell Line|Cellular Microenvironment|Computational Biology|Computer Simulation|Embryoid Bodies|Embryonic Stem Cells|Mice|Models, Biological|Pluripotent Stem Cells|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002952', '23516345', 'Pluripotent embryonic stem cells (ESCs) have the unique ability to differentiate into cells from all germ lineages, making them a potentially robust cell source for regenerative medicine therapies, but difficulties in predicting and controlling ESC differentiation currently limit the development of therapies and applications from such cells. A common approach to induce the differentiation of ESCs in vitro is via the formation of multicellular aggregates known as embryoid bodies (EBs), yet cell fate specification within EBs is generally considered an ill-defined and poorly controlled process. Thus, the objective of this study was to use rules-based cellular modeling to provide insight into which processes influence initial cell fate transitions in 3-dimensional microenvironments. Mouse embryonic stem cells (D3 cell line) were differentiated to examine the temporal and spatial patterns associated with loss of pluripotency as measured through Oct4 expression. Global properties of the multicellular aggregates were accurately recapitulated by a physics-based aggregation simulation when compared to experimentally measured physical parameters of EBs. Oct4 expression patterns were analyzed by confocal microscopy over time and compared to simulated trajectories of EB patterns. The simulations demonstrated that loss of Oct4 can be modeled as a binary process, and that associated patterns can be explained by a set of simple rules that combine baseline stochasticity with intercellular communication. Competing influences between Oct4+ and Oct4- neighbors result in the observed patterns of pluripotency loss within EBs, establishing the utility of rules-based modeling for hypothesis generation of underlying ESC differentiation processes. Importantly, the results indicate that the rules dominate the emergence of patterns independent of EB structure, size, or cell division. In combination with strategies to engineer cellular microenvironments, this type of modeling approach is a powerful tool to predict stem cell behavior under a number of culture conditions that emulate characteristics of 3D stem cell niches.'),
(85924, 2013, 'plos', 'Signaling pathways involved in striatal synaptic plasticity are sensitive to temporal pattern and exhibit spatial specificity', 'Kim, BoHung|Hawes, Sarah L|Gillani, Fawad|Wallace, Lane J|Blackwell, Kim T', 'School of Mechanical Engineering, University of Ulsan, Ulsan, South Korea.|School of Mechanical Engineering, University of Ulsan, Ulsan, South Korea.|School of Mechanical Engineering, University of Ulsan, Ulsan, South Korea.|School of Mechanical Engineering, University of Ulsan, Ulsan, South Korea.|School of Mechanical Engineering, University of Ulsan, Ulsan, South Korea.', '-|-|-|-|-', 15, 'Animals|Benzophenanthridines|Cell Membrane|Computer Simulation|Corpus Striatum|Learning|Male|Mice|Mice, Inbred C57BL|Models, Molecular|Models, Neurological|Neuronal Plasticity|Protein Kinase C|Reproducibility of Results|Signal Transduction|Stochastic Processes|Synapses', 'Journal Article', '10.1371/journal.pcbi.1002953', '23516346', 'The basal ganglia is a brain region critically involved in reinforcement learning and motor control. Synaptic plasticity in the striatum of the basal ganglia is a cellular mechanism implicated in learning and neuronal information processing. Therefore, understanding how different spatio-temporal patterns of synaptic input select for different types of plasticity is key to understanding learning mechanisms. In striatal medium spiny projection neurons (MSPN), both long term potentiation (LTP) and long term depression (LTD) require an elevation in intracellular calcium concentration, however, it is unknown how the post-synaptic neuron discriminates between different patterns of calcium influx. Using computer modeling, we investigate the hypothesis that temporal pattern of stimulation can select for either endocannabinoid production (for LTD) or protein kinase C (PKC) activation (for LTP) in striatal MSPNs. We implement a stochastic model of the post-synaptic signaling pathways in a dendrite with one or more diffusionally coupled spines. The model is validated by comparison to experiments measuring endocannabinoid-dependent depolarization induced suppression of inhibition. Using the validated model, simulations demonstrate that theta burst stimulation, which produces LTP, increases the activation of PKC as compared to 20 Hz stimulation, which produces LTD. The model prediction that PKC activation is required for theta burst LTP is confirmed experimentally. Using the ratio of PKC to endocannabinoid production as an index of plasticity direction, model simulations demonstrate that LTP exhibits spine level spatial specificity, whereas LTD is more diffuse. These results suggest that spatio-temporal control of striatal information processing employs these Gq coupled pathways.'),
(85925, 2013, 'plos', 'Functional knowledge transfer for high-accuracy prediction of under-studied biological processes', 'Park, Christopher Y|Wong, Aaron K|Greene, Casey S|Rowland, Jessica|Guan, Yuanfang|Bongo, Lars A|Burdine, Rebecca D|Troyanskaya, Olga G', 'Department of Computer Science, Princeton University, Princeton, New Jersey, USA.|Department of Computer Science, Princeton University, Princeton, New Jersey, USA.|Department of Computer Science, Princeton University, Princeton, New Jersey, USA.|Department of Computer Science, Princeton University, Princeton, New Jersey, USA.|Department of Computer Science, Princeton University, Princeton, New Jersey, USA.|Department of Computer Science, Princeton University, Princeton, New Jersey, USA.|Department of Computer Science, Princeton University, Princeton, New Jersey, USA.|Department of Computer Science, Princeton University, Princeton, New Jersey, USA.', 'Jersey|Jersey|Jersey|Jersey|Jersey|Jersey|Jersey|Jersey', 38, 'Animals|Bayes Theorem|Biological Phenomena|Caenorhabditis elegans|Computational Biology|Drosophila melanogaster|Embryo, Nonmammalian|Embryonic Development|Genes|Humans|Mice|Models, Biological|Models, Statistical|Rats|Sequence Analysis, DNA|Support Vector Machine|Zebrafish', 'Journal Article', '10.1371/journal.pcbi.1002957', '23516347', 'A key challenge in genetics is identifying the functional roles of genes in pathways. Numerous functional genomics techniques (e.g. machine learning) that predict protein function have been developed to address this question. These methods generally build from existing annotations of genes to pathways and thus are often unable to identify additional genes participating in processes that are not already well studied. Many of these processes are well studied in some organism, but not necessarily in an investigators organism of interest. Sequence-based search methods (e.g. BLAST) have been used to transfer such annotation information between organisms. We demonstrate that functional genomics can complement traditional sequence similarity to improve the transfer of gene annotations between organisms. Our method transfers annotations only when functionally appropriate as determined by genomic data and can be used with any prediction algorithm to combine transferred gene function knowledge with organism-specific high-throughput data to enable accurate function prediction. We show that diverse state-of-art machine learning algorithms leveraging functional knowledge transfer (FKT) dramatically improve their accuracy in predicting gene-pathway membership, particularly for processes with little experimental knowledge in an organism. We also show that our method compares favorably to annotation transfer by sequence similarity. Next, we deploy FKT with state-of-the-art SVM classifier to predict novel genes to 11,000 biological processes across six diverse organisms and expand the coverage of accurate function predictions to processes that are often ignored because of a dearth of annotated genes in an organism. Finally, we perform in vivo experimental investigation in Danio rerio and confirm the regulatory role of our top predicted novel gene, wnt5b, in leftward cell migration during heart development. FKT is immediately applicable to many bioinformatics techniques and will help biologists systematically integrate prior knowledge from diverse systems to direct targeted experiments in their organism of study.'),
(85926, 2013, 'plos', 'Analysis of hepatitis C virus decline during treatment with the protease inhibitor danoprevir using a multiscale model', 'Rong, Libin|Guedj, Jeremie|Dahari, Harel|Coffield, Daniel J|Levi, Micha|Smith, Patrick|Perelson, Alan S', 'Department of Mathematics and Statistics and Center for Biomedical Research, Oakland University, Rochester, Michigan, USA.|Department of Mathematics and Statistics and Center for Biomedical Research, Oakland University, Rochester, Michigan, USA.|Department of Mathematics and Statistics and Center for Biomedical Research, Oakland University, Rochester, Michigan, USA.|Department of Mathematics and Statistics and Center for Biomedical Research, Oakland University, Rochester, Michigan, USA.|Department of Mathematics and Statistics and Center for Biomedical Research, Oakland University, Rochester, Michigan, USA.|Department of Mathematics and Statistics and Center for Biomedical Research, Oakland University, Rochester, Michigan, USA.|Department of Mathematics and Statistics and Center for Biomedical Research, Oakland University, Rochester, Michigan, USA.', 'United States|United States|United States|United States|United States|United States|United States', 58, 'Antiviral Agents|Computational Biology|Hepacivirus|Hepatitis C|Humans|Lactams|Models, Biological|RNA, Viral|Sulfonamides|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.1002959', '23516348', 'The current paradigm for studying hepatitis C virus (HCV) dynamics in patients utilizes a standard viral dynamic model that keeps track of uninfected (target) cells, infected cells, and virus. The model does not account for the dynamics of intracellular viral replication, which is the major target of direct-acting antiviral agents (DAAs). Here we describe and study a recently developed multiscale age-structured model that explicitly considers the potential effects of DAAs on intracellular viral RNA production, degradation, and secretion as virus into the circulation. We show that when therapy significantly blocks both intracellular viral RNA production and virus secretion, the serum viral load decline has three phases, with slopes reflecting the rate of serum viral clearance, the rate of loss of intracellular viral RNA, and the rate of loss of intracellular replication templates and infected cells, respectively. We also derive analytical approximations of the multiscale model and use one of them to analyze data from patients treated for 14 days with the HCV protease inhibitor danoprevir. Analysis suggests that danoprevir significantly blocks intracellular viral production (with mean effectiveness 99.2%), enhances intracellular viral RNA degradation about 5-fold, and moderately inhibits viral secretion (with mean effectiveness 56%). The multiscale model can be used to study viral dynamics in patients treated with other DAAs and explore their mechanisms of action in treatment of hepatitis C.'),
(85927, 2013, 'plos', 'Revealing a two-loop transcriptional feedback mechanism in the cyanobacterial circadian clock', 'Hertel, Stefanie|Brettschneider, Christian|Axmann, Ilka M', 'Institute for Theoretical Biology, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Institute for Theoretical Biology, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Institute for Theoretical Biology, Charité-Universitätsmedizin Berlin, Berlin, Germany.', 'Germany|Germany|Germany', 14, 'Bacterial Proteins|Circadian Clocks|Circadian Rhythm Signaling Peptides and Proteins|Computational Biology|Computer Simulation|Cyanobacteria|Feedback, Physiological|Gene Expression Regulation, Bacterial|Models, Biological|Mutation|Phosphorylation|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002966', '23516349', 'Molecular genetic studies in the circadian model organism Synechococcus have revealed that the KaiC protein, the central component of the circadian clock in cyanobacteria, is involved in activation and repression of its own gene transcription. During 24 hours, KaiC hexamers run through different phospho-states during daytime. So far, it has remained unclear which phospho-state of KaiC promotes kaiBC expression and which opposes transcriptional activation. We systematically analyzed various combinations of positive and negative transcriptional feedback regulation by introducing a combined TTFL/PTO model consisting of our previous post-translational oscillator that considers all four phospho-states of KaiC and a transcriptional/translational feedback loop. Only a particular two-loop feedback mechanism out of 32 we have extensively tested is able to reproduce existing experimental observations, including the effects of knockout or overexpression of kai genes. Here, threonine and double phosphorylated KaiC hexamers activate and unphosphorylated KaiC hexamers suppress kaiBC transcription. Our model simulations suggest that the peak expression ratio of the positive and the negative component of kaiBC expression is the main factor for how the different two-loop feedback models respond to removal or to overexpression of kai genes. We discuss parallels between our proposed TTFL/PTO model and two-loop feedback structures found in the mammalian clock.'),
(85928, 2013, 'plos', 'Differential expression analysis for pathways', 'Haynes, Winston A|Higdon, Roger|Stanberry, Larissa|Collins, Dwayne|Kolker, Eugene', 'Bioinformatics & High-Throughput Analysis Laboratory, Seattle Childrens Research Institute, Seattle, Washington, USA.|Bioinformatics & High-Throughput Analysis Laboratory, Seattle Childrens Research Institute, Seattle, Washington, USA.|Bioinformatics & High-Throughput Analysis Laboratory, Seattle Childrens Research Institute, Seattle, Washington, USA.|Bioinformatics & High-Throughput Analysis Laboratory, Seattle Childrens Research Institute, Seattle, Washington, USA.|Bioinformatics & High-Throughput Analysis Laboratory, Seattle Childrens Research Institute, Seattle, Washington, USA.', 'United States|United States|United States|United States|United States', 55, 'Algorithms|Computational Biology|Computer Simulation|Databases, Genetic|Disease|Gene Expression Profiling|Humans|Models, Biological|Reproducibility of Results|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002967', '23516350', 'Life science technologies generate a deluge of data that hold the keys to unlocking the secrets of important biological functions and disease mechanisms. We present DEAP, Differential Expression Analysis for Pathways, which capitalizes on information about biological pathways to identify important regulatory patterns from differential expression data. DEAP makes significant improvements over existing approaches by including information about pathway structure and discovering the most differentially expressed portion of the pathway. On simulated data, DEAP significantly outperformed traditional methods: with high differential expression, DEAP increased power by two orders of magnitude, with very low differential expression, DEAP doubled the power. DEAP performance was illustrated on two different gene and protein expression studies. DEAP discovered fourteen important pathways related to chronic obstructive pulmonary disease and interferon treatment that existing approaches omitted. On the interferon study, DEAP guided focus towards a four protein path within the 26 protein Notch signalling pathway.'),
(85929, 2013, 'plos', 'Directional summation in non-direction selective retinal ganglion cells', 'Abbas, Syed Y|Hamade, Khaldoun C|Yang, Ellen J|Nawy, Scott|Smith, Robert G|Pettit, Diana L', 'Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, New York, USA.|Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, New York, USA.|Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, New York, USA.|Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, New York, USA.|Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, New York, USA.|Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, New York, USA.', 'United States|United States|United States|United States|United States|United States', 9, 'Animals|Computational Biology|Cyclic Nucleotide-Gated Cation Channels|Dendrites|Glutamates|Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels|Models, Neurological|Photochemical Processes|Postsynaptic Potential Summation|Potassium Channels|Pyrimidines|Rats|Rats, Sprague-Dawley|Retinal Ganglion Cells', 'Journal Article', '10.1371/journal.pcbi.1002969', '23516351', 'Retinal ganglion cells receive inputs from multiple bipolar cells which must be integrated before a decision to fire is made. Theoretical studies have provided clues about how this integration is accomplished but have not directly determined the rules regulating summation of closely timed inputs along single or multiple dendrites. Here we have examined dendritic summation of multiple inputs along On ganglion cell dendrites in whole mount rat retina. We activated inputs at targeted locations by uncaging glutamate sequentially to generate apparent motion along On ganglion cell dendrites in whole mount retina. Summation was directional and dependent13 on input sequence. Input moving away from the soma (centrifugal) resulted in supralinear summation, while activation sequences moving toward the soma (centripetal) were linear. Enhanced summation for centrifugal activation was robust as it was also observed in cultured retinal ganglion cells. This directional summation was dependent on hyperpolarization activated cyclic nucleotide-gated (HCN) channels as blockade with ZD7288 eliminated directionality. A computational model confirms that activation of HCN channels can override a preference for centripetal summation expected from cell anatomy. This type of direction selectivity could play a role in coding movement similar to the axial selectivity seen in locust ganglion cells which detect looming stimuli. More generally, these results suggest that non-directional retinal ganglion cells can discriminate between input sequences independent of the retina network.'),
(85930, 2013, 'plos', 'Chaste: an open source C++ library for computational physiology and biology', 'Mirams, Gary R|Arthurs, Christopher J|Bernabeu, Miguel O|Bordas, Rafel|Cooper, Jonathan|Corrias, Alberto|Davit, Yohan|Dunn, Sara-Jane|Fletcher, Alexander G|Harvey, Daniel G|Marsh, Megan E|Osborne, James M|Pathmanathan, Pras|Pitt-Francis, Joe|Southern, James|Zemzemi, Nejib|Gavaghan, David J', 'Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk|Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk|Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk|Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk|Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk|Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk|Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk|Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk|Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk|Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk|Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk|Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk|Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk|Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk|Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk|Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk|Computational Biology, Department of Computer Science, University of Oxford, Oxford, United Kingdom. gary.mirams@cs.ox.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 200, 'Computational Biology|Computer Simulation|Databases, Factual|Humans|Models, Cardiovascular|Neoplasms', 'Journal Article', '10.1371/journal.pcbi.1002970', '23516352', 'Chaste - Cancer, Heart And Soft Tissue Environment - is an open source C++ library for the computational simulation of mathematical models developed for physiology and biology. Code development has been driven by two initial applications: cardiac electrophysiology and cancer development. A large number of cardiac electrophysiology studies have been enabled and performed, including high-performance computational investigations of defibrillation on realistic human cardiac geometries. New models for the initiation and growth of tumours have been developed. In particular, cell-based simulations have provided novel insight into the role of stem cells in the colorectal crypt. Chaste is constantly evolving and is now being applied to a far wider range of problems. The code provides modules for handling common scientific computing components, such as meshes and solvers for ordinary and partial differential equations (ODEs/PDEs). Re-use of these components avoids the need for researchers to re-invent the wheel with each new project, accelerating the rate of progress in new applications. Chaste is developed using industrially-derived techniques, in particular test-driven development, to ensure code quality, re-use and reliability. In this article we provide examples that illustrate the types of problems Chaste can be used to solve, which can be run on a desktop computer. We highlight some scientific studies that have used or are using Chaste, and the insights they have provided. The source code, both for specific releases and the development version, is available to download under an open source Berkeley Software Distribution (BSD) licence at http://www.cs.ox.ac.uk/chaste, together with details of a mailing list and links to documentation and tutorials.'),
(85931, 2013, 'plos', 'Processing of multi-dimensional sensorimotor information in the spinal and cerebellar neuronal circuitry: a new hypothesis', 'Spanne, Anton|Jörntell, Henrik', 'Neural basis for Sensorimotor Control, BMC F10, Lund University, SE-22184 Lund, Sweden.|Neural basis for Sensorimotor Control, BMC F10, Lund University, SE-22184 Lund, Sweden.', 'Sweden|Sweden', 35, 'Algorithms|Animals|Cerebellar Cortex|Computational Biology|Humans|Mammals|Models, Neurological|Nerve Fibers|Neural Networks (Computer)|Nonlinear Dynamics|Purkinje Cells|Spine|Spinocerebellar Tracts', 'Journal Article', '10.1371/journal.pcbi.1002979', '23516353', 'Why are sensory signals and motor command signals combined in the neurons of origin of the spinocerebellar pathways and why are the granule cells that receive this input thresholded with respect to their spike output? In this paper, we synthesize a number of findings into a new hypothesis for how the spinocerebellar systems and the cerebellar cortex can interact to support coordination of our multi-segmented limbs and bodies. A central idea is that recombination of the signals available to the spinocerebellar neurons can be used to approximate a wide array of functions including the spatial and temporal dependencies between limb segments, i.e. information that is necessary in order to achieve coordination. We find that random recombination of sensory and motor signals is not a good strategy since, surprisingly, the number of granule cells severely limits the number of recombinations that can be represented within the cerebellum. Instead, we propose that the spinal circuitry provides useful recombinations, which can be described as linear projections through aspects of the multi-dimensional sensorimotor input space. Granule cells, potentially with the aid of differentiated thresholding from Golgi cells, enhance the utility of these projections by allowing the Purkinje cell to establish piecewise-linear approximations of non-linear functions. Our hypothesis provides a novel view on the function of the spinal circuitry and cerebellar granule layer, illustrating how the coordinating functions of the cerebellum can be crucially supported by the recombinations performed by the neurons of the spinocerebellar systems.'),
(85932, 2013, 'plos', 'Computational predictions provide insights into the biology of TAL effector target sites', 'Grau, Jan|Wolf, Annett|Reschke, Maik|Bonas, Ulla|Posch, Stefan|Boch, Jens', 'Institute of Computer Science, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. grau@informatik.uni-halle.de|Institute of Computer Science, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. grau@informatik.uni-halle.de|Institute of Computer Science, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. grau@informatik.uni-halle.de|Institute of Computer Science, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. grau@informatik.uni-halle.de|Institute of Computer Science, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. grau@informatik.uni-halle.de|Institute of Computer Science, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. grau@informatik.uni-halle.de', 'Germany|Germany|Germany|Germany|Germany|Germany', 64, 'Amino Acid Sequence|Bacterial Proteins|Computational Biology|DNA-Binding Proteins|Gene Expression Profiling|Gene Expression Regulation, Plant|Oligonucleotide Array Sequence Analysis|Plant Diseases|Protein Binding|Reproducibility of Results|Transcription Factors|Xanthomonas', 'Journal Article', '10.1371/journal.pcbi.1002962', '23526890', 'Transcription activator-like (TAL) effectors are injected into host plant cells by Xanthomonas bacteria to function as transcriptional activators for the benefit of the pathogen. The DNA binding domain of TAL effectors is composed of conserved amino acid repeat structures containing repeat-variable diresidues (RVDs) that determine DNA binding specificity. In this paper, we present TALgetter, a new approach for predicting TAL effector target sites based on a statistical model. In contrast to previous approaches, the parameters of TALgetter are estimated from training data computationally. We demonstrate that TALgetter successfully predicts known TAL effector target sites and often yields a greater number of predictions that are consistent with up-regulation in gene expression microarrays than an existing approach, Target Finder of the TALE-NT suite. We study the binding specificities estimated by TALgetter and approve that different RVDs are differently important for transcriptional activation. In subsequent studies, the predictions of TALgetter indicate a previously unreported positional preference of TAL effector target sites relative to the transcription start site. In addition, several TAL effectors are predicted to bind to the TATA-box, which might constitute one general mode of transcriptional activation by TAL effectors. Scrutinizing the predicted target sites of TALgetter, we propose several novel TAL effector virulence targets in rice and sweet orange. TAL-mediated induction of the candidates is supported by gene expression microarrays. Validity of these targets is also supported by functional analogy to known TAL effector targets, by an over-representation of TAL effector targets with similar function, or by a biological function related to pathogen infection. Hence, these predicted TAL effector virulence targets are promising candidates for studying the virulence function of TAL effectors. TALgetter is implemented as part of the open-source Java library Jstacs, and is freely available as a web-application and a command line program.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85933, 2013, 'plos', 'RFECS: a random-forest based algorithm for enhancer identification from chromatin state', 'Rajagopal, Nisha|Xie, Wei|Li, Yan|Wagner, Uli|Wang, Wei|Stamatoyannopoulos, John|Ernst, Jason|Kellis, Manolis|Ren, Bing', 'Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.|Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.|Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.|Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.|Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.|Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.|Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.|Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.|Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States|United States', 116, 'Algorithms|Area Under Curve|Binding Sites|Cell Line|Chromatin|Cluster Analysis|Computational Biology|Databases, Genetic|Decision Trees|Enhancer Elements, Genetic|Histones|Humans|Reproducibility of Results|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002968', '23526891', 'Transcriptional enhancers play critical roles in regulation of gene expression, but their identification in the eukaryotic genome has been challenging. Recently, it was shown that enhancers in the mammalian genome are associated with characteristic histone modification patterns, which have been increasingly exploited for enhancer identification. However, only a limited number of cell types or chromatin marks have previously been investigated for this purpose, leaving the question unanswered whether there exists an optimal set of histone modifications for enhancer prediction in different cell types. Here, we address this issue by exploring genome-wide profiles of 24 histone modifications in two distinct human cell types, embryonic stem cells and lung fibroblasts. We developed a Random-Forest based algorithm, RFECS (Random Forest based Enhancer identification from Chromatin States) to integrate histone modification profiles for identification of enhancers, and used it to identify enhancers in a number of cell-types. We show that RFECS not only leads to more accurate and precise prediction of enhancers than previous methods, but also helps identify the most informative and robust set of three chromatin marks for enhancer prediction.'),
(85934, 2013, 'plos', 'Evolving digital ecological networks', 'Fortuna, Miguel A|Zaman, Luis|Wagner, Aaron P|Ofria, Charles', 'Integrative Ecology Group, Estación Biológica de Doñana (EDB-CSIC), Sevilla, Spain. fortuna@ebd.csic.es|Integrative Ecology Group, Estación Biológica de Doñana (EDB-CSIC), Sevilla, Spain. fortuna@ebd.csic.es|Integrative Ecology Group, Estación Biológica de Doñana (EDB-CSIC), Sevilla, Spain. fortuna@ebd.csic.es|Integrative Ecology Group, Estación Biológica de Doñana (EDB-CSIC), Sevilla, Spain. fortuna@ebd.csic.es', 'Spain|Spain|Spain|Spain', 21, 'Animals|Biological Evolution|Computational Biology|Computer Simulation|Ecology|Genome|Host-Parasite Interactions|Models, Biological|Plants|Symbiosis', 'Journal Article', '10.1371/journal.pcbi.1002928', '23533370', 'It is hard to realize that the living world as we know it is just one among many possibilities [1]. Evolving digital ecological networks are webs of interacting, self-replicating, and evolving computer programs (i.e., digital organisms) that experience the same major ecological interactions as biological organisms (e.g., competition, predation, parasitism, and mutualism). Despite being computational, these programs evolve quickly in an open-ended way, and starting from only one or two ancestral organisms, the formation of ecological networks can be observed in real-time by tracking interactions between the constantly evolving organism phenotypes. These phenotypes may be defined by combinations of logical computations (hereafter tasks) that digital organisms perform and by expressed behaviors that have evolved. The types and outcomes of interactions between phenotypes are determined by task overlap for logic-defined phenotypes and by responses to encounters in the case of behavioral phenotypes. Biologists use these evolving networks to study active and fundamental topics within evolutionary ecology (e.g., the extent to which the architecture of multispecies networks shape coevolutionary outcomes, and the processes involved).'),
(85935, 2013, 'plos', 'Do ants need to estimate the geometrical properties of trail bifurcations to find an efficient route? A swarm robotics test bed', 'Garnier, Simon|Combe, Maud|Jost, Christian|Theraulaz, Guy', 'Centre de Recherche sur la Cognition Animale, UMR-CNRS 5169, Université Paul Sabatier, Bât 4R3, Toulouse, France. garnier@njit.edu|Centre de Recherche sur la Cognition Animale, UMR-CNRS 5169, Université Paul Sabatier, Bât 4R3, Toulouse, France. garnier@njit.edu|Centre de Recherche sur la Cognition Animale, UMR-CNRS 5169, Université Paul Sabatier, Bât 4R3, Toulouse, France. garnier@njit.edu|Centre de Recherche sur la Cognition Animale, UMR-CNRS 5169, Université Paul Sabatier, Bât 4R3, Toulouse, France. garnier@njit.edu', 'France|France|France|France', 29, 'Animal Communication|Animals|Ants|Computational Biology|Feeding Behavior|Models, Biological|Pheromones|Robotics', 'Journal Article', '10.1371/journal.pcbi.1002903', '23555202', 'Interactions between individuals and the structure of their environment play a crucial role in shaping self-organized collective behaviors. Recent studies have shown that ants crossing asymmetrical bifurcations in a network of galleries tend to follow the branch that deviates the least from their incoming direction. At the collective level, the combination of this tendency and the pheromone-based recruitment results in a greater likelihood of selecting the shortest path between the colonys nest and a food source in a network containing asymmetrical bifurcations. It was not clear however what the origin of this behavioral bias is. Here we propose that it results from a simple interaction between the behavior of the ants and the geometry of the network, and that it does not require the ability to measure the angle of the bifurcation. We tested this hypothesis using groups of ant-like robots whose perceptual and cognitive abilities can be fully specified. We programmed them only to lay down and follow light trails, avoid obstacles and move according to a correlated random walk, but not to use more sophisticated orientation methods. We recorded the behavior of the robots in networks of galleries presenting either only symmetrical bifurcations or a combination of symmetrical and asymmetrical bifurcations. Individual robots displayed the same pattern of branch choice as individual ants when crossing a bifurcation, suggesting that ants do not actually measure the geometry of the bifurcations when travelling along a pheromone trail. Finally at the collective level, the group of robots was more likely to select one of the possible shorter paths between two designated areas when moving in an asymmetrical network, as observed in ants. This study reveals the importance of the shape of trail networks for foraging in ants and emphasizes the underestimated role of the geometrical properties of transportation networks in general.'),
(85936, 2013, 'plos', 'Viral phylodynamics', 'Volz, Erik M|Koelle, Katia|Bedford, Trevor', 'Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America. erikvolz@umich.edu|Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America. erikvolz@umich.edu|Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America. erikvolz@umich.edu', 'United States|United States|United States', 0, 'Adaptation, Biological|Computational Biology|Evolution, Molecular|Humans|Models, Biological|Phylogeny|Virus Diseases|Virus Physiological Phenomena|Viruses', 'Journal Article', '10.1371/journal.pcbi.1002947', '23555203', 'Viral phylodynamics is defined as the study of how epidemiological, immunological, and evolutionary processes act and potentially interact to shape viralphylogenies. Since the coining of the term in 2004, research on viral phylodynamics has focused on transmission dynamics in an effort to shed light on how these dynamics impact viral genetic variation. Transmission dynamics can be considered at the level of cells within an infected host, individual hosts within a population, or entire populations of hosts. Many viruses, especially RNA viruses, rapidly accumulate genetic variation because of short generation times and high mutation rates. Patterns of viral genetic variation are therefore heavily influenced by how quickly transmission occurs and by which entities transmit to one another. Patterns of viral genetic variation will also be affected by selection acting on viral phenotypes. Although viruses can differ with respect to many phenotypes, phylodynamic studies have to date tended to focus on a limited number of viral phenotypes. These include virulence phenotypes, phenotypes associated with viral transmissibility, cell or tissue tropism phenotypes, and antigenic phenotypes that can facilitate escape from host immunity. Due to the impact that transmission dynamics and selection can have on viral genetic variation, viral phylogenies can therefore be used to investigate important epidemiological, immunological, and evolutionary processes, such as epidemic spread[2], spatio-temporal dynamics including metapopulation dynamics[3], zoonotic transmission, tissue tropism[4], and antigenic drift[5]. The quantitative investigation of these processes through the consideration of viral phylogenies is the central aim of viral phylodynamics.'),
(85937, 2013, 'plos', 'A discriminative approach for unsupervised clustering of DNA sequence motifs', 'Stegmaier, Philip|Kel, Alexander|Wingender, Edgar|Borlak, Jürgen', 'Biobase GmbH, Wolfenbüttel, Germany. philip.stegmaier@genexplain.com|Biobase GmbH, Wolfenbüttel, Germany. philip.stegmaier@genexplain.com|Biobase GmbH, Wolfenbüttel, Germany. philip.stegmaier@genexplain.com|Biobase GmbH, Wolfenbüttel, Germany. philip.stegmaier@genexplain.com', 'Germany|Germany|Germany|Germany', 0, 'Algorithms|Cluster Analysis|Computational Biology|DNA|Databases, Genetic|Gene Regulatory Networks|Logistic Models|Nucleotide Motifs|Phylogeny|Sequence Alignment|Sequence Analysis, DNA|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002958', '23555204', 'Algorithmic comparison of DNA sequence motifs is a problem in bioinformatics that has received increased attention during the last years. Its main applications concern characterization of potentially novel motifs and clustering of a motif collection in order to remove redundancy. Despite growing interest in motif clustering, the question which motif clusters to aim at has so far not been systematically addressed. Here we analyzed motif similarities in a comprehensive set of vertebrate transcription factor classes. For this we developed enhanced similarity scores by inclusion of the information coverage (IC) criterion, which evaluates the fraction of information an alignment covers in aligned motifs. A network-based method enabled us to identify motif clusters with high correspondence to DNA-binding domain phylogenies and prior experimental findings. Based on this analysis we derived a set of motif families representing distinct binding specificities. These motif families were used to train a classifier which was further integrated into a novel algorithm for unsupervised motif clustering. Application of the new algorithm demonstrated its superiority to previously published methods and its ability to reproduce entrained motif families. As a result, our work proposes a probabilistic approach to decide whether two motifs represent common or distinct binding specificities.'),
(85938, 2013, 'plos', 'Combined model of intrinsic and extrinsic variability for computational network design with application to synthetic biology', 'Toni, Tina|Tidor, Bruce', 'Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. ttoni@mit.edu|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. ttoni@mit.edu', 'United States|United States', 31, 'Algorithms|Computational Biology|Gene Expression Regulation|MicroRNAs|Models, Genetic|RNA, Messenger|Synthetic Biology|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002960', '23555205', 'Biological systems are inherently variable, with their dynamics influenced by intrinsic and extrinsic sources. These systems are often only partially characterized, with large uncertainties about specific sources of extrinsic variability and biochemical properties. Moreover, it is not yet well understood how different sources of variability combine and affect biological systems in concert. To successfully design biomedical therapies or synthetic circuits with robust performance, it is crucial to account for uncertainty and effects of variability. Here we introduce an efficient modeling and simulation framework to study systems that are simultaneously subject to multiple sources of variability, and apply it to make design decisions on small genetic networks that play a role of basic design elements of synthetic circuits. Specifically, the framework was used to explore the effect of transcriptional and post-transcriptional autoregulation on fluctuations in protein expression in simple genetic networks. We found that autoregulation could either suppress or increase the output variability, depending on specific noise sources and network parameters. We showed that transcriptional autoregulation was more successful than post-transcriptional in suppressing variability across a wide range of intrinsic and extrinsic magnitudes and sources. We derived the following design principles to guide the design of circuits that best suppress variability: (i) high protein cooperativity and low miRNA cooperativity, (ii) imperfect complementarity between miRNA and mRNA was preferred to perfect complementarity, and (iii) correlated expression of mRNA and miRNA--for example, on the same transcript--was best for suppression of protein variability. Results further showed that correlations in kinetic parameters between cells affected the ability to suppress variability, and that variability in transient states did not necessarily follow the same principles as variability in the steady state. Our model and findings provide a general framework to guide design principles in synthetic biology.'),
(85939, 2013, 'plos', 'Multi-scale inference of interaction rules in animal groups using Bayesian model selection', 'Mann, Richard P|Perna, Andrea|Strömbom, Daniel|Garnett, Roman|Herbert-Read, James E|Sumpter, David J T|Ward, Ashley J W', 'Department of Mathematics, Uppsala University, Uppsala, Sweden. rmann@math.uu.se|Department of Mathematics, Uppsala University, Uppsala, Sweden. rmann@math.uu.se|Department of Mathematics, Uppsala University, Uppsala, Sweden. rmann@math.uu.se|Department of Mathematics, Uppsala University, Uppsala, Sweden. rmann@math.uu.se|Department of Mathematics, Uppsala University, Uppsala, Sweden. rmann@math.uu.se|Department of Mathematics, Uppsala University, Uppsala, Sweden. rmann@math.uu.se|Department of Mathematics, Uppsala University, Uppsala, Sweden. rmann@math.uu.se', 'Sweden|Sweden|Sweden|Sweden|Sweden|Sweden|Sweden', 0, 'Animals|Bayes Theorem|Behavior, Animal|Computational Biology|Computer Simulation|Decapoda (Crustacea)|Models, Biological|Social Behavior|Spatial Behavior', 'Journal Article', '10.1371/journal.pcbi.1002961', '23555206', 'Inference of interaction rules of animals moving in groups usually relies on an analysis of large scale system behaviour. Models are tuned through repeated simulation until they match the observed behaviour. More recent work has used the fine scale motions of animals to validate and fit the rules of interaction of animals in groups. Here, we use a Bayesian methodology to compare a variety of models to the collective motion of glass prawns (Paratya australiensis). We show that these exhibit a stereotypical phase transition, whereby an increase in density leads to the onset of collective motion in one direction. We fit models to this data, which range from: a mean-field model where all prawns interact globally, to a spatial Markovian model where prawns are self-propelled particles influenced only by the current positions and directions of their neighbours, up to non-Markovian models where prawns have memory of previous interactions, integrating their experiences over time when deciding to change behaviour. We show that the mean-field model fits the large scale behaviour of the system, but does not capture the observed locality of interactions. Traditional self-propelled particle models fail to capture the fine scale dynamics of the system. The most sophisticated model, the non-Markovian model, provides a good match to the data at both the fine scale and in terms of reproducing global dynamics, while maintaining a biologically plausible perceptual range. We conclude that prawns movements are influenced by not just the current direction of nearby conspecifics, but also those encountered in the recent past. Given the simplicity of prawns as a study system our research suggests that self-propelled particle models of collective motion should, if they are to be realistic at multiple biological scales, include memory of previous interactions and other non-Markovian effects.'),
(85940, 2013, 'plos', 'Optimal vaccine allocation for the early mitigation of pandemic influenza', 'Matrajt, Laura|Halloran, M Elizabeth|Longini, Ira M', 'Department of Applied Mathematics, University of Washington, Seattle, Washington, United States of America. laurama@uw.edu|Department of Applied Mathematics, University of Washington, Seattle, Washington, United States of America. laurama@uw.edu|Department of Applied Mathematics, University of Washington, Seattle, Washington, United States of America. laurama@uw.edu', 'United States|United States|United States', 0, 'Asia, Southeastern|Cluster Analysis|Computational Biology|Humans|Influenza A Virus, H5N1 Subtype|Influenza Vaccines|Influenza, Human|Models, Biological|Pandemics', 'Journal Article', '10.1371/journal.pcbi.1002964', '23555207', 'With new cases of avian influenza H5N1 (H5N1AV) arising frequently, the threat of a new influenza pandemic remains a challenge for public health. Several vaccines have been developed specifically targeting H5N1AV, but their production is limited and only a few million doses are readily available. Because there is an important time lag between the emergence of new pandemic strain and the development and distribution of a vaccine, shortage of vaccine is very likely at the beginning of a pandemic. We coupled a mathematical model with a genetic algorithm to optimally and dynamically distribute vaccine in a network of cities, connected by the airline transportation network. By minimizing the illness attack rate (i.e., the percentage of people in the population who become infected and ill), we focus on optimizing vaccine allocation in a network of 16 cities in Southeast Asia when only a few million doses are available. In our base case, we assume the vaccine is well-matched and vaccination occurs 5 to 10 days after the beginning of the epidemic. The effectiveness of all the vaccination strategies drops off as the timing is delayed or the vaccine is less well-matched. Under the best assumptions, optimal vaccination strategies substantially reduced the illness attack rate, with a maximal reduction in the attack rate of 85%. Furthermore, our results suggest that cooperative strategies where the resources are optimally distributed among the cities perform much better than the strategies where the vaccine is equally distributed among the network, yielding an illness attack rate 17% lower. We show that it is possible to significantly mitigate a more global epidemic with limited quantities of vaccine, provided that the vaccination campaign is extremely fast and it occurs within the first weeks of transmission.'),
(85941, 2013, 'plos', 'The fidelity of dynamic signaling by noisy biomolecular networks', 'Bowsher, Clive G|Voliotis, Margaritis|Swain, Peter S', 'School of Mathematics, University of Bristol, Bristol, United Kingdom. c.bowsher@bristol.ac.uk|School of Mathematics, University of Bristol, Bristol, United Kingdom. c.bowsher@bristol.ac.uk|School of Mathematics, University of Bristol, Bristol, United Kingdom. c.bowsher@bristol.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 39, 'Computational Biology|Feedback, Physiological|Gene Expression|Models, Biological|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002965', '23555208', 'Cells live in changing, dynamic environments. To understand cellular decision-making, we must therefore understand how fluctuating inputs are processed by noisy biomolecular networks. Here we present a general methodology for analyzing the fidelity with which different statistics of a fluctuating input are represented, or encoded, in the output of a signaling system over time. We identify two orthogonal sources of error that corrupt perfect representation of the signal: dynamical error, which occurs when the network responds on average to other features of the input trajectory as well as to the signal of interest, and mechanistic error, which occurs because biochemical reactions comprising the signaling mechanism are stochastic. Trade-offs between these two errors can determine the systems fidelity. By developing mathematical approaches to derive dynamics conditional on input trajectories we can show, for example, that increased biochemical noise (mechanistic error) can improve fidelity and that both negative and positive feedback degrade fidelity, for standard models of genetic autoregulation. For a group of cells, the fidelity of the collective output exceeds that of an individual cell and negative feedback then typically becomes beneficial. We can also predict the dynamic signal for which a given system has highest fidelity and, conversely, how to modify the network design to maximize fidelity for a given dynamic signal. Our approach is general, has applications to both systems and synthetic biology, and will help underpin studies of cellular behavior in natural, dynamic environments.'),
(85942, 2013, 'plos', 'Explaining the determinants of first phase HIV decay dynamics through the effects of stage-dependent drug action', 'Gilmore, James B|Kelleher, Anthony D|Cooper, David A|Murray, John M', 'School of Mathematics and Statistics, University of New South Wales, Sydney, New South Wales, Australia.|School of Mathematics and Statistics, University of New South Wales, Sydney, New South Wales, Australia.|School of Mathematics and Statistics, University of New South Wales, Sydney, New South Wales, Australia.|School of Mathematics and Statistics, University of New South Wales, Sydney, New South Wales, Australia.', 'Australia|Australia|Australia|Australia', 14, 'Anti-HIV Agents|CD4-Positive T-Lymphocytes|HIV Infections|HIV-1|Humans|Models, Biological|Viral Load', 'Journal Article', '10.1371/journal.pcbi.1002971', '23555209', 'A recent investigation of the effect of different antiretroviral drug classes on first phase dynamics of HIV RNA plasma virus levels has indicated that drugs acting at stages closer to viral production, such as the integrase inhibitor raltegravir, can produce a steeper first phase decay slope that may not be due to drug efficacy. Moreover it was found that for most drug classes the first phase transitions from a faster (phase IA) to a slightly slower decay region (phase IB) before the start of the usual second phase. Neither of these effects has been explained to date. We use a mathematical model that incorporates the different stages of the HIV viral life cycle in CD4+ T cells: viral entry, reverse transcription, integration, and viral production, to investigate the intracellular HIV mechanisms responsible for these complex plasma virus decay dynamics. We find differences in the phase IA slope across drug classes arise from a higher death rate of cells when they enter the productively infected stage post-integration, with a half-life of approximately 8 hours in this stage, whereas cells in earlier stages of the infection cycle have half-lives similar to uninfected cells. This implies any immune clearance is predominantly limited to the productive infection stage. We also show that the slowing of phase IA to phase IB at day 2 to 4 of monotherapy, depending on drug class, is a result of new rounds of infection. The level at which this slowing occurs is a better indicator of drug efficacy than the slope of the initial decay.'),
(85943, 2013, 'plos', 'Bayesian estimation of mixture models with prespecified elements to compare drug resistance in treatment-naïve and experienced tuberculosis cases', 'Izu, Alane|Cohen, Ted|Degruttola, Victor', 'Department of Science and Technology/National Research Foundation, Vaccine Preventable Diseases and Respiratory & Meningeal Pathogens Research Unit, University of Witwatersrand, Faculty of Health Science, Johannesburg, Gauteng, South Africa. izua@rmpru.co.za|Department of Science and Technology/National Research Foundation, Vaccine Preventable Diseases and Respiratory & Meningeal Pathogens Research Unit, University of Witwatersrand, Faculty of Health Science, Johannesburg, Gauteng, South Africa. izua@rmpru.co.za|Department of Science and Technology/National Research Foundation, Vaccine Preventable Diseases and Respiratory & Meningeal Pathogens Research Unit, University of Witwatersrand, Faculty of Health Science, Johannesburg, Gauteng, South Africa. izua@rmpru.co.za', 'South Africa|South Africa|South Africa', 0, 'Antitubercular Agents|Bayes Theorem|Computational Biology|Databases, Factual|Humans|Markov Chains|Microbial Sensitivity Tests|Models, Biological|Mycobacterium tuberculosis|Tuberculosis, Multidrug-Resistant', 'Journal Article', '10.1371/journal.pcbi.1002973', '23555210', 'We propose a Bayesian approach for estimating branching tree mixture models to compare drug-resistance pathways (i.e. patterns of sequential acquisition of resistance to individual antibiotics) that are observed among Mycobacterium tuberculosis isolates collected from treatment-naïve and treatment-experienced patients. Resistant pathogens collected from treatment-naïve patients are strains for which fitness costs of resistance were not sufficient to prevent transmission, whereas those collected from treatment-experienced patients reflect both transmitted and acquired resistance, the latter of which may or may not be associated with lower transmissibility. The comparison of the resistance pathways constructed from these two groups of drug-resistant strains provides insight into which pathways preferentially lead to the development of multiple drug resistant strains that are transmissible. We apply the proposed statistical methods to data from worldwide surveillance of drug-resistant tuberculosis collected by the World Health Organization over 13 years.'),
(85944, 2013, 'plos', 'Bursts of vertex activation and epidemics in evolving networks', 'Rocha, Luis E C|Blondel, Vincent D', 'Department of Mathematical Engineering, Université catholique de Louvain, Louvain-la-Neuve, Belgium. luis.rocha@uclouvain.be|Department of Mathematical Engineering, Université catholique de Louvain, Louvain-la-Neuve, Belgium. luis.rocha@uclouvain.be', 'Belgium|Belgium', 62, 'Communicable Diseases|Computational Biology|Computer Simulation|Epidemics|Humans|Models, Biological|Prevalence|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002974', '23555211', 'The dynamic nature of contact patterns creates diverse temporal structures. In particular, empirical studies have shown that contact patterns follow heterogeneous inter-event time intervals, meaning that periods of high activity are followed by long periods of inactivity. To investigate the impact of these heterogeneities in the spread of infection from a theoretical perspective, we propose a stochastic model to generate temporal networks where vertices make instantaneous contacts following heterogeneous inter-event intervals, and may leave and enter the system. We study how these properties affect the prevalence of an infection and estimate R(0), the number of secondary infections of an infectious individual in a completely susceptible population, by modeling simulated infections (SI and SIR) that co-evolve with the network structure. We find that heterogeneous contact patterns cause earlier and larger epidemics in the SIR model in comparison to homogeneous scenarios for a vast range of parameter values, while smaller epidemics may happen in some combinations of parameters. In the case of SI and heterogeneous patterns, the epidemics develop faster in the earlier stages followed by a slowdown in the asymptotic limit. For increasing vertex turnover rates, heterogeneous patterns generally cause higher prevalence in comparison to homogeneous scenarios with the same average inter-event interval. We find that [Formula: see text] is generally higher for heterogeneous patterns, except for sufficiently large infection duration and transmission probability.'),
(85945, 2013, 'plos', 'Network-based survival analysis reveals subnetwork signatures for predicting outcomes of ovarian cancer treatment', 'Zhang, Wei|Ota, Takayo|Shridhar, Viji|Chien, Jeremy|Wu, Baolin|Kuang, Rui', 'Department of Computer Science and Engineering, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Computer Science and Engineering, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Computer Science and Engineering, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Computer Science and Engineering, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Computer Science and Engineering, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Computer Science and Engineering, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States of America.', 'United States|United States|United States|United States|United States|United States', 89, 'Biomarkers, Tumor|Computational Biology|Female|Fibrillin-1|Fibrillins|Gene Expression Profiling|Humans|Microfilament Proteins|Neoplasm Recurrence, Local|Ovarian Neoplasms|Proportional Hazards Models|Protein Interaction Maps|Reproducibility of Results|Survival Analysis|Treatment Outcome', 'Journal Article', '10.1371/journal.pcbi.1002975', '23555212', 'Cox regression is commonly used to predict the outcome by the time to an event of interest and in addition, identify relevant features for survival analysis in cancer genomics. Due to the high-dimensionality of high-throughput genomic data, existing Cox models trained on any particular dataset usually generalize poorly to other independent datasets. In this paper, we propose a network-based Cox regression model called Net-Cox and applied Net-Cox for a large-scale survival analysis across multiple ovarian cancer datasets. Net-Cox integrates gene network information into the Coxs proportional hazard model to explore the co-expression or functional relation among high-dimensional gene expression features in the gene network. Net-Cox was applied to analyze three independent gene expression datasets including the TCGA ovarian cancer dataset and two other public ovarian cancer datasets. Net-Cox with the network information from gene co-expression or functional relations identified highly consistent signature genes across the three datasets, and because of the better generalization across the datasets, Net-Cox also consistently improved the accuracy of survival prediction over the Cox models regularized by L(2) or L(1). This study focused on analyzing the death and recurrence outcomes in the treatment of ovarian carcinoma to identify signature genes that can more reliably predict the events. The signature genes comprise dense protein-protein interaction subnetworks, enriched by extracellular matrix receptors and modulators or by nuclear signaling components downstream of extracellular signal-regulated kinases. In the laboratory validation of the signature genes, a tumor array experiment by protein staining on an independent patient cohort from Mayo Clinic showed that the protein expression of the signature gene FBN1 is a biomarker significantly associated with the early recurrence after 12 months of the treatment in the ovarian cancer patients who are initially sensitive to chemotherapy. Net-Cox toolbox is available at http://compbio.cs.umn.edu/Net-Cox/.'),
(85946, 2013, 'plos', 'Automated analysis of a diverse synapse population', 'Busse, Brad|Smith, Stephen', 'Biophysics Program, Stanford University, Stanford, California, United States of America. bbusse@gmail.com|Biophysics Program, Stanford University, Stanford, California, United States of America. bbusse@gmail.com', 'United States|United States', 0, 'Algorithms|Animals|Artificial Intelligence|Humans|Image Processing, Computer-Assisted|Mice|Molecular Imaging|Observer Variation|Principal Component Analysis|Proteome|Proteomics|Reproducibility of Results|Somatosensory Cortex|Synapses|Tomography', 'Journal Article', '10.1371/journal.pcbi.1002976', '23555213', 'Synapses of the mammalian central nervous system are highly diverse in function and molecular composition. Synapse diversity per se may be critical to brain function, since memory and homeostatic mechanisms are thought to be rooted primarily in activity-dependent plastic changes in specific subsets of individual synapses. Unfortunately, the measurement of synapse diversity has been restricted by the limitations of methods capable of measuring synapse properties at the level of individual synapses. Array tomography is a new high-resolution, high-throughput proteomic imaging method that has the potential to advance the measurement of unit-level synapse diversity across large and diverse synapse populations. Here we present an automated feature extraction and classification algorithm designed to quantify synapses from high-dimensional array tomographic data too voluminous for manual analysis. We demonstrate the use of this method to quantify laminar distributions of synapses in mouse somatosensory cortex and validate the classification process by detecting the presence of known but uncommon proteomic profiles. Such classification and quantification will be highly useful in identifying specific subpopulations of synapses exhibiting plasticity in response to perturbations from the environment or the sensory periphery.'),
(85947, 2013, 'plos', 'Analysis of physicochemical and structural properties determining HIV-1 coreceptor usage', 'Bozek, Katarzyna|Lengauer, Thomas|Sierra, Saleta|Kaiser, Rolf|Domingues, Francisco S', 'Max Planck Institute for Computer Science, Saarbrucken, Germany. bozek@mpi-inf.mpg.de|Max Planck Institute for Computer Science, Saarbrucken, Germany. bozek@mpi-inf.mpg.de|Max Planck Institute for Computer Science, Saarbrucken, Germany. bozek@mpi-inf.mpg.de|Max Planck Institute for Computer Science, Saarbrucken, Germany. bozek@mpi-inf.mpg.de|Max Planck Institute for Computer Science, Saarbrucken, Germany. bozek@mpi-inf.mpg.de', 'Germany|Germany|Germany|Germany|Germany', 21, 'Amino Acid Sequence|Cluster Analysis|Computer Simulation|HIV Envelope Protein gp120|HIV Infections|HIV-1|Humans|Models, Molecular|Protein Conformation|Receptors, CCR5|Receptors, CXCR4|Structure-Activity Relationship|Support Vector Machine|Tropism', 'Journal Article', '10.1371/journal.pcbi.1002977', '23555214', 'The relationship of HIV tropism with disease progression and the recent development of CCR5-blocking drugs underscore the importance of monitoring virus coreceptor usage. As an alternative to costly phenotypic assays, computational methods aim at predicting virus tropism based on the sequence and structure of the V3 loop of the virus gp120 protein. Here we present a numerical descriptor of the V3 loop encoding its physicochemical and structural properties. The descriptor allows for structure-based prediction of HIV tropism and identification of properties of the V3 loop that are crucial for coreceptor usage. Use of the proposed descriptor for prediction results in a statistically significant improvement over the prediction based solely on V3 sequence with 3 percentage points improvement in AUC and 7 percentage points in sensitivity at the specificity of the 11/25 rule (95%). We additionally assessed the predictive power of the new method on clinically derived bulk sequence data and obtained a statistically significant improvement in AUC of 3 percentage points over sequence-based prediction. Furthermore, we demonstrated the capacity of our method to predict therapy outcome by applying it to 53 samples from patients undergoing Maraviroc therapy. The analysis of structural features of the loop informative of tropism indicates the importance of two loop regions and their physicochemical properties. The regions are located on opposite strands of the loop stem and the respective features are predominantly charge-, hydrophobicity- and structure-related. These regions are in close proximity in the bound conformation of the loop potentially forming a site determinant for the coreceptor binding. The method is available via server under http://structure.bioinf.mpi-inf.mpg.de/.'),
(85948, 2013, 'plos', 'The RAVEN toolbox and its use for generating a genome-scale metabolic model for Penicillium chrysogenum', 'Agren, Rasmus|Liu, Liming|Shoaie, Saeed|Vongsangnak, Wanwipa|Nookaew, Intawat|Nielsen, Jens', 'Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.|Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.|Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.|Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.|Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.|Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.', 'Sweden|Sweden|Sweden|Sweden|Sweden|Sweden', 224, 'Adenosine Triphosphate|Bioengineering|Computational Biology|Databases, Genetic|Genome, Bacterial|Metabolic Networks and Pathways|Models, Biological|NADP|Penicillins|Penicillium chrysogenum|Software', 'Journal Article', '10.1371/journal.pcbi.1002980', '23555215', 'We present the RAVEN (Reconstruction, Analysis and Visualization of Metabolic Networks) Toolbox: a software suite that allows for semi-automated reconstruction of genome-scale models. It makes use of published models and/or the KEGG database, coupled with extensive gap-filling and quality control features. The software suite also contains methods for visualizing simulation results and omics data, as well as a range of methods for performing simulations and analyzing the results. The software is a useful tool for system-wide data analysis in a metabolic context and for streamlined reconstruction of metabolic networks based on protein homology. The RAVEN Toolbox workflow was applied in order to reconstruct a genome-scale metabolic model for the important microbial cell factory Penicillium chrysogenum Wisconsin54-1255. The model was validated in a bibliomic study of in total 440 references, and it comprises 1471 unique biochemical reactions and 1006 ORFs. It was then used to study the roles of ATP and NADPH in the biosynthesis of penicillin, and to identify potential metabolic engineering targets for maximization of penicillin production.'),
(85949, 2013, 'plos', 'Probabilistic inference of biochemical reactions in microbial communities from metagenomic sequences', 'Jiao, Dazhi|Ye, Yuzhen|Tang, Haixu', 'School of Informatics and Computing, Indiana University, Bloomington, Indiana, United States of America.|School of Informatics and Computing, Indiana University, Bloomington, Indiana, United States of America.|School of Informatics and Computing, Indiana University, Bloomington, Indiana, United States of America.', 'India|India|India', 9, 'Algorithms|Cluster Analysis|Databases, Genetic|Environmental Microbiology|Humans|Markov Chains|Metabolic Networks and Pathways|Metagenome|Metagenomics', 'Journal Article', '10.1371/journal.pcbi.1002981', '23555216', 'Shotgun metagenomics has been applied to the studies of the functionality of various microbial communities. As a critical analysis step in these studies, biological pathways are reconstructed based on the genes predicted from metagenomic shotgun sequences. Pathway reconstruction provides insights into the functionality of a microbial community and can be used for comparing multiple microbial communities. The utilization of pathway reconstruction, however, can be jeopardized because of imperfect functional annotation of genes, and ambiguity in the assignment of predicted enzymes to biochemical reactions (e.g., some enzymes are involved in multiple biochemical reactions). Considering that metabolic functions in a microbial community are carried out by many enzymes in a collaborative manner, we present a probabilistic sampling approach to profiling functional content in a metagenomic dataset, by sampling functions of catalytically promiscuous enzymes within the context of the entire metabolic network defined by the annotated metagenome. We test our approach on metagenomic datasets from environmental and human-associated microbial communities. The results show that our approach provides a more accurate representation of the metabolic activities encoded in a metagenome, and thus improves the comparative analysis of multiple microbial communities. In addition, our approach reports likelihood scores of putative reactions, which can be used to identify important reactions and metabolic pathways that reflect the environmental adaptation of the microbial communities. Source code for sampling metabolic networks is available online at http://omics.informatics.indiana.edu/mg/MetaNetSam/.'),
(85950, 2013, 'plos', 'Sustained firing of model central auditory neurons yields a discriminative spectro-temporal representation for natural sounds', 'Carlin, Michael A|Elhilali, Mounya', 'Department of Electrical and Computer Engineering, The Center for Language and Speech Processing, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Electrical and Computer Engineering, The Center for Language and Speech Processing, Johns Hopkins University, Baltimore, Maryland, United States of America.', 'United States|United States', 9, 'Acoustic Stimulation|Animals|Auditory Cortex|Auditory Perception|Cluster Analysis|Computational Biology|Female|Ferrets|Humans|Male|Models, Neurological|Neurons|Noise|Speech|Vocalization, Animal', 'Journal Article', '10.1371/journal.pcbi.1002982', '23555217', 'The processing characteristics of neurons in the central auditory system are directly shaped by and reflect the statistics of natural acoustic environments, but the principles that govern the relationship between natural sound ensembles and observed responses in neurophysiological studies remain unclear. In particular, accumulating evidence suggests the presence of a code based on sustained neural firing rates, where central auditory neurons exhibit strong, persistent responses to their preferred stimuli. Such a strategy can indicate the presence of ongoing sounds, is involved in parsing complex auditory scenes, and may play a role in matching neural dynamics to varying time scales in acoustic signals. In this paper, we describe a computational framework for exploring the influence of a code based on sustained firing rates on the shape of the spectro-temporal receptive field (STRF), a linear kernel that maps a spectro-temporal acoustic stimulus to the instantaneous firing rate of a central auditory neuron. We demonstrate the emergence of richly structured STRFs that capture the structure of natural sounds over a wide range of timescales, and show how the emergent ensembles resemble those commonly reported in physiological studies. Furthermore, we compare ensembles that optimize a sustained firing code with one that optimizes a sparse code, another widely considered coding strategy, and suggest how the resulting population responses are not mutually exclusive. Finally, we demonstrate how the emergent ensembles contour the high-energy spectro-temporal modulations of natural sounds, forming a discriminative representation that captures the full range of modulation statistics that characterize natural sound ensembles. These findings have direct implications for our understanding of how sensory systems encode the informative components of natural stimuli and potentially facilitate multi-sensory integration.'),
(85951, 2013, 'plos', 'Angiogenesis: an adaptive dynamic biological patterning problem', 'Secomb, Timothy W|Alberding, Jonathan P|Hsu, Richard|Dewhirst, Mark W|Pries, Axel R', 'Department of Physiology and Arizona Research Laboratories, University of Arizona, Tucson, Arizona, United States of America. secomb@u.arizona.edu|Department of Physiology and Arizona Research Laboratories, University of Arizona, Tucson, Arizona, United States of America. secomb@u.arizona.edu|Department of Physiology and Arizona Research Laboratories, University of Arizona, Tucson, Arizona, United States of America. secomb@u.arizona.edu|Department of Physiology and Arizona Research Laboratories, University of Arizona, Tucson, Arizona, United States of America. secomb@u.arizona.edu|Department of Physiology and Arizona Research Laboratories, University of Arizona, Tucson, Arizona, United States of America. secomb@u.arizona.edu', 'United States|United States|United States|United States|United States', 71, 'Animals|Blood Vessels|Computational Biology|Male|Models, Cardiovascular|Neovascularization, Pathologic|Neovascularization, Physiologic|Oxygen|Rats|Rats, Wistar|Vascular Endothelial Growth Factor A', 'Journal Article', '10.1371/journal.pcbi.1002983', '23555218', 'Formation of functionally adequate vascular networks by angiogenesis presents a problem in biological patterning. Generated without predetermined spatial patterns, networks must develop hierarchical tree-like structures for efficient convective transport over large distances, combined with dense space-filling meshes for short diffusion distances to every point in the tissue. Moreover, networks must be capable of restructuring in response to changing functional demands without interruption of blood flow. Here, theoretical simulations based on experimental data are used to demonstrate that this patterning problem can be solved through over-abundant stochastic generation of vessels in response to a growth factor generated in hypoxic tissue regions, in parallel with refinement by structural adaptation and pruning. Essential biological mechanisms for generation of adequate and efficient vascular patterns are identified and impairments in vascular properties resulting from defects in these mechanisms are predicted. The results provide a framework for understanding vascular network formation in normal or pathological conditions and for predicting effects of therapies targeting angiogenesis.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85952, 2013, 'plos', 'Stability and responsiveness in a self-organized living architecture', 'Garnier, Simon|Murphy, Tucker|Lutz, Matthew|Hurme, Edward|Leblanc, Simon|Couzin, Iain D', 'Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America. simon.garnier@gmail.com|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America. simon.garnier@gmail.com|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America. simon.garnier@gmail.com|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America. simon.garnier@gmail.com|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America. simon.garnier@gmail.com|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America. simon.garnier@gmail.com', 'Jersey|Jersey|Jersey|Jersey|Jersey|Jersey', 18, 'Animal Communication|Animals|Ants|Appetitive Behavior|Biomechanical Phenomena|Computational Biology|Computer Simulation|Motor Activity|Statistics, Nonparametric', 'Journal Article', '10.1371/journal.pcbi.1002984', '23555219', 'Robustness and adaptability are central to the functioning of biological systems, from gene networks to animal societies. Yet the mechanisms by which living organisms achieve both stability to perturbations and sensitivity to input are poorly understood. Here, we present an integrated study of a living architecture in which army ants interconnect their bodies to span gaps. We demonstrate that these self-assembled bridges are a highly effective means of maintaining traffic flow over unpredictable terrain. The individual-level rules responsible depend only on locally-estimated traffic intensity and the number of neighbours to which ants are attached within the structure. We employ a parameterized computational model to reveal that bridges are tuned to be maximally stable in the face of regular, periodic fluctuations in traffic. However analysis of the model also suggests that interactions among ants give rise to feedback processes that result in bridges being highly responsive to sudden interruptions in traffic. Subsequent field experiments confirm this prediction and thus the dual nature of stability and flexibility in living bridges. Our study demonstrates the importance of robust and adaptive modular architecture to efficient traffic organisation and reveals general principles regarding the regulation of form in biological self-assemblies.'),
(85953, 2013, 'plos', 'Neuronal avalanches differ from wakefulness to deep sleep--evidence from intracranial depth recordings in humans', 'Priesemann, Viola|Valderrama, Mario|Wibral, Michael|Le Van Quyen, Michel', 'Department of Neural Systems and Coding, Max Planck Institute for Brain Research, Frankfurt, Germany. viola.priesemann@brain.mpg.de|Department of Neural Systems and Coding, Max Planck Institute for Brain Research, Frankfurt, Germany. viola.priesemann@brain.mpg.de|Department of Neural Systems and Coding, Max Planck Institute for Brain Research, Frankfurt, Germany. viola.priesemann@brain.mpg.de|Department of Neural Systems and Coding, Max Planck Institute for Brain Research, Frankfurt, Germany. viola.priesemann@brain.mpg.de', 'Germany|Germany|Germany|Germany', 85, 'Adult|Brain|Computational Biology|Electrodes, Implanted|Electroencephalography|Female|Humans|Male|Middle Aged|Models, Neurological|Neurons|Sleep Stages|Wakefulness', 'Journal Article', '10.1371/journal.pcbi.1002985', '23555220', 'Neuronal activity differs between wakefulness and sleep states. In contrast, an attractor state, called self-organized critical (SOC), was proposed to govern brain dynamics because it allows for optimal information coding. But is the human brain SOC for each vigilance state despite the variations in neuronal dynamics? We characterized neuronal avalanches--spatiotemporal waves of enhanced activity--from dense intracranial depth recordings in humans. We showed that avalanche distributions closely follow a power law--the hallmark feature of SOC--for each vigilance state. However, avalanches clearly differ with vigilance states: slow wave sleep (SWS) shows large avalanches, wakefulness intermediate, and rapid eye movement (REM) sleep small ones. Our SOC model, together with the data, suggested first that the differences are mediated by global but tiny changes in synaptic strength, and second, that the changes with vigilance states reflect small deviations from criticality to the subcritical regime, implying that the human brain does not operate at criticality proper but close to SOC. Independent of criticality, the analysis confirms that SWS shows increased correlations between cortical areas, and reveals that REM sleep shows more fragmented cortical dynamics.'),
(85954, 2013, 'plos', 'A circadian clock-regulated toggle switch explains AtGRP7 and AtGRP8 oscillations in Arabidopsis thaliana', 'Schmal, Christoph|Reimann, Peter|Staiger, Dorothee', 'Condensed Matter Theory, Faculty of Physics, Bielefeld University, Bielefeld, Germany. cschmal@cebitec.uni-bielefeld.de|Condensed Matter Theory, Faculty of Physics, Bielefeld University, Bielefeld, Germany. cschmal@cebitec.uni-bielefeld.de|Condensed Matter Theory, Faculty of Physics, Bielefeld University, Bielefeld, Germany. cschmal@cebitec.uni-bielefeld.de', 'Germany|Germany|Germany', 42, 'Alternative Splicing|Arabidopsis|Arabidopsis Proteins|Circadian Clocks|Computational Biology|Computer Simulation|Feedback, Physiological|Gene Expression Regulation, Plant|Models, Genetic|Mutation|RNA-Binding Proteins', 'Journal Article', '10.1371/journal.pcbi.1002986', '23555221', 'The circadian clock controls many physiological processes in higher plants and causes a large fraction of the genome to be expressed with a 24h rhythm. The transcripts encoding the RNA-binding proteins AtGRP7 (Arabidopsis thaliana Glycine Rich Protein 7) and AtGRP8 oscillate with evening peaks. The circadian clock components CCA1 and LHY negatively affect AtGRP7 expression at the level of transcription. AtGRP7 and AtGRP8, in turn, negatively auto-regulate and reciprocally cross-regulate post-transcriptionally: high protein levels promote the generation of an alternative splice form that is rapidly degraded. This clock-regulated feedback loop has been proposed to act as a molecular slave oscillator in clock output. While mathematical models describing the circadian core oscillator in Arabidopsis thaliana were introduced recently, we propose here the first model of a circadian slave oscillator. We define the slave oscillator in terms of ordinary differential equations and identify the models parameters by an optimization procedure based on experimental results. The model successfully reproduces the pertinent experimental findings such as waveforms, phases, and half-lives of the time-dependent concentrations. Furthermore, we obtain insights into possible mechanisms underlying the observed experimental dynamics: the negative auto-regulation and reciprocal cross-regulation via alternative splicing could be responsible for the sharply peaking waveforms of the AtGRP7 and AtGRP8 mRNA. Moreover, our results suggest that the AtGRP8 transcript oscillations are subordinated to those of AtGRP7 due to a higher impact of AtGRP7 protein on alternative splicing of its own and of the AtGRP8 pre-mRNA compared to the impact of AtGRP8 protein. Importantly, a bifurcation analysis provides theoretical evidence that the slave oscillator could be a toggle switch, arising from the reciprocal cross-regulation at the post-transcriptional level. In view of this, transcriptional repression of AtGRP7 and AtGRP8 by LHY and CCA1 induces oscillations of the toggle switch, leading to the observed high-amplitude oscillations of AtGRP7 mRNA.'),
(85955, 2013, 'plos', 'Inferring metabolic states in uncharacterized environments using gene-expression measurements', 'Rossell, Sergio|Huynen, Martijn A|Notebaart, Richard A', 'Department of Bioinformatics (CMBI), Centre for Molecular Life Sciences, Radboud University Nijmegen, The Netherlands. s.rossell@cmbi.ru.nl|Department of Bioinformatics (CMBI), Centre for Molecular Life Sciences, Radboud University Nijmegen, The Netherlands. s.rossell@cmbi.ru.nl|Department of Bioinformatics (CMBI), Centre for Molecular Life Sciences, Radboud University Nijmegen, The Netherlands. s.rossell@cmbi.ru.nl', 'Netherlands|Netherlands|Netherlands', 22, 'Ethanol|Gene Expression Profiling|Glucose|Metabolic Networks and Pathways|Models, Biological|Models, Statistical|Saccharomyces cerevisiae|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002988', '23555222', 'The large size of metabolic networks entails an overwhelming multiplicity in the possible steady-state flux distributions that are compatible with stoichiometric constraints. This space of possibilities is largest in the frequent situation where the nutrients available to the cells are unknown. These two factors: network size and lack of knowledge of nutrient availability, challenge the identification of the actual metabolic state of living cells among the myriad possibilities. Here we address this challenge by developing a method that integrates gene-expression measurements with genome-scale models of metabolism as a means of inferring metabolic states. Our method explores the space of alternative flux distributions that maximize the agreement between gene expression and metabolic fluxes, and thereby identifies reactions that are likely to be active in the culture from which the gene-expression measurements were taken. These active reactions are used to build environment-specific metabolic models and to predict actual metabolic states. We applied our method to model the metabolic states of Saccharomyces cerevisiae growing in rich media supplemented with either glucose or ethanol as the main energy source. The resulting models comprise about 50% of the reactions in the original model, and predict environment-specific essential genes with high sensitivity. By minimizing the sum of fluxes while forcing our predicted active reactions to carry flux, we predicted the metabolic states of these yeast cultures that are in large agreement with what is known about yeast physiology. Most notably, our method predicts the Crabtree effect in yeast cells growing in excess glucose, a long-known phenomenon that could not have been predicted by traditional constraint-based modeling approaches. Our method is of immediate practical relevance for medical and industrial applications, such as the identification of novel drug targets, and the development of biotechnological processes that use complex, largely uncharacterized media, such as biofuel production.'),
(85956, 2013, 'plos', 'A multi-scale analysis of influenza A virus fitness trade-offs due to temperature-dependent virus persistence', 'Handel, Andreas|Brown, Justin|Stallknecht, David|Rohani, Pejman', 'Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens, Georgia, United States of America. ahandel@uga.edu|Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens, Georgia, United States of America. ahandel@uga.edu|Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens, Georgia, United States of America. ahandel@uga.edu|Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens, Georgia, United States of America. ahandel@uga.edu', 'Georgia|Georgia|Georgia|Georgia', 33, 'Animals|Birds|Computational Biology|Feces|Genetic Fitness|Host-Pathogen Interactions|Humans|Influenza A virus|Influenza, Human|Models, Biological|Orthomyxoviridae Infections|Temperature', 'Journal Article', '10.1371/journal.pcbi.1002989', '23555223', 'Successful replication within an infected host and successful transmission between hosts are key to the continued spread of most pathogens. Competing selection pressures exerted at these different scales can lead to evolutionary trade-offs between the determinants of fitness within and between hosts. Here, we examine such a trade-off in the context of influenza A viruses and the differential pressures exerted by temperature-dependent virus persistence. For a panel of avian influenza A virus strains, we find evidence for a trade-off between the persistence at high versus low temperatures. Combining a within-host model of influenza infection dynamics with a between-host transmission model, we study how such a trade-off affects virus fitness on the host population level. We show that conclusions regarding overall fitness are affected by the type of link assumed between the within- and between-host levels and the main route of transmission (direct or environmental). The relative importance of virulence and immune response mediated virus clearance are also found to influence the fitness impacts of virus persistence at low versus high temperatures. Based on our results, we predict that if transmission occurs mainly directly and scales linearly with virus load, and virulence or immune responses are negligible, the evolutionary pressure for influenza viruses to evolve toward good persistence at high within-host temperatures dominates. For all other scenarios, influenza viruses with good environmental persistence at low temperatures seem to be favored.'),
(85957, 2013, 'plos', 'In-silico assessment of protein-protein electron transfer a case study: cytochrome c peroxidase--cytochrome c', 'Wallrapp, Frank H|Voityuk, Alexander A|Guallar, Victor', 'Department of Life Sciences, Barcelona Supercomputing Center, Nexus II Building, Barcelona, Spain.|Department of Life Sciences, Barcelona Supercomputing Center, Nexus II Building, Barcelona, Spain.|Department of Life Sciences, Barcelona Supercomputing Center, Nexus II Building, Barcelona, Spain.', 'Spain|Spain|Spain', 18, 'Animals|Computer Simulation|Cytochrome-c Peroxidase|Cytochromes c|Electron Transport|Horses|Molecular Dynamics Simulation|Multiprotein Complexes|Oxidation-Reduction|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1002990', '23555224', 'The fast development of software and hardware is notably helping in closing the gap between macroscopic and microscopic data. Using a novel theoretical strategy combining molecular dynamics simulations, conformational clustering, ab-initio quantum mechanics and electronic coupling calculations, we show how computational methodologies are mature enough to provide accurate atomistic details into the mechanism of electron transfer (ET) processes in complex protein systems, known to be a significant challenge. We performed a quantitative study of the ET between Cytochrome c Peroxidase and its redox partner Cytochrome c. Our results confirm the ET mechanism as hole transfer (HT) through residues Ala194, Ala193, Gly192 and Trp191 of CcP. Furthermore, our findings indicate the fine evolution of the enzyme to approach an elevated turnover rate of 5.47 × 10(6) s(-1) for the ET between Cytc and CcP through establishment of a localized bridge state in Trp191.'),
(85958, 2013, 'plos', 'A model of binocular rivalry and cross-orientation suppression', 'Said, Christopher P|Heeger, David J', 'Center for Neural Science and Department of Psychology, New York University, New York, New York, United States of America. chris.said@nyu.edu|Center for Neural Science and Department of Psychology, New York University, New York, New York, United States of America. chris.said@nyu.edu', 'United States|United States', 58, 'Adult|Computational Biology|Computer Simulation|Female|Humans|Male|Models, Biological|Perceptual Masking|Photic Stimulation|Psychophysics|Vision, Binocular', 'Journal Article', '10.1371/journal.pcbi.1002991', '23555225', 'Binocular rivalry and cross-orientation suppression are well-studied forms of competition in visual cortex, but models of these two types of competition are in tension with one another. Binocular rivalry occurs during the presentation of dichoptic grating stimuli, where two orthogonal gratings presented separately to the two eyes evoke strong alternations in perceptual dominance. Cross-orientation suppression occurs during the presentation of plaid stimuli, where the responses to a component grating presented to both eyes is weakened by the presence of a superimposed orthogonal grating. Conventional models of rivalry that rely on strong competition between orientation-selective neurons incorrectly predict rivalry between the components of plaids. Lowering the inhibitory weights in such models reduces rivalry for plaids, but also reduces it for dichoptic gratings. Using an exhaustive grid search, we show that this problem cannot be solved simply by adjusting the parameters of the model. Instead, we propose a robust class of models that rely on ocular opponency neurons, previously proposed as a mechanism for efficient stereo coding, to yield rivalry only for dichoptic gratings, not for plaids. This class of models reconciles models of binocular rivalry with the divisive normalization framework that has been used to explain cross-orientation. Our model makes novel predictions that we confirmed with psychophysical tests.'),
(85959, 2013, 'plos', 'Under-dominance constrains the evolution of negative autoregulation in diploids', 'Stewart, Alexander J|Seymour, Robert M|Pomiankowski, Andrew|Reuter, Max', 'Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. alstew@sas.upenn.edu|Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. alstew@sas.upenn.edu|Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. alstew@sas.upenn.edu|Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. alstew@sas.upenn.edu', 'United States|United States|United States|United States', 8, 'Animals|Binding Sites|Diploidy|Drosophila melanogaster|Escherichia coli|Evolution, Molecular|Gene Expression Regulation|Gene Regulatory Networks|Homeostasis|Humans|Models, Genetic|Molecular Dynamics Simulation|Monte Carlo Method|Mutation|Saccharomyces cerevisiae|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002992', '23555226', 'Regulatory networks have evolved to allow gene expression to rapidly track changes in the environment as well as to buffer perturbations and maintain cellular homeostasis in the absence of change. Theoretical work and empirical investigation in Escherichia coli have shown that negative autoregulation confers both rapid response times and reduced intrinsic noise, which is reflected in the fact that almost half of Escherichia coli transcription factors are negatively autoregulated. However, negative autoregulation is rare amongst the transcription factors of Saccharomyces cerevisiae. This difference is surprising because E. coli and S. cerevisiae otherwise have similar profiles of network motifs. In this study we investigate regulatory interactions amongst the transcription factors of Drosophila melanogaster and humans, and show that they have a similar dearth of negative autoregulation to that seen in S. cerevisiae. We then present a model demonstrating that this striking difference in the noise reduction strategies used amongst species can be explained by constraints on the evolution of negative autoregulation in diploids. We show that regulatory interactions between pairs of homologous genes within the same cell can lead to under-dominance--mutations which result in stronger autoregulation, and decrease noise in homozygotes, paradoxically can cause increased noise in heterozygotes. This severely limits a diploids ability to evolve negative autoregulation as a noise reduction mechanism. Our work offers a simple and general explanation for a previously unexplained difference between the regulatory architectures of E. coli and yeast, Drosophila and humans. It also demonstrates that the effects of diploidy in gene networks can have counter-intuitive consequences that may profoundly influence the course of evolution.'),
(85960, 2013, 'plos', 'The fate of cooperation during range expansions', 'Korolev, Kirill S', 'Department of Physics, Massachusetts Institute of Technology, Cambridge, Massacusetts, United States of America. papers.korolev@gmail.com', 'United States', 0, 'Animal Migration|Animals|Biological Evolution|Computational Biology|Cooperative Behavior|Diffusion|Ecology|Feedback|Models, Biological|Population Dynamics|Selection, Genetic|Spatial Behavior', 'Journal Article', '10.1371/journal.pcbi.1002994', '23555227', 'Species expand their geographical ranges following an environmental change, long range dispersal, or a new adaptation. Range expansions not only bring an ecological change, but also affect the evolution of the expanding species. Although the dynamics of deleterious, neutral, and beneficial mutations have been extensively studied in expanding populations, the fate of alleles under frequency-dependent selection remains largely unexplored. The dynamics of cooperative alleles are particularly interesting because selection can be both frequency and density dependent, resulting in a coupling between population and evolutionary dynamics. This coupling leads to an increase in the frequency of cooperators at the expansion front, and, under certain conditions, the entire front can be taken over by cooperators. Thus, a mixed population wave can split into an expansion wave of only cooperators followed by an invasion wave of defectors. After the splitting, cooperators increase in abundance by expanding into new territories faster than they are invaded by defectors. Our results not only provide an explanation for the maintenance of cooperation but also elucidate the effect of eco-evolutionary feedback on the maintenance of genetic diversity during range expansions. When cooperators do not split away, we find that defectors can spread much faster with cooperators than they would be able to on their own or by invading cooperators. This enhanced rate of expansion in mixed waves could counterbalance the loss of genetic diversity due to the founder effect for mutations under frequency-dependent selection. Although we focus on cooperator-defector interactions, our analysis could also be relevant for other systems described by reaction-diffusion equations.'),
(85961, 2013, 'plos', 'Rampant exchange of the structure and function of extramembrane domains between membrane and water soluble proteins', 'Nam, Hyun-Jun|Han, Seong Kyu|Bowie, James U|Kim, Sanguk', 'Department of Life Science, Division of IT Convergence Engineering, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Korea.|Department of Life Science, Division of IT Convergence Engineering, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Korea.|Department of Life Science, Division of IT Convergence Engineering, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Korea.|Department of Life Science, Division of IT Convergence Engineering, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Korea.', '-|-|-|-', 7, 'Amino Acid Sequence|Computational Biology|Databases, Protein|Eukaryota|Humans|Membrane Proteins|Models, Molecular|Phylogeny|Protein Structure, Tertiary|Proteome|Sequence Alignment|Solubility|Water', 'Journal Article', '10.1371/journal.pcbi.1002997', '23555228', 'Of the membrane proteins of known structure, we found that a remarkable 67% of the water soluble domains are structurally similar to water soluble proteins of known structure. Moreover, 41% of known water soluble protein structures share a domain with an already known membrane protein structure. We also found that functional residues are frequently conserved between extramembrane domains of membrane and soluble proteins that share structural similarity. These results suggest membrane and soluble proteins readily exchange domains and their attendant functionalities. The exchanges between membrane and soluble proteins are particularly frequent in eukaryotes, indicating that this is an important mechanism for increasing functional complexity. The high level of structural overlap between the two classes of proteins provides an opportunity to employ the extensive information on soluble proteins to illuminate membrane protein structure and function, for which much less is known. To this end, we employed structure guided sequence alignment to elucidate the functions of membrane proteins in the human genome. Our results bridge the gap of fold space between membrane and water soluble proteins and provide a resource for the prediction of membrane protein function. A database of predicted structural and functional relationships for proteins in the human genome is provided at sbi.postech.ac.kr/emdmp.'),
(85962, 2013, 'plos', 'Systematic prediction of pharmacodynamic drug-drug interactions through protein-protein-interaction network', 'Huang, Jialiang|Niu, Chaoqun|Green, Christopher D|Yang, Lun|Mei, Hongkang|Han, Jing-Dong J', 'Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.', 'China|China|China|China|China|China', 0, 'Algorithms|Bayes Theorem|Computational Biology|Databases, Protein|Drug Interactions|Humans|Models, Chemical|Models, Statistical|Pharmaceutical Preparations|Pharmacokinetics|Pharmacology|Protein Interaction Maps', 'Journal Article', '10.1371/journal.pcbi.1002998', '23555229', 'Identifying drug-drug interactions (DDIs) is a major challenge in drug development. Previous attempts have established formal approaches for pharmacokinetic (PK) DDIs, but there is not a feasible solution for pharmacodynamic (PD) DDIs because the endpoint is often a serious adverse event rather than a measurable change in drug concentration. Here, we developed a metric S-score that measures the strength of network connection between drug targets to predict PD DDIs. Utilizing known PD DDIs as golden standard positives (GSPs), we observed a significant correlation between S-score and the likelihood a PD DDI occurs. Our prediction was robust and surpassed existing methods as validated by two independent GSPs. Analysis of clinical side effect data suggested that the drugs having predicted DDIs have similar side effects. We further incorporated this clinical side effects evidence with S-score to increase the prediction specificity and sensitivity through a Bayesian probabilistic model. We have predicted 9,626 potential PD DDIs at the accuracy of 82% and the recall of 62%. Importantly, our algorithm provided opportunities for better understanding the potential molecular mechanisms or physiological effects underlying DDIs, as illustrated by the case studies.'),
(85963, 2013, 'plos', 'Outlier responses reflect sensitivity to statistical structure in the human brain', 'Garrido, Marta I|Sahani, Maneesh|Dolan, Raymond J', 'University College London, Wellcome Trust Centre for Neuroimaging, London, United Kingdom. m.garrido@uq.edu.au|University College London, Wellcome Trust Centre for Neuroimaging, London, United Kingdom. m.garrido@uq.edu.au|University College London, Wellcome Trust Centre for Neuroimaging, London, United Kingdom. m.garrido@uq.edu.au', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Acoustic Stimulation|Analysis of Variance|Brain|Computational Biology|Evoked Potentials, Auditory|Humans|Learning|Magnetoencephalography|Models, Neurological|Models, Statistical|Noise|Perception|Reaction Time', 'Journal Article', '10.1371/journal.pcbi.1002999', '23555230', 'We constantly look for patterns in the environment that allow us to learn its key regularities. These regularities are fundamental in enabling us to make predictions about what is likely to happen next. The physiological study of regularity extraction has focused primarily on repetitive sequence-based rules within the sensory environment, or on stimulus-outcome associations in the context of reward-based decision-making. Here we ask whether we implicitly encode non-sequential stochastic regularities, and detect violations therein. We addressed this question using a novel experimental design and both behavioural and magnetoencephalographic (MEG) metrics associated with responses to pure-tone sounds with frequencies sampled from a Gaussian distribution. We observed that sounds in the tail of the distribution evoked a larger response than those that fell at the centre. This response resembled the mismatch negativity (MMN) evoked by surprising or unlikely events in traditional oddball paradigms. Crucially, responses to physically identical outliers were greater when the distribution was narrower. These results show that humans implicitly keep track of the uncertainty induced by apparently random distributions of sensory events. Source reconstruction suggested that the statistical-context-sensitive responses arose in a temporo-parietal network, areas that have been associated with attention orientation to unexpected events. Our results demonstrate a very early neurophysiological marker of the brains ability to implicitly encode complex statistical structure in the environment. We suggest that this sensitivity provides a computational basis for our ability to make perceptual inferences in noisy environments and to make decisions in an uncertain world.'),
(85964, 2013, 'plos', 'Transcriptome profiling of Giardia intestinalis using strand-specific RNA-seq', 'Franzén, Oscar|Jerlström-Hultqvist, Jon|Einarsson, Elin|Ankarklev, Johan|Ferella, Marcela|Andersson, Björn|Svärd, Staffan G', 'Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.|Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.|Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.|Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.|Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.|Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.|Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.', 'Sweden|Sweden|Sweden|Sweden|Sweden|Sweden|Sweden', 0, 'Antigens, Protozoan|Computational Biology|Databases, Genetic|Gene Expression Profiling|Gene Expression Regulation|Giardia lamblia|Giardiasis|Humans|Phylogeny|Polyadenylation|Protozoan Proteins|RNA, Messenger|Reverse Transcriptase Polymerase Chain Reaction|Sequence Analysis, RNA|Statistics, Nonparametric', 'Journal Article', '10.1371/journal.pcbi.1003000', '23555231', 'Giardia intestinalis is a common cause of diarrheal disease and it consists of eight genetically distinct genotypes or assemblages (A-H). Only assemblages A and B infect humans and are suggested to represent two different Giardia species. Correlations exist between assemblage type and host-specificity and to some extent symptoms. Phenotypical differences have been documented between assemblages and genome sequences are available for A, B and E. We have characterized and compared the polyadenylated transcriptomes of assemblages A, B and E. Four genetically different isolates were studied (WB (AI), AS175 (AII), P15 (E) and GS (B)) using paired-end, strand-specific RNA-seq. Most of the genome was transcribed in trophozoites grown in vitro, but at vastly different levels. RNA-seq confirmed many of the present annotations and refined the current genome annotation. Gene expression divergence was found to recapitulate the known phylogeny, and uncovered lineage-specific differences in expression. Polyadenylation sites were mapped for over 70% of the genes and revealed many examples of conserved and unexpectedly long 3 UTRs. 28 open reading frames were found in a non-transcribed gene cluster on chromosome 5 of the WB isolate. Analysis of allele-specific expression revealed a correlation between allele-dosage and allele expression in the GS isolate. Previously reported cis-splicing events were confirmed and global mapping of cis-splicing identified only one novel intron. These observations can possibly explain differences in host-preference and symptoms, and it will be the basis for further studies of Giardia pathogenesis and biology.'),
(85965, 2013, 'plos', 'Folding pathways of a knotted protein with a realistic atomistic force field', 'a Beccara, Silvio|xc5xa0krbixc4x87, Tatjana|Covino, Roberto|Micheletti, Cristian|Faccioli, Pietro', 'LISC, Bruno Kessler Foundation, Trento, Italy.|LISC, Bruno Kessler Foundation, Trento, Italy.|LISC, Bruno Kessler Foundation, Trento, Italy.|LISC, Bruno Kessler Foundation, Trento, Italy.|LISC, Bruno Kessler Foundation, Trento, Italy.', 'Italy|Italy|Italy|Italy|Italy', 0, 'Algorithms|Archaeal Proteins|Computational Biology|Molecular Dynamics Simulation|Monte Carlo Method|Protein Conformation|Protein Folding|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003002', '23555232', 'We report on atomistic simulation of the folding of a natively-knotted protein, MJ0366, based on a realistic force field. To the best of our knowledge this is the first reported effort where a realistic force field is used to investigate the folding pathways of a protein with complex native topology. By using the dominant-reaction pathway scheme we collected about 30 successful folding trajectories for the 82-amino acid long trefoil-knotted protein. Despite the dissimilarity of their initial unfolded configuration, these trajectories reach the natively-knotted state through a remarkably similar succession of steps. In particular it is found that knotting occurs essentially through a threading mechanism, involving the passage of the C-terminal through an open region created by the formation of the native [Formula: see text]-sheet at an earlier stage. The dominance of the knotting by threading mechanism is not observed in MJ0366 folding simulations using simplified, native-centric models. This points to a previously underappreciated role of concerted amino acid interactions, including non-native ones, in aiding the appropriate order of contact formation to achieve knotting.'),
(85966, 2013, 'plos', 'Connecting the kinetics and energy landscape of tRNA translocation on the ribosome', 'Whitford, Paul C|Blanchard, Scott C|Cate, Jamie H D|Sanbonmatsu, Karissa Y', 'Department of Physics, Northeastern University, Boston, Massachusetts, United States of America. p.whitford@neu.edu|Department of Physics, Northeastern University, Boston, Massachusetts, United States of America. p.whitford@neu.edu|Department of Physics, Northeastern University, Boston, Massachusetts, United States of America. p.whitford@neu.edu|Department of Physics, Northeastern University, Boston, Massachusetts, United States of America. p.whitford@neu.edu', 'United States|United States|United States|United States', 0, 'Algorithms|Computational Biology|Diffusion|Kinetics|Molecular Dynamics Simulation|Nucleic Acid Conformation|RNA, Transfer|Ribosomes|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003003', '23555233', 'Functional rearrangements in biomolecular assemblies result from diffusion across an underlying energy landscape. While bulk kinetic measurements rely on discrete state-like approximations to the energy landscape, single-molecule methods can project the free energy onto specific coordinates. With measures of the diffusion, one may establish a quantitative bridge between state-like kinetic measurements and the continuous energy landscape. We used an all-atom molecular dynamics simulation of the 70S ribosome (2.1 million atoms, 1.3 microseconds) to provide this bridge for specific conformational events associated with the process of tRNA translocation. Starting from a pre-translocation configuration, we identified sets of residues that collectively undergo rotary rearrangements implicated in ribosome function. Estimates of the diffusion coefficients along these collective coordinates for translocation were then used to interconvert between experimental rates and measures of the energy landscape. This analysis, in conjunction with previously reported experimental rates of translocation, provides an upper-bound estimate of the free-energy barriers associated with translocation. While this analysis was performed for a particular kinetic scheme of translocation, the quantitative framework is general and may be applied to energetic and kinetic descriptions that include any number of intermediates and transition states.'),
(85967, 2013, 'plos', 'Systems model of T cell receptor proximal signaling reveals emergent ultrasensitivity', 'Mukhopadhyay, Himadri|Cordoba, Shaun-Paul|Maini, Philip K|van der Merwe, P Anton|Dushek, Omer', 'Sir William Dunn School of Pathology, University of Oxford, Oxford, Oxfordshire, United Kingdom.|Sir William Dunn School of Pathology, University of Oxford, Oxford, Oxfordshire, United Kingdom.|Sir William Dunn School of Pathology, University of Oxford, Oxford, Oxfordshire, United Kingdom.|Sir William Dunn School of Pathology, University of Oxford, Oxford, Oxfordshire, United Kingdom.|Sir William Dunn School of Pathology, University of Oxford, Oxford, Oxfordshire, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 30, 'Animals|Humans|Models, Immunological|Phosphorylation|Protein Binding|Protein-Tyrosine Kinases|Receptors, Antigen, T-Cell|Signal Transduction|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1003004', '23555234', 'Receptor phosphorylation is thought to be tightly regulated because phosphorylated receptors initiate signaling cascades leading to cellular activation. The T cell antigen receptor (TCR) on the surface of T cells is phosphorylated by the kinase Lck and dephosphorylated by the phosphatase CD45 on multiple immunoreceptor tyrosine-based activation motifs (ITAMs). Intriguingly, Lck sequentially phosphorylates ITAMs and ZAP-70, a cytosolic kinase, binds to phosphorylated ITAMs with differential affinities. The purpose of multiple ITAMs, their sequential phosphorylation, and the differential ZAP-70 affinities are unknown. Here, we use a systems model to show that this signaling architecture produces emergent ultrasensitivity resulting in switch-like responses at the scale of individual TCRs. Importantly, this switch-like response is an emergent property, so that removal of multiple ITAMs, sequential phosphorylation, or differential affinities abolishes the switch. We propose that highly regulated TCR phosphorylation is achieved by an emergent switch-like response and use the systems model to design novel chimeric antigen receptors for therapy.'),
(85968, 2013, 'plos', 'An integrated computational/experimental model of lymphoma growth', 'Frieboes, Hermann B|Smith, Bryan R|Chuang, Yao-Li|Ito, Ken|Roettgers, Allison M|Gambhir, Sanjiv S|Cristini, Vittorio', 'Department of Bioengineering, University of Louisville, Louisville, Kentucky, United States of America. hbfrie01@louisville.edu|Department of Bioengineering, University of Louisville, Louisville, Kentucky, United States of America. hbfrie01@louisville.edu|Department of Bioengineering, University of Louisville, Louisville, Kentucky, United States of America. hbfrie01@louisville.edu|Department of Bioengineering, University of Louisville, Louisville, Kentucky, United States of America. hbfrie01@louisville.edu|Department of Bioengineering, University of Louisville, Louisville, Kentucky, United States of America. hbfrie01@louisville.edu|Department of Bioengineering, University of Louisville, Louisville, Kentucky, United States of America. hbfrie01@louisville.edu|Department of Bioengineering, University of Louisville, Louisville, Kentucky, United States of America. hbfrie01@louisville.edu', 'United States|United States|United States|United States|United States|United States|United States', 0, 'Animals|Antineoplastic Agents|Apoptosis|Calibration|Cell Proliferation|Cell Survival|Computational Biology|Cyclophosphamide|Disease Progression|Doxorubicin|Drug Resistance, Neoplasm|Immunohistochemistry|Lymphoma, Non-Hodgkin|Mice|Mice, Inbred C57BL|Mice, Transgenic|Models, Biological|Neovascularization, Pathologic|Tumor Suppressor Protein p53', 'Journal Article', '10.1371/journal.pcbi.1003008', '23555235', 'Non-Hodgkins lymphoma is a disseminated, highly malignant cancer, with resistance to drug treatment based on molecular- and tissue-scale characteristics that are intricately linked. A critical element of molecular resistance has been traced to the loss of functionality in proteins such as the tumor suppressor p53. We investigate the tissue-scale physiologic effects of this loss by integrating in vivo and immunohistological data with computational modeling to study the spatiotemporal physical dynamics of lymphoma growth. We compare between drug-sensitive Excexbc-myc Arf-/- and drug-resistant Excexbc-myc p53-/- lymphoma cell tumors grown in live mice. Initial values for the model parameters are obtained in part by extracting values from the cellular-scale from whole-tumor histological staining of the tumor-infiltrated inguinal lymph node in vivo. We compare model-predicted tumor growth with that observed from intravital microscopy and macroscopic imaging in vivo, finding that the model is able to accurately predict lymphoma growth. A critical physical mechanism underlying drug-resistant phenotypes may be that the Excexbc-myc p53-/- cells seem to pack more closely within the tumor than the Excexbc-myc Arf-/- cells, thus possibly exacerbating diffusion gradients of oxygen, leading to cell quiescence and hence resistance to cell-cycle specific drugs. Tighter cell packing could also maintain steeper gradients of drug and lead to insufficient toxicity. The transport phenomena within the lymphoma may thus contribute in nontrivial, complex ways to the difference in drug sensitivity between Excexbc-myc Arf-/- and Excexbc-myc p53-/- tumors, beyond what might be solely expected from loss of functionality at the molecular scale. We conclude that computational modeling tightly integrated with experimental data gives insight into the dynamics of Non-Hodgkins lymphoma and provides a platform to generate confirmable predictions of tumor growth.'),
(85969, 2013, 'plos', 'Origin and evolution of protein fold designs inferred from phylogenomic analysis of CATH domain structures in proteomes', 'Bukhari, Syed Abbas|Caetano-Anollxc3xa9s, Gustavo', 'Evolutionary Bioinformatics Laboratory, Department of Crop Sciences, University of Illinois, Urbana, Illinois, United States of America.|Evolutionary Bioinformatics Laboratory, Department of Crop Sciences, University of Illinois, Urbana, Illinois, United States of America.', 'United States|United States', 25, 'Archaea|Bacteria|Computational Biology|Eukaryota|Evolution, Molecular|Models, Genetic|Phylogeny|Protein Structure, Tertiary|Proteins|Proteome', 'Journal Article', '10.1371/journal.pcbi.1003009', '23555236', 'The spatial arrangements of secondary structures in proteins, irrespective of their connectivity, depict the overall shape and organization of protein domains. These features have been used in the CATH and SCOP classifications to hierarchically partition fold space and define the architectural make up of proteins. Here we use phylogenomic methods and a census of CATH structures in hundreds of genomes to study the origin and diversification of protein architectures (A) and their associated topologies (T) and superfamilies (H). Phylogenies that describe the evolution of domain structures and proteomes were reconstructed from the structural census and used to generate timelines of domain discovery. Phylogenies of CATH domains at T and H levels of structural abstraction and associated chronologies revealed patterns of reductive evolution, the early rise of Archaea, three epochs in the evolution of the protein world, and patterns of structural sharing between superkingdoms. Phylogenies of proteomes confirmed the early appearance of Archaea. While these findings are in agreement with previous phylogenomic studies based on the SCOP classification, phylogenies unveiled sharing patterns between Archaea and Eukarya that are recent and can explain the canonical bacterial rooting typically recovered from sequence analysis. Phylogenies of CATH domains at A level uncovered general patterns of architectural origin and diversification. The tree of A structures showed that ancient structural designs such as the 3-layer (xcexb1xcexb2xcexb1) sandwich (3.40) or the orthogonal bundle (1.10) are comparatively simpler in their makeup and are involved in basic cellular functions. In contrast, modern structural designs such as prisms, propellers, 2-solenoid, super-roll, clam, trefoil and box are not widely distributed and were probably adopted to perform specialized functions. Our timelines therefore uncover a universal tendency towards protein structural complexity that is remarkable.'),
(85970, 2013, 'plos', 'Sparse distributed representation of odors in a large-scale olfactory bulb circuit', 'Yu, Yuguo|McTavish, Thomas S|Hines, Michael L|Shepherd, Gordon M|Valenti, Cesare|Migliore, Michele', 'Centre for Computational Systems Biology, School of Life Sciences, Fudan University, Shanghai, Peoples Republic of China.|Centre for Computational Systems Biology, School of Life Sciences, Fudan University, Shanghai, Peoples Republic of China.|Centre for Computational Systems Biology, School of Life Sciences, Fudan University, Shanghai, Peoples Republic of China.|Centre for Computational Systems Biology, School of Life Sciences, Fudan University, Shanghai, Peoples Republic of China.|Centre for Computational Systems Biology, School of Life Sciences, Fudan University, Shanghai, Peoples Republic of China.|Centre for Computational Systems Biology, School of Life Sciences, Fudan University, Shanghai, Peoples Republic of China.', 'China|China|China|China|China|China', 0, 'Animals|Computational Biology|Computer Simulation|Feedback, Physiological|Male|Models, Neurological|Nerve Net|Neuronal Plasticity|Neurons|Odorants|Olfactory Bulb|Rats|Synapses', 'Journal Article', '10.1371/journal.pcbi.1003014', '23555237', 'In the olfactory bulb, lateral inhibition mediated by granule cells has been suggested to modulate the timing of mitral cell firing, thereby shaping the representation of input odorants. Current experimental techniques, however, do not enable a clear study of how the mitral-granule cell network sculpts odor inputs to represent odor information spatially and temporally. To address this critical step in the neural basis of odor recognition, we built a biophysical network model of mitral and granule cells, corresponding to 1/100th of the real system in the rat, and used direct experimental imaging data of glomeruli activated by various odors. The model allows the systematic investigation and generation of testable hypotheses of the functional mechanisms underlying odor representation in the olfactory bulb circuit. Specifically, we demonstrate that lateral inhibition emerges within the olfactory bulb network through recurrent dendrodendritic synapses when constrained by a range of balanced excitatory and inhibitory conductances. We find that the spatio-temporal dynamics of lateral inhibition plays a critical role in building the glomerular-related cell clusters observed in experiments, through the modulation of synaptic weights during odor training. Lateral inhibition also mediates the development of sparse and synchronized spiking patterns of mitral cells related to odor inputs within the network, with the frequency of these synchronized spiking patterns also modulated by the sniff cycle.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85971, 2013, 'plos', 'Colocalization of coregulated genes: a steered molecular dynamics study of human chromosome 19', 'Di Stefano, Marco|Rosa, Angelo|Belcastro, Vincenzo|di Bernardo, Diego|Micheletti, Cristian', 'International School for Advanced Studies, SISSA, Trieste, Italy.|International School for Advanced Studies, SISSA, Trieste, Italy.|International School for Advanced Studies, SISSA, Trieste, Italy.|International School for Advanced Studies, SISSA, Trieste, Italy.|International School for Advanced Studies, SISSA, Trieste, Italy.', 'Italy|Italy|Italy|Italy|Italy', 37, 'Chromosomes, Human, Pair 19|Cluster Analysis|Computational Biology|Gene Regulatory Networks|Genes|Humans|Interphase|Mitosis|Molecular Dynamics Simulation|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1003019', '23555238', 'The connection between chromatin nuclear organization and gene activity is vividly illustrated by the observation that transcriptional coregulation of certain genes appears to be directly influenced by their spatial proximity. This fact poses the more general question of whether it is at all feasible that the numerous genes that are coregulated on a given chromosome, especially those at large genomic distances, might become proximate inside the nucleus. This problem is studied here using steered molecular dynamics simulations in order to enforce the colocalization of thousands of knowledge-based gene sequences on a model for the gene-rich human chromosome 19. Remarkably, it is found that most (xe2x89x88 88%) gene pairs can be brought simultaneously into contact. This is made possible by the low degree of intra-chromosome entanglement and the large number of cliques in the gene coregulatory network. A clique is a set of genes coregulated all together as a group. The constrained conformations for the model chromosome 19 are further shown to be organized in spatial macrodomains that are similar to those inferred from recent HiC measurements. The findings indicate that gene coregulation and colocalization are largely compatible and that this relationship can be exploited to draft the overall spatial organization of the chromosome in vivo. The more general validity and implications of these findings could be investigated by applying to other eukaryotic chromosomes the general and transferable computational strategy introduced here.'),
(85972, 2013, 'plos', 'Noise suppression and surplus synchrony by coincidence detection', 'Schultze-Kraft, Matthias|Diesmann, Markus|Grün, Sonja|Helias, Moritz', 'Machine Learning Group, Berlin Institute of Technology, Berlin, Germany. schultze-kraft@tu-berlin.de|Machine Learning Group, Berlin Institute of Technology, Berlin, Germany. schultze-kraft@tu-berlin.de|Machine Learning Group, Berlin Institute of Technology, Berlin, Germany. schultze-kraft@tu-berlin.de|Machine Learning Group, Berlin Institute of Technology, Berlin, Germany. schultze-kraft@tu-berlin.de', 'Germany|Germany|Germany|Germany', 0, 'Action Potentials|Animals|Computational Biology|Computer Simulation|Diffusion|Humans|Models, Neurological|Models, Statistical|Neural Networks (Computer)|Neurons|Normal Distribution|Synapses|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002904', '23592953', 'The functional significance of correlations between action potentials of neurons is still a matter of vivid debate. In particular, it is presently unclear how much synchrony is caused by afferent synchronized events and how much is intrinsic due to the connectivity structure of cortex. The available analytical approaches based on the diffusion approximation do not allow to model spike synchrony, preventing a thorough analysis. Here we theoretically investigate to what extent common synaptic afferents and synchronized inputs each contribute to correlated spiking on a fine temporal scale between pairs of neurons. We employ direct simulation and extend earlier analytical methods based on the diffusion approximation to pulse-coupling, allowing us to introduce precisely timed correlations in the spiking activity of the synaptic afferents. We investigate the transmission of correlated synaptic input currents by pairs of integrate-and-fire model neurons, so that the same input covariance can be realized by common inputs or by spiking synchrony. We identify two distinct regimes: In the limit of low correlation linear perturbation theory accurately determines the correlation transmission coefficient, which is typically smaller than unity, but increases sensitively even for weakly synchronous inputs. In the limit of high input correlation, in the presence of synchrony, a qualitatively new picture arises. As the non-linear neuronal response becomes dominant, the output correlation becomes higher than the total correlation in the input. This transmission coefficient larger unity is a direct consequence of non-linear neural processing in the presence of noise, elucidating how synchrony-coded signals benefit from these generic properties present in cortical networks.'),
(85973, 2013, 'plos', 'Optimal balance of the striatal medium spiny neuron network', 'Ponzi, Adam|Wickens, Jeffery R', 'Neurobiology Research Unit, Okinawa Institute of Science and Technology (OIST), Okinawa, Japan. adamp@oist.jp|Neurobiology Research Unit, Okinawa Institute of Science and Technology (OIST), Okinawa, Japan. adamp@oist.jp', 'Japan|Japan', 26, 'Action Potentials|Algorithms|Animals|Basal Ganglia|Computational Biology|Computer Simulation|Corpus Striatum|Humans|Inhibitory Postsynaptic Potentials|Models, Neurological|Neural Inhibition|Neurons|Post-Synaptic Density|Reproducibility of Results|Software|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002954', '23592954', 'Slowly varying activity in the striatum, the main Basal Ganglia input structure, is important for the learning and execution of movement sequences. Striatal medium spiny neurons (MSNs) form cell assemblies whose population firing rates vary coherently on slow behaviourally relevant timescales. It has been shown that such activity emerges in a model of a local MSN network but only at realistic connectivities of 10 ~ 20% and only when MSN generated inhibitory post-synaptic potentials (IPSPs) are realistically sized. Here we suggest a reason for this. We investigate how MSN network generated population activity interacts with temporally varying cortical driving activity, as would occur in a behavioural task. We find that at unrealistically high connectivity a stable winners-take-all type regime is found where network activity separates into fixed stimulus dependent regularly firing and quiescent components. In this regime only a small number of population firing rate components interact with cortical stimulus variations. Around 15% connectivity a transition to a more dynamically active regime occurs where all cells constantly switch between activity and quiescence. In this low connectivity regime, MSN population components wander randomly and here too are independent of variations in cortical driving. Only in the transition regime do weak changes in cortical driving interact with many population components so that sequential cell assemblies are reproducibly activated for many hundreds of milliseconds after stimulus onset and peri-stimulus time histograms display strong stimulus and temporal specificity. We show that, remarkably, this activity is maximized at striatally realistic connectivities and IPSP sizes. Thus, we suggest the local MSN network has optimal characteristics - it is neither too stable to respond in a dynamically complex temporally extended way to cortical variations, nor is it too unstable to respond in a consistent repeatable way. Rather, it is optimized to generate stimulus dependent activity patterns for long periods after variations in cortical excitation.'),
(85974, 2013, 'plos', 'Computational biomarker pipeline from discovery to clinical implementation: plasma proteomic biomarkers for cardiac transplantation', 'Cohen Freue, Gabriela V|Meredith, Anna|Smith, Derek|Bergman, Axel|Sasaki, Mayu|Lam, Karen K Y|Hollander, Zsuzsanna|Opushneva, Nina|Takhar, Mandeep|Lin, David|Wilson-McManus, Janet|Balshaw, Robert|Keown, Paul A|Borchers, Christoph H|McManus, Bruce|Ng, Raymond T|McMaster, W Robert|Biomarkers in Transplantation and the NCE CECR Prevention of Organ Failure Centre of Excellence Teams', 'NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.|NCE CECR Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.', 'Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Ca', 31, 'Biomarkers|Blood Proteins|Calibration|Cohort Studies|Computational Biology|Enzyme-Linked Immunosorbent Assay|Graft Rejection|Heart Failure|Heart Transplantation|Humans|Inflammation|Mass Spectrometry|Proteome|Proteomics', 'Journal Article', '10.1371/journal.pcbi.1002963', '23592955', 'Recent technical advances in the field of quantitative proteomics have stimulated a large number of biomarker discovery studies of various diseases, providing avenues for new treatments and diagnostics. However, inherent challenges have limited the successful translation of candidate biomarkers into clinical use, thus highlighting the need for a robust analytical methodology to transition from biomarker discovery to clinical implementation. We have developed an end-to-end computational proteomic pipeline for biomarkers studies. At the discovery stage, the pipeline emphasizes different aspects of experimental design, appropriate statistical methodologies, and quality assessment of results. At the validation stage, the pipeline focuses on the migration of the results to a platform appropriate for external validation, and the development of a classifier score based on corroborated protein biomarkers. At the last stage towards clinical implementation, the main aims are to develop and validate an assay suitable for clinical deployment, and to calibrate the biomarker classifier using the developed assay. The proposed pipeline was applied to a biomarker study in cardiac transplantation aimed at developing a minimally invasive clinical test to monitor acute rejection. Starting with an untargeted screening of the human plasma proteome, five candidate biomarker proteins were identified. Rejection-regulated proteins reflect cellular and humoral immune responses, acute phase inflammatory pathways, and lipid metabolism biological processes. A multiplex multiple reaction monitoring mass-spectrometry (MRM-MS) assay was developed for the five candidate biomarkers and validated by enzyme-linked immune-sorbent (ELISA) and immunonephelometric assays (INA). A classifier score based on corroborated proteins demonstrated that the developed MRM-MS assay provides an appropriate methodology for an external validation, which is still in progress. Plasma proteomic biomarkers of acute cardiac rejection may offer a relevant post-transplant monitoring tool to effectively guide clinical care. The proposed computational pipeline is highly applicable to a wide range of biomarker proteomic studies.'),
(85975, 2013, 'plos', 'Analysis of accuracy in pointing with redundant hand-held tools: a geometric approach to the uncontrolled manifold method', 'Campolo, Domenico|Widjaja, Ferdinan|Xu, Hong|Ang, Wei Tech|Burdet, Etienne', 'School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore. d.campolo@ntu.edu.sg|School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore. d.campolo@ntu.edu.sg|School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore. d.campolo@ntu.edu.sg|School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore. d.campolo@ntu.edu.sg|School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore. d.campolo@ntu.edu.sg', 'Singapore|Singapore|Singapore|Singapore|Singapore', 0, 'Algorithms|Arm|Biomechanical Phenomena|Brain|Computational Biology|Computer Simulation|Hand|Humans|Models, Theoretical|Movement|Range of Motion, Articular|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1002978', '23592956', 'This work introduces a coordinate-independent method to analyse movement variability of tasks performed with hand-held tools, such as a pen or a surgical scalpel. We extend the classical uncontrolled manifold (UCM) approach by exploiting the geometry of rigid body motions, used to describe tool configurations. In particular, we analyse variability during a static pointing task with a hand-held tool, where subjects are asked to keep the tool tip in steady contact with another object. In this case the tool is redundant with respect to the task, as subjects control position/orientation of the tool, i.e. 6 degrees-of-freedom (dof), to maintain the tool tip position (3dof) steady. To test the new method, subjects performed a pointing task with and without arm support. The additional dof introduced in the unsupported condition, injecting more variability into the system, represented a resource to minimise variability in the task space via coordinated motion. The results show that all of the seven subjects channeled more variability along directions not directly affecting the task (UCM), consistent with previous literature but now shown in a coordinate-independent way. Variability in the unsupported condition was only slightly larger at the endpoint but much larger in the UCM.'),
(85976, 2013, 'plos', 'Generative FDG-PET and MRI model of aging and disease progression in Alzheimers disease', 'Dukart, Juergen|Kherif, Ferath|Mueller, Karsten|Adaszewski, Stanislaw|Schroeter, Matthias L|Frackowiak, Richard S J|Draganski, Bogdan|Alzheimers Disease Neuroimaging Initiative', 'LREN, Département des Neurosciences Cliniques, CHUV, Université de Lausanne, Lausanne, Switzerland. dukart@cbs.mpg.de|LREN, Département des Neurosciences Cliniques, CHUV, Université de Lausanne, Lausanne, Switzerland. dukart@cbs.mpg.de|LREN, Département des Neurosciences Cliniques, CHUV, Université de Lausanne, Lausanne, Switzerland. dukart@cbs.mpg.de|LREN, Département des Neurosciences Cliniques, CHUV, Université de Lausanne, Lausanne, Switzerland. dukart@cbs.mpg.de|LREN, Département des Neurosciences Cliniques, CHUV, Université de Lausanne, Lausanne, Switzerland. dukart@cbs.mpg.de|LREN, Département des Neurosciences Cliniques, CHUV, Université de Lausanne, Lausanne, Switzerland. dukart@cbs.mpg.de|LREN, Département des Neurosciences Cliniques, CHUV, Université de Lausanne, Lausanne, Switzerland. dukart@cbs.mpg.de|LREN, Département des Neurosciences Cliniques, CHUV, Université de Lausanne, Lausanne, Switzerland. dukart@cbs.mpg.de', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 0, 'Aged|Aged, 80 and over|Aging|Alzheimer Disease|Brain|Case-Control Studies|Disease Progression|Female|Fluorodeoxyglucose F18|Glucose|Humans|Image Processing, Computer-Assisted|Magnetic Resonance Imaging|Male|Middle Aged|Positron-Emission Tomography|Radiopharmaceuticals|Software', 'Journal Article', '10.1371/journal.pcbi.1002987', '23592957', 'The failure of current strategies to provide an explanation for controversial findings on the pattern of pathophysiological changes in Alzheimers Disease (AD) motivates the necessity to develop new integrative approaches based on multi-modal neuroimaging data that captures various aspects of disease pathology. Previous studies using [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) and structural magnetic resonance imaging (sMRI) report controversial results about time-line, spatial extent and magnitude of glucose hypometabolism and atrophy in AD that depend on clinical and demographic characteristics of the studied populations. Here, we provide and validate at a group level a generative anatomical model of glucose hypo-metabolism and atrophy progression in AD based on FDG-PET and sMRI data of 80 patients and 79 healthy controls to describe expected age and symptom severity related changes in AD relative to a baseline provided by healthy aging. We demonstrate a high level of anatomical accuracy for both modalities yielding strongly age- and symptom-severity- dependant glucose hypometabolism in temporal, parietal and precuneal regions and a more extensive network of atrophy in hippocampal, temporal, parietal, occipital and posterior caudate regions. The model suggests greater and more consistent changes in FDG-PET compared to sMRI at earlier and the inversion of this pattern at more advanced AD stages. Our model describes, integrates and predicts characteristic patterns of AD related pathology, uncontaminated by normal age effects, derived from multi-modal data. It further provides an integrative explanation for findings suggesting a dissociation between early- and late-onset AD. The generative model offers a basis for further development of individualized biomarkers allowing accurate early diagnosis and treatment evaluation.'),
(85977, 2013, 'plos', 'A computational model predicting disruption of blood vessel development', 'Kleinstreuer, Nicole|Dix, David|Rountree, Michael|Baker, Nancy|Sipes, Nisha|Reif, David|Spencer, Richard|Knudsen, Thomas', 'National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA.|National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA.|National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA.|National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA.|National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA.|National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA.|National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA.|National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States', 75, 'Algorithms|Animals|Blood Vessels|Chemokines|Chemotaxis|Computer Simulation|Endothelial Cells|Endothelium, Vascular|Humans|Inflammation|Models, Theoretical|Neovascularization, Physiologic|Phenotype|Signal Transduction|Software|Vascular Endothelial Growth Factor A', 'Journal Article', '10.1371/journal.pcbi.1002996', '23592958', 'Vascular development is a complex process regulated by dynamic biological networks that vary in topology and state across different tissues and developmental stages. Signals regulating de novo blood vessel formation (vasculogenesis) and remodeling (angiogenesis) come from a variety of biological pathways linked to endothelial cell (EC) behavior, extracellular matrix (ECM) remodeling and the local generation of chemokines and growth factors. Simulating these interactions at a systems level requires sufficient biological detail about the relevant molecular pathways and associated cellular behaviors, and tractable computational models that offset mathematical and biological complexity. Here, we describe a novel multicellular agent-based model of vasculogenesis using the CompuCell3D (http://www.compucell3d.org/) modeling environment supplemented with semi-automatic knowledgebase creation. The model incorporates vascular endothelial growth factor signals, pro- and anti-angiogenic inflammatory chemokine signals, and the plasminogen activating system of enzymes and proteases linked to ECM interactions, to simulate nascent EC organization, growth and remodeling. The model was shown to recapitulate stereotypical capillary plexus formation and structural emergence of non-coded cellular behaviors, such as a heterologous bridging phenomenon linking endothelial tip cells together during formation of polygonal endothelial cords. Molecular targets in the computational model were mapped to signatures of vascular disruption derived from in vitro chemical profiling using the EPAs ToxCast high-throughput screening (HTS) dataset. Simulating the HTS data with the cell-agent based model of vascular development predicted adverse effects of a reference anti-angiogenic thalidomide analog, 5HPP-33, on in vitro angiogenesis with respect to both concentration-response and morphological consequences. These findings support the utility of cell agent-based models for simulating a morphogenetic series of events and for the first time demonstrate the applicability of these models for predictive toxicology.'),
(85978, 2013, 'plos', 'Cooperative adaptive responses in gene regulatory networks with many degrees of freedom', 'Inoue, Masayo|Kaneko, Kunihiko', 'Cybermedia Center, Osaka University, Toyonaka, Japan. inoue@cp.cmc.osaka-u.ac.jp|Cybermedia Center, Osaka University, Toyonaka, Japan. inoue@cp.cmc.osaka-u.ac.jp', 'Japan|Japan', 13, 'Adaptation, Biological|Algorithms|Biological Evolution|Computational Biology|Computer Simulation|Gene Expression Regulation|Gene Expression Regulation, Fungal|Gene Regulatory Networks|Homeostasis|Models, Biological|Probability|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1003001', '23592959', 'Cells generally adapt to environmental changes by first exhibiting an immediate response and then gradually returning to their original state to achieve homeostasis. Although simple network motifs consisting of a few genes have been shown to exhibit such adaptive dynamics, they do not reflect the complexity of real cells, where the expression of a large number of genes activates or represses other genes, permitting adaptive behaviors. Here, we investigated the responses of gene regulatory networks containing many genes that have undergone numerical evolution to achieve high fitness due to the adaptive response of only a single target gene, this single target gene responds to changes in external inputs and later returns to basal levels. Despite setting a single target, most genes showed adaptive responses after evolution. Such adaptive dynamics were not due to common motifs within a few genes, even without such motifs, almost all genes showed adaptation, albeit sometimes partial adaptation, in the sense that expression levels did not always return to original levels. The genes split into two groups: genes in the first group exhibited an initial increase in expression and then returned to basal levels, while genes in the second group exhibited the opposite changes in expression. From this model, genes in the first group received positive input from other genes within the first group, but negative input from genes in the second group, and vice versa. Thus, the adaptation dynamics of genes from both groups were consolidated. This cooperative adaptive behavior was commonly observed if the number of genes involved was larger than the order of ten. These results have implications in the collective responses of gene expression networks in microarray measurements of yeast Saccharomyces cerevisiae and the significance to the biological homeostasis of systems with many components.'),
(85979, 2013, 'plos', 'Combinatorial pooling enables selective sequencing of the barley gene space', 'Lonardi, Stefano|Duma, Denisa|Alpert, Matthew|Cordero, Francesca|Beccuti, Marco|Bhat, Prasanna R|Wu, Yonghui|Ciardo, Gianfranco|Alsaihati, Burair|Ma, Yaqin|Wanamaker, Steve|Resnik, Josh|Bozdag, Serdar|Luo, Ming-Cheng|Close, Timothy J', 'Department of Computer Science and Engineering, University of California, Riverside, California, USA. stelo@cs.ucr.edu|Department of Computer Science and Engineering, University of California, Riverside, California, USA. stelo@cs.ucr.edu|Department of Computer Science and Engineering, University of California, Riverside, California, USA. stelo@cs.ucr.edu|Department of Computer Science and Engineering, University of California, Riverside, California, USA. stelo@cs.ucr.edu|Department of Computer Science and Engineering, University of California, Riverside, California, USA. stelo@cs.ucr.edu|Department of Computer Science and Engineering, University of California, Riverside, California, USA. stelo@cs.ucr.edu|Department of Computer Science and Engineering, University of California, Riverside, California, USA. stelo@cs.ucr.edu|Department of Computer Science and Engineering, University of California, Riverside, California, USA. stelo@cs.ucr.edu|Department of Computer Science and Engineering, University of California, Riverside, California, USA. stelo@cs.ucr.edu|Department of Computer Science and Engineering, University of California, Riverside, California, USA. stelo@cs.ucr.edu|Department of Computer Science and Engineering, University of California, Riverside, California, USA. stelo@cs.ucr.edu|Department of Computer Science and Engineering, University of California, Riverside, California, USA. stelo@cs.ucr.edu|Department of Computer Science and Engineering, University of California, Riverside, California, USA. stelo@cs.ucr.edu|Department of Computer Science and Engineering, University of California, Riverside, California, USA. stelo@cs.ucr.edu|Department of Computer Science and Engineering, University of California, Riverside, California, USA. stelo@cs.ucr.edu', 'United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States', 0, 'Chromosomes, Artificial, Bacterial|Cloning, Molecular|Computational Biology|Computer Simulation|Contig Mapping|Genes, Plant|Genetic Markers|Genomic Library|Genomics|Hordeum|Models, Genetic|Oryza|Physical Chromosome Mapping|Sequence Analysis, DNA|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.1003010', '23592960', 'For the vast majority of species - including many economically or ecologically important organisms, progress in biological research is hampered due to the lack of a reference genome sequence. Despite recent advances in sequencing technologies, several factors still limit the availability of such a critical resource. At the same time, many research groups and international consortia have already produced BAC libraries and physical maps and now are in a position to proceed with the development of whole-genome sequences organized around a physical map anchored to a genetic map. We propose a BAC-by-BAC sequencing protocol that combines combinatorial pooling design and second-generation sequencing technology to efficiently approach denovo selective genome sequencing. We show that combinatorial pooling is a cost-effective and practical alternative to exhaustive DNA barcoding when preparing sequencing libraries for hundreds or thousands of DNA samples, such as in this case gene-bearing minimum-tiling-path BAC clones. The novelty of the protocol hinges on the computational ability to efficiently compare hundred millions of short reads and assign them to the correct BAC clones (deconvolution) so that the assembly can be carried out clone-by-clone. Experimental results on simulated data for the rice genome show that the deconvolution is very accurate, and the resulting BAC assemblies have high quality. Results on real data for a gene-rich subset of the barley genome confirm that the deconvolution is accurate and the BAC assemblies have good quality. While our method cannot provide the level of completeness that one would achieve with a comprehensive whole-genome sequencing project, we show that it is quite successful in reconstructing the gene sequences within BACs. In the case of plants such as barley, this level of sequence knowledge is sufficient to support critical end-point objectives such as map-based cloning and marker-assisted breeding.'),
(85980, 2013, 'plos', 'Data-driven modeling of SRC control on the mitochondrial pathway of apoptosis: implication for anticancer therapy optimization', 'Ballesta, Annabelle|Lopez, Jonathan|Popgeorgiev, Nikolay|Gonzalo, Philippe|Doumic, Marie|Gillet, Germain', 'BANG project team, INRIA Rocquencourt, Le Chesnay, Yvelines, France. annabelle.ballesta@inria.fr|BANG project team, INRIA Rocquencourt, Le Chesnay, Yvelines, France. annabelle.ballesta@inria.fr|BANG project team, INRIA Rocquencourt, Le Chesnay, Yvelines, France. annabelle.ballesta@inria.fr|BANG project team, INRIA Rocquencourt, Le Chesnay, Yvelines, France. annabelle.ballesta@inria.fr|BANG project team, INRIA Rocquencourt, Le Chesnay, Yvelines, France. annabelle.ballesta@inria.fr|BANG project team, INRIA Rocquencourt, Le Chesnay, Yvelines, France. annabelle.ballesta@inria.fr', 'France|France|France|France|France|France', 0, 'Animals|Antineoplastic Agents|Apoptosis|Cell Death|Cell Line, Transformed|Computer Simulation|Down-Regulation|Drug Screening Assays, Antitumor|Fibroblasts|Humans|Mice|Microscopy, Confocal|Mitochondria|Models, Biological|NIH 3T3 Cells|Proto-Oncogene Proteins c-bcl-2|bcl-2-Associated X Protein|src-Family Kinases', 'Journal Article', '10.1371/journal.pcbi.1003011', '23592961', 'Src tyrosine kinases are deregulated in numerous cancers and may favor tumorigenesis and tumor progression. We previously described that Src activation in NIH-3T3 mouse fibroblasts promoted cell resistance to apoptosis. Indeed, Src was found to accelerate the degradation of the pro-apoptotic BH3-only protein Bik and compromised Bax activation as well as subsequent mitochondrial outer membrane permeabilization. The present study undertook a systems biomedicine approach to design optimal anticancer therapeutic strategies using Src-transformed and parental fibroblasts as a biological model. First, a mathematical model of Bik kinetics was designed and fitted to biological data. It guided further experimental investigation that showed that Bik total amount remained constant during staurosporine exposure, and suggested that Bik protein might undergo activation to induce apoptosis. Then, a mathematical model of the mitochondrial pathway of apoptosis was designed and fitted to experimental results. It showed that Src inhibitors could circumvent resistance to apoptosis in Src-transformed cells but gave no specific advantage to parental cells. In addition, it predicted that inhibitors of Bcl-2 antiapoptotic proteins such as ABT-737 should not be used in this biological system in which apoptosis resistance relied on the deficiency of an apoptosis accelerator but not on the overexpression of an apoptosis inhibitor, which was experimentally verified. Finally, we designed theoretically optimal therapeutic strategies using the data-calibrated model. All of them relied on the observed Bax overexpression in Src-transformed cells compared to parental fibroblasts. Indeed, they all involved Bax downregulation such that Bax levels would still be high enough to induce apoptosis in Src-transformed cells but not in parental ones. Efficacy of this counterintuitive therapeutic strategy was further experimentally validated. Thus, the use of Bax inhibitors might be an unexpected way to specifically target cancer cells with deregulated Src tyrosine kinase activity.'),
(85981, 2013, 'plos', 'Dual process for intentional and reactive decisions', 'Devaine, Marie|Waszak, Florian|Mamassian, Pascal', 'Université Paris Descartes, Sorbonne Paris Cité, Paris, France. marie.devaine@gmail.com|Université Paris Descartes, Sorbonne Paris Cité, Paris, France. marie.devaine@gmail.com|Université Paris Descartes, Sorbonne Paris Cité, Paris, France. marie.devaine@gmail.com', 'France|France|France', 3, 'Adult|Algorithms|Behavior|Cognition|Computer Simulation|Decision Making|Female|Humans|Male|Models, Theoretical|Perception|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1003013', '23592962', 'Efficient cognitive decisions should be adjustable to incoming novel information. However, most current models of decision making have so far neglected any potential interaction between intentional and stimulus-driven decisions. We report here behavioral results and a new model on the interaction between a perceptual decision and non-predictable novel information. We asked participants to anticipate their response to an external stimulus and presented this stimulus with variable delay. Participants were clearly able to adjust their initial decision to the new stimulus if this latter appeared sufficiently early. To account for these results, we present a two-stage model in which two systems, an intentional and a stimulus-driven, interact only in the second stage. In the first stage of the model, the intentional and stimulus-driven processes race independently to reach a transition threshold between the two stages. The model can also account for results of a second experiment where a response bias is introduced. Our model is consistent with some physiological results that indicate that both parallel and interactive processing take place between intentional and stimulus-driven information. It emphasizes that in natural conditions, both types of processing are important and it helps pinpoint the transition between parallel and interactive processing.'),
(85982, 2013, 'plos', 'A healthy fear of the unknown: perspectives on the interpretation of parameter fits from computational models in neuroscience', 'Nassar, Matthew R|Gold, Joshua I', 'Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania, USA.', 'United States|United States', 14, 'Algorithms|Behavior|Computational Biology|Computer Simulation|Data Interpretation, Statistical|Humans|Learning|Models, Psychological|Motivation|Neurosciences|Problem Solving|Reinforcement (Psychology)', 'Journal Article', '10.1371/journal.pcbi.1003015', '23592963', 'Fitting models to behavior is commonly used to infer the latent computational factors responsible for generating behavior. However, the complexity of many behaviors can handicap the interpretation of such models. Here we provide perspectives on problems that can arise when interpreting parameter fits from models that provide incomplete descriptions of behavior. We illustrate these problems by fitting commonly used and neurophysiologically motivated reinforcement-learning models to simulated behavioral data sets from learning tasks. These model fits can pass a host of standard goodness-of-fit tests and other model-selection diagnostics even when the models do not provide a complete description of the behavioral data. We show that such incomplete models can be misleading by yielding biased estimates of the parameters explicitly included in the models. This problem is particularly pernicious when the neglected factors are unknown and therefore not easily identified by model comparisons and similar methods. An obvious conclusion is that a parsimonious description of behavioral data does not necessarily imply an accurate description of the underlying computations. Moreover, general goodness-of-fit measures are not a strong basis to support claims that a particular model can provide a generalized understanding of the computations that govern behavior. To help overcome these challenges, we advocate the design of tasks that provide direct reports of the computational variables of interest. Such direct reports complement model-fitting approaches by providing a more complete, albeit possibly more task-specific, representation of the factors that drive behavior. Computational models then provide a means to connect such task-specific results to a more general algorithmic understanding of the brain.'),
(85983, 2013, 'plos', 'Synthetic lethality between gene defects affecting a single non-essential molecular pathway with reversible steps', 'Zinovyev, Andrei|Kuperstein, Inna|Barillot, Emmanuel|Heyer, Wolf-Dietrich', 'Institut Curie, Paris, France. Andrei.Zinovyev@curie.fr|Institut Curie, Paris, France. Andrei.Zinovyev@curie.fr|Institut Curie, Paris, France. Andrei.Zinovyev@curie.fr|Institut Curie, Paris, France. Andrei.Zinovyev@curie.fr', 'France|France|France|France', 0, 'Algorithms|Animals|Catalysis|Computational Biology|Computer Simulation|DNA|DNA Repair|Drosophila melanogaster|Enzymes|Gene Expression Profiling|Gene Expression Regulation|Gene Regulatory Networks|Humans|Models, Genetic|Mutation|Neoplasms|Recombination, Genetic', 'Journal Article', '10.1371/journal.pcbi.1003016', '23592964', 'Systematic analysis of synthetic lethality (SL) constitutes a critical tool for systems biology to decipher molecular pathways. The most accepted mechanistic explanation of SL is that the two genes function in parallel, mutually compensatory pathways, known as between-pathway SL. However, recent genome-wide analyses in yeast identified a significant number of within-pathway negative genetic interactions. The molecular mechanisms leading to within-pathway SL are not fully understood. Here, we propose a novel mechanism leading to within-pathway SL involving two genes functioning in a single non-essential pathway. This type of SL termed within-reversible-pathway SL involves reversible pathway steps, catalyzed by different enzymes in the forward and backward directions, and kinetic trapping of a potentially toxic intermediate. Experimental data with recombinational DNA repair genes validate the concept. Mathematical modeling recapitulates the possibility of kinetic trapping and revealed the potential contributions of synthetic, dosage-lethal interactions in such a genetic system as well as the possibility of within-pathway positive masking interactions. Analysis of yeast gene interaction and pathway data suggests broad applicability of this novel concept. These observations extend the canonical interpretation of synthetic-lethal or synthetic-sick interactions with direct implications to reconstruct molecular pathways and improve therapeutic approaches to diseases such as cancer.'),
(85984, 2013, 'plos', 'Divergence of mammalian higher order chromatin structure is associated with developmental loci', 'Chambers, Emily V|Bickmore, Wendy A|Semple, Colin A', 'MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.|MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.|MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 30, 'Animals|Chromatin|Cluster Analysis|Computational Biology|Databases, Genetic|Embryonic Stem Cells|Evolution, Molecular|Gene Expression Regulation, Developmental|Genome|Genome, Human|Humans|Mice|Telomere', 'Journal Article', '10.1371/journal.pcbi.1003017', '23592965', 'Several recent studies have examined different aspects of mammalian higher order chromatin structure - replication timing, lamina association and Hi-C inter-locus interactions - and have suggested that most of these features of genome organisation are conserved over evolution. However, the extent of evolutionary divergence in higher order structure has not been rigorously measured across the mammalian genome, and until now little has been known about the characteristics of any divergent loci present. Here, we generate a dataset combining multiple measurements of chromatin structure and organisation over many embryonic cell types for both human and mouse that, for the first time, allows a comprehensive assessment of the extent of structural divergence between mammalian genomes. Comparison of orthologous regions confirms that all measurable facets of higher order structure are conserved between human and mouse, across the vast majority of the detectably orthologous genome. This broad similarity is observed in spite of many loci possessing cell type specific structures. However, we also identify hundreds of regions (from 100 Kb to 2.7 Mb in size) showing consistent evidence of divergence between these species, constituting at least 10% of the orthologous mammalian genome and encompassing many hundreds of human and mouse genes. These regions show unusual shifts in human GC content, are unevenly distributed across both genomes, and are enriched in human subtelomeric regions. Divergent regions are also relatively enriched for genes showing divergent expression patterns between human and mouse ES cells, implying these regions cause divergent regulation. Particular divergent loci are strikingly enriched in genes implicated in vertebrate development, suggesting important roles for structural divergence in the evolution of mammalian developmental programmes. These data suggest that, though relatively rare in the mammalian genome, divergence in higher order chromatin structure has played important roles during evolution.'),
(85985, 2013, 'plos', 'A two-state model for the dynamics of the pyrophosphate ion release in bacterial RNA polymerase', 'Da, Lin-Tai|Pardo Avila, Fxc3xa1tima|Wang, Dong|Huang, Xuhui', 'Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.|Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.|Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.|Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.', 'Hong Kong|Hong Kong|Hong Kong|Hong Kong', 0, 'Amino Acid Motifs|Catalytic Domain|Computational Biology|DNA|DNA-Directed RNA Polymerases|Diphosphates|Ions|Markov Chains|Molecular Dynamics Simulation|Probability|Protein Folding|RNA|Thermus|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1003020', '23592966', 'The dynamics of the PPi release during the transcription elongation of bacterial RNA polymerase and its effects on the Trigger Loop (TL) opening motion are still elusive. Here, we built a Markov State Model (MSM) from extensive all-atom molecular dynamics (MD) simulations to investigate the mechanism of the PPi release. Our MSM has identified a simple two-state mechanism for the PPi release instead of a more complex four-state mechanism observed in RNA polymerase II (Pol II). We observed that the PPi release in bacterial RNA polymerase occurs at sub-microsecond timescale, which is xe2x88xbc3-fold faster than that in Pol II. After escaping from the active site, the (Mg-PPi)(2-) group passes through a single elongated metastable region where several positively charged residues on the secondary channel provide favorable interactions. Surprisingly, we found that the PPi release is not coupled with the TL unfolding but correlates tightly with the side-chain rotation of the TL residue R1239. Our work sheds light on the dynamics underlying the transcription elongation of the bacterial RNA polymerase.'),
(85986, 2013, 'plos', 'Trading speed and accuracy by coding time: a coupled-circuit cortical model', 'Standage, Dominic|You, Hongzhi|Wang, Da-Hui|Dorris, Michael C', 'Department of Biomedical and Molecular Sciences and Center for Neuroscience Studies, Queens University, Kingston, Ontario, Canada. standage@queensu.ca|Department of Biomedical and Molecular Sciences and Center for Neuroscience Studies, Queens University, Kingston, Ontario, Canada. standage@queensu.ca|Department of Biomedical and Molecular Sciences and Center for Neuroscience Studies, Queens University, Kingston, Ontario, Canada. standage@queensu.ca|Department of Biomedical and Molecular Sciences and Center for Neuroscience Studies, Queens University, Kingston, Ontario, Canada. standage@queensu.ca', 'Canada|Canada|Canada|Canada', 15, 'Algorithms|Behavior|Computational Biology|Computer Simulation|Decision Making|Humans|Interneurons|Learning|Models, Neurological|Neurons|Perception|Reproducibility of Results|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1003021', '23592967', 'Our actions take place in space and time, but despite the role of time in decision theory and the growing acknowledgement that the encoding of time is crucial to behaviour, few studies have considered the interactions between neural codes for objects in space and for elapsed time during perceptual decisions. The speed-accuracy trade-off (SAT) provides a window into spatiotemporal interactions. Our hypothesis is that temporal coding determines the rate at which spatial evidence is integrated, controlling the SAT by gain modulation. Here, we propose that local cortical circuits are inherently suited to the relevant spatial and temporal coding. In simulations of an interval estimation task, we use a generic local-circuit model to encode time by climbing activity, seen in cortex during tasks with a timing requirement. The model is a network of simulated pyramidal cells and inhibitory interneurons, connected by conductance synapses. A simple learning rule enables the network to quickly produce new interval estimates, which show signature characteristics of estimates by experimental subjects. Analysis of network dynamics formally characterizes this generic, local-circuit timing mechanism. In simulations of a perceptual decision task, we couple two such networks. Network function is determined only by spatial selectivity and NMDA receptor conductance strength, all other parameters are identical. To trade speed and accuracy, the timing network simply learns longer or shorter intervals, driving the rate of downstream decision processing by spatially non-selective input, an established form of gain modulation. Like the timing networks interval estimates, decision times show signature characteristics of those by experimental subjects. Overall, we propose, demonstrate and analyse a generic mechanism for timing, a generic mechanism for modulation of decision processing by temporal codes, and we make predictions for experimental verification.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85987, 2013, 'plos', 'Ab initio modeling and experimental assessment of Janus Kinase 2 (JAK2) kinase-pseudokinase complex structure', 'Wan, Xiaobo|Ma, Yue|McClendon, Christopher L|Huang, Lily Jun-shen|Huang, Niu', 'Graduate School in Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.|Graduate School in Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.|Graduate School in Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.|Graduate School in Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.|Graduate School in Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.', 'China|China|China|China|China', 7, 'Allosteric Site|Binding Sites|Cell Proliferation|Cluster Analysis|Computational Biology|Crystallography, X-Ray|ErbB Receptors|Gene Expression Regulation, Enzymologic|Humans|Janus Kinase 2|Models, Theoretical|Molecular Dynamics Simulation|Mutagenesis, Site-Directed|Mutation|Protein Binding|Protein Interaction Mapping|Protein Structure, Tertiary|Software|Static Electricity', 'Journal Article', '10.1371/journal.pcbi.1003022', '23592968', 'The Janus Kinase 2 (JAK2) plays essential roles in transmitting signals from multiple cytokine receptors, and constitutive activation of JAK2 results in hematopoietic disorders and oncogenesis. JAK2 kinase activity is negatively regulated by its pseudokinase domain (JH2), where the gain-of-function mutation V617F that causes myeloproliferative neoplasms resides. In the absence of a crystal structure of full-length JAK2, how JH2 inhibits the kinase domain (JH1), and how V617F hyperactivates JAK2 remain elusive. We modeled the JAK2 JH1-JH2 complex structure using a novel informatics-guided protein-protein docking strategy. A detailed JAK2 JH2-mediated auto-inhibition mechanism is proposed, where JH2 traps the activation loop of JH1 in an inactive conformation and blocks the movement of kinase xcexb1C helix through critical hydrophobic contacts and extensive electrostatic interactions. These stabilizing interactions are less favorable in JAK2-V617F. Notably, several predicted binding interfacial residues in JH2 were confirmed to hyperactivate JAK2 kinase activity in site-directed mutagenesis and BaF3/EpoR cell transformation studies. Although there may exist other JH2-mediated mechanisms to control JH1, our JH1-JH2 structural model represents a verifiable working hypothesis for further experimental studies to elucidate the role of JH2 in regulating JAK2 in both normal and pathological settings.'),
(85988, 2013, 'plos', 'Evolutionary capacitance and control of protein stability in protein-protein interaction networks', 'Dixit, Purushottam D|Maslov, Sergei', 'Biology, Brookhaven National Laboratory, Upton, New York, USA.|Biology, Brookhaven National Laboratory, Upton, New York, USA.', 'United States|United States', 12, 'Computational Biology|Cytoplasm|Evolution, Molecular|Fungal Proteins|HSP90 Heat-Shock Proteins|Protein Binding|Protein Conformation|Protein Denaturation|Protein Folding|Protein Interaction Mapping|Protein Interaction Maps|Proteins|Saccharomyces cerevisiae|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1003023', '23592969', 'In addition to their biological function, protein complexes reduce the exposure of the constituent proteins to the risk of undesired oligomerization by reducing the concentration of the free monomeric state. We interpret this reduced risk as a stabilization of the functional state of the protein. We estimate that protein-protein interactions can account for ~2-4 k(B)T of additional stabilization, a substantial contribution to intrinsic stability. We hypothesize that proteins in the interaction network act as evolutionary capacitors which allows their binding partners to explore regions of the sequence space which correspond to less stable proteins. In the interaction network of bakers yeast, we find that statistically proteins that receive higher energetic benefits from the interaction network are more likely to misfold. A simplified fitness landscape wherein the fitness of an organism is inversely proportional to the total concentration of unfolded proteins provides an evolutionary justification for the proposed trends. We conclude by outlining clear biophysical experiments to test our predictions.'),
(85989, 2013, 'plos', 'Reinforcement learning using a continuous time actor-critic framework with spiking neurons', 'Frémaux, Nicolas|Sprekeler, Henning|Gerstner, Wulfram', 'School of Computer and Communication Sciences and School of Life Sciences, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, 1015 Lausanne EPFL, Switzerland.|School of Computer and Communication Sciences and School of Life Sciences, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, 1015 Lausanne EPFL, Switzerland.|School of Computer and Communication Sciences and School of Life Sciences, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, 1015 Lausanne EPFL, Switzerland.', 'Switzerland|Switzerland|Switzerland', 0, 'Action Potentials|Animals|Behavior, Animal|Computational Biology|Computer Simulation|Learning|Maze Learning|Models, Neurological|Nerve Net|Neurons|Rats|Reinforcement (Psychology)|Reproducibility of Results|Reward|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1003024', '23592970', 'Animals repeat rewarded behaviors, but the physiological basis of reward-based learning has only been partially elucidated. On one hand, experimental evidence shows that the neuromodulator dopamine carries information about rewards and affects synaptic plasticity. On the other hand, the theory of reinforcement learning provides a framework for reward-based learning. Recent models of reward-modulated spike-timing-dependent plasticity have made first steps towards bridging the gap between the two approaches, but faced two problems. First, reinforcement learning is typically formulated in a discrete framework, ill-adapted to the description of natural situations. Second, biologically plausible models of reward-modulated spike-timing-dependent plasticity require precise calculation of the reward prediction error, yet it remains to be shown how this can be computed by neurons. Here we propose a solution to these problems by extending the continuous temporal difference (TD) learning of Doya (2000) to the case of spiking neurons in an actor-critic network operating in continuous time, and with continuous state and action representations. In our model, the critic learns to predict expected future rewards in real time. Its activity, together with actual rewards, conditions the delivery of a neuromodulatory TD signal to itself and to the actor, which is responsible for action choice. In simulations, we show that such an architecture can solve a Morris water-maze-like navigation task, in a number of trials consistent with reported animal performance. We also use our model to solve the acrobot and the cartpole problems, two complex motor control tasks. Our model provides a plausible way of computing reward prediction error in the brain. Moreover, the analytically derived learning rule is consistent with experimental evidence for dopamine-modulated spike-timing-dependent plasticity.'),
(85990, 2013, 'plos', 'Systems modeling of molecular mechanisms controlling cytokine-driven CD4+ T cell differentiation and phenotype plasticity', 'Carbo, Adria|Hontecillas, Raquel|Kronsteiner, Barbara|Viladomiu, Monica|Pedragosa, Mireia|Lu, Pinyi|Philipson, Casandra W|Hoops, Stefan|Marathe, Madhav|Eubank, Stephen|Bisset, Keith|Wendelsdorf, Katherine|Jarrah, Abdul|Mei, Yongguo|Bassaganya-Riera, Josep', 'Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA.|Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA.|Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA.|Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA.|Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA.|Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA.|Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA.|Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA.|Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA.|Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA.|Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA.|Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA.|Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA.|Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA.|Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States', 0, 'Animals|CD4-Positive T-Lymphocytes|Cell Differentiation|Computational Biology|Computer Simulation|Cytokines|Dose-Response Relationship, Drug|Flow Cytometry|Immunophenotyping|Mice|Mice, Inbred C57BL|Mice, SCID|Models, Molecular|Models, Theoretical|PPAR gamma|Phenotype|Signal Transduction|Th17 Cells', 'Journal Article', '10.1371/journal.pcbi.1003027', '23592971', 'Differentiation of CD4+ T cells into effector or regulatory phenotypes is tightly controlled by the cytokine milieu, complex intracellular signaling networks and numerous transcriptional regulators. We combined experimental approaches and computational modeling to investigate the mechanisms controlling differentiation and plasticity of CD4+ T cells in the gut of mice. Our computational model encompasses the major intracellular pathways involved in CD4+ T cell differentiation into T helper 1 (Th1), Th2, Th17 and induced regulatory T cells (iTreg). Our modeling efforts predicted a critical role for peroxisome proliferator-activated receptor gamma (PPARxcexb3) in modulating plasticity between Th17 and iTreg cells. PPARxcexb3 regulates differentiation, activation and cytokine production, thereby controlling the induction of effector and regulatory responses, and is a promising therapeutic target for dysregulated immune responses and inflammation. Our modeling efforts predict that following PPARxcexb3 activation, Th17 cells undergo phenotype switch and become iTreg cells. This prediction was validated by results of adoptive transfer studies showing an increase of colonic iTreg and a decrease of Th17 cells in the gut mucosa of mice with colitis following pharmacological activation of PPARxcexb3. Deletion of PPARxcexb3 in CD4+ T cells impaired mucosal iTreg and enhanced colitogenic Th17 responses in mice with CD4+ T cell-induced colitis. Thus, for the first time we provide novel molecular evidence in vivo demonstrating that PPARxcexb3 in addition to regulating CD4+ T cell differentiation also plays a major role controlling Th17 and iTreg plasticity in the gut mucosa.'),
(85991, 2013, 'plos', 'Surface dynamics in allosteric regulation of protein-protein interactions: modulation of calmodulin functions by Ca2+', 'Kuttner, Yosef Y|Nagar, Tal|Engel, Stanislav', 'Bioinformatics Core Facility, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Bioinformatics Core Facility, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Bioinformatics Core Facility, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.', 'Israel|Israel|Israel', 7, 'Allosteric Site|Binding Sites|Calcium|Calmodulin|Computational Biology|Fungal Proteins|Ions|Models, Molecular|Molecular Dynamics Simulation|Probability|Protein Binding|Protein Interaction Mapping|Protein Structure, Tertiary|Saccharomyces cerevisiae|Surface Properties', 'Journal Article', '10.1371/journal.pcbi.1003028', '23592972', 'Knowledge of the structural basis of protein-protein interactions (PPI) is of fundamental importance for understanding the organization and functioning of biological networks and advancing the design of therapeutics which target PPI. Allosteric modulators play an important role in regulating such interactions by binding at site(s) orthogonal to the complex interface and altering the proteins propensity for complex formation. In this work, we apply an approach recently developed by us for analyzing protein surfaces based on steered molecular dynamics simulation (SMD) to the study of the dynamic properties of functionally distinct conformations of a model protein, calmodulin (CaM), whose ability to interact with target proteins is regulated by the presence of the allosteric modulator Ca(2+). Calmodulin is a regulatory protein that acts as an intracellular Ca(2+) sensor to control a wide variety of cellular processes. We demonstrate that SMD analysis is capable of pinpointing CaM surfaces implicated in the recognition of both the allosteric modulator Ca(2+) and target proteins. Our analysis of changes in the dynamic properties of the CaM backbone elicited by Ca(2+) binding yielded new insights into the molecular mechanism of allosteric regulation of CaM-target interactions.'),
(85992, 2013, 'plos', 'Shining a light on dark sequencing: characterising errors in Ion Torrent PGM data', 'Bragg, Lauren M|Stone, Glenn|Butler, Margaret K|Hugenholtz, Philip|Tyson, Gene W', 'Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia. lauren.bragg@csiro.au|Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia. lauren.bragg@csiro.au|Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia. lauren.bragg@csiro.au|Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia. lauren.bragg@csiro.au|Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia. lauren.bragg@csiro.au', 'Australia|Australia|Australia|Australia|Australia', 193, 'Algorithms|Bacillus|Computational Biology|Computers|Deinococcus|Genome|Genomics|INDEL Mutation|Ions|Linear Models|Polymers|Polymorphism, Genetic|Reproducibility of Results|Sequence Analysis, DNA|Software|Sulfolobus', 'Journal Article', '10.1371/journal.pcbi.1003031', '23592973', 'The Ion Torrent Personal Genome Machine (PGM) is a new sequencing platform that substantially differs from other sequencing technologies by measuring pH rather than light to detect polymerisation events. Using re-sequencing datasets, we comprehensively characterise the biases and errors introduced by the PGM at both the base and flow level, across a combination of factors, including chip density, sequencing kit, template species and machine. We found two distinct insertion/deletion (indel) error types that accounted for the majority of errors introduced by the PGM. The main error source was inaccurate flow-calls, which introduced indels at a raw rate of 2.84% (1.38% after quality clipping) using the OneTouch 200 bp kit. Inaccurate flow-calls typically resulted in over-called short-homopolymers and under-called long-homopolymers. Flow-call accuracy decreased with consecutive flow cycles, but we also found significant periodic fluctuations in the flow error-rate, corresponding to specific positions within the flow-cycle pattern. Another less common PGM error, high frequency indel (HFI) errors, are indels that occur at very high frequency in the reads relative to a given base position in the reference genome, but in the majority of instances were not replicated consistently across separate runs. HFI errors occur approximately once every thousand bases in the reference, and correspond to 0.06% of bases in reads. Currently, the PGM does not achieve the accuracy of competing light-based technologies. However, flow-call inaccuracy is systematic and the statistical models of flow-values developed here will enable PGM-specific bioinformatics approaches to be developed, which will account for these errors. HFI errors may prove more challenging to address, especially for polymorphism and amplicon applications, but may be overcome by sequencing the same DNA template across multiple chips.'),
(85993, 2013, 'plos', 'Steered molecular dynamics simulations of a type IV pilus probe initial stages of a force-induced conformational transition', 'Baker, Joseph L|Biais, Nicolas|Tama, Florence', 'Department of Physics, University of Arizona, Tucson, Arizona, USA.|Department of Physics, University of Arizona, Tucson, Arizona, USA.|Department of Physics, University of Arizona, Tucson, Arizona, USA.', 'United States|United States|United States', 13, 'Algorithms|Computational Biology|Drug Design|Fimbriae Proteins|Fimbriae, Bacterial|Hydrogen Bonding|Hydrophobic and Hydrophilic Interactions|Molecular Dynamics Simulation|Mutation|Neisseria gonorrhoeae|Protein Processing, Post-Translational|Protein Structure, Tertiary|Solvents|Surface Properties|Water', 'Journal Article', '10.1371/journal.pcbi.1003032', '23592974', 'Type IV pili are long, protein filaments built from a repeating subunit that protrudes from the surface of a wide variety of infectious bacteria. They are implicated in a vast array of functions, ranging from bacterial motility to microcolony formation to infection. One of the most well-studied type IV filaments is the gonococcal type IV pilus (GC-T4P) from Neisseria gonorrhoeae, the causative agent of gonorrhea. Cryo-electron microscopy has been used to construct a model of this filament, offering insights into the structure of type IV pili. In addition, experiments have demonstrated that GC-T4P can withstand very large tension forces, and transition to a force-induced conformation. However, the details of force-generation, and the atomic-level characteristics of the force-induced conformation, are unknown. Here, steered molecular dynamics (SMD) simulation was used to exert a force in silico on an 18 subunit segment of GC-T4P to address questions regarding the nature of the interactions that lead to the extraordinary strength of bacterial pili. SMD simulations revealed that the buried pilin xcexb11 domains maintain hydrophobic contacts with one another within the core of the filament, leading to GC-T4Ps structural stability. At the filament surface, gaps between pilin globular head domains in both the native and pulled states provide water accessible routes between the external environment and the interior of the filament, allowing water to access the pilin xcexb11 domains as reported for VC-T4P in deuterium exchange experiments. Results were also compared to the experimentally observed force-induced conformation. In particular, an exposed amino acid sequence in the experimentally stretched filament was also found to become exposed during the SMD simulations, suggesting that initial stages of the force induced transition are well captured. Furthermore, a second sequence was shown to be initially hidden in the native filament and became exposed upon stretching.'),
(85994, 2013, 'plos', 'Reduced lateral mobility of lipids and proteins in crowded membranes', 'Goose, Joseph E|Sansom, Mark S P', 'Department of Biochemistry, University of Oxford, Oxford, United Kingdom.|Department of Biochemistry, University of Oxford, Oxford, United Kingdom.', 'United Kingdom|United Kingdom', 0, 'Algorithms|Bacterial Outer Membrane Proteins|Cell Membrane|Computational Biology|Diffusion|Escherichia coli|Lipid Bilayers|Lipids|Membrane Lipids|Molecular Dynamics Simulation|Phospholipids|Protein Conformation|Protein Interaction Mapping|Proteins|Software', 'Journal Article', '10.1371/journal.pcbi.1003033', '23592975', 'Coarse-grained molecular dynamics simulations of the E. coli outer membrane proteins FhuA, LamB, NanC, OmpA and OmpF in a POPE/POPG (3:1) bilayer were performed to characterise the diffusive nature of each component of the membrane. At small observation times (<10 ns) particle vibrations dominate phospholipid diffusion elevating the calculated values from the longer time-scale bulk value (>50 ns) of 8.5xc3x9710(-7) cm(2) s(-1). The phospholipid diffusion around each protein was found to vary based on distance from protein. An asymmetry in the diffusion of annular lipids in the inner and outer leaflets was observed and correlated with an asymmetry in charged residues in the vicinity of the inner and outer leaflet head-groups. Protein rotational and translational diffusion were also found to vary with observation time and were inversely correlated with the radius of gyration of the protein in the plane of the bilayer. As the concentration of protein within the bilayer was increased, the overall mobility of the membrane decreased reflected in reduced lipid diffusion coefficients for both lipid and protein components. The increase in protein concentration also resulted in a decrease in the anomalous diffusion exponent xcexb1 of the lipid. Formation of extended clusters and networks of proteins led to compartmentalisation of lipids in extreme cases.'),
(85995, 2013, 'plos', 'Formation of raft-like assemblies within clusters of influenza hemagglutinin observed by MD simulations', 'Parton, Daniel L|Tek, Alex|Baaden, Marc|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', 39, 'Algorithms|Cell Membrane|Computational Biology|Diffusion|Hemagglutinin Glycoproteins, Influenza Virus|Influenza A Virus, H3N8 Subtype|Lipid Bilayers|Lipids|Membrane Microdomains|Membrane Proteins|Molecular Dynamics Simulation|Protein Binding|Protein Structure, Tertiary', 'Journal Article', '10.1371/journal.pcbi.1003034', '23592976', 'The association of hemagglutinin (HA) with lipid rafts in the plasma membrane is an important feature of the assembly process of influenza virus A. Lipid rafts are thought to be small, fluctuating patches of membrane enriched in saturated phospholipids, sphingolipids, cholesterol and certain types of protein. However, raft-associating transmembrane (TM) proteins generally partition into Ld domains in model membranes, which are enriched in unsaturated lipids and depleted in saturated lipids and cholesterol. The reason for this apparent disparity in behavior is unclear, but model membranes differ from the plasma membrane in a number of ways. In particular, the higher protein concentration in the plasma membrane may influence the partitioning of membrane proteins for rafts. To investigate the effect of high local protein concentration, we have conducted coarse-grained molecular dynamics (CG MD) simulations of HA clusters in domain-forming bilayers. During the simulations, we observed a continuous increase in the proportion of raft-type lipids (saturated phospholipids and cholesterol) within the area of membrane spanned by the protein cluster. Lateral diffusion of unsaturated lipids was significantly attenuated within the cluster, while saturated lipids were relatively unaffected. On this basis, we suggest a possible explanation for the change in lipid distribution, namely that steric crowding by the slow-diffusing proteins increases the chemical potential for unsaturated lipids within the cluster region. We therefore suggest that a local aggregation of HA can be sufficient to drive association of the protein with raft-type lipids. This may also represent a general mechanism for the targeting of TM proteins to rafts in the plasma membrane, which is of functional importance in a wide range of cellular processes.'),
(85996, 2013, 'plos', 'Chapter 15: disease gene prioritization', 'Bromberg, Yana', 'Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers University, New Brunswick, New Jersey, USA. YanaB@rci.rutgers.edu', 'Jersey', 0, 'Animals|Computational Biology|Computer Simulation|Exons|Genetic Predisposition to Disease|Genetics|Humans|Models, Theoretical|Mutation|Phenotype|Protein Interaction Mapping|Software', 'Journal Article', '10.1371/journal.pcbi.1002902', '23633938', 'Disease-causing aberrations in the normal function of a gene define that gene as a disease gene. Proving a causal link between a gene and a disease experimentally is expensive and time-consuming. Comprehensive prioritization of candidate genes prior to experimental testing drastically reduces the associated costs. Computational gene prioritization is based on various pieces of correlative evidence that associate each gene with the given disease and suggest possible causal links. A fair amount of this evidence comes from high-throughput experimentation. Thus, well-developed methods are necessary to reliably deal with the quantity of information at hand. Existing gene prioritization techniques already significantly improve the outcomes of targeted experimental studies. Faster and more reliable techniques that account for novel data types are necessary for the development of new diagnostics, treatments, and cure for many diseases.'),
(85997, 2013, 'plos', 'The interaction of vinculin with actin', 'Golji, Javad|Mofrad, Mohammad R K', 'Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, Berkeley, California, USA.|Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, Berkeley, California, USA.', 'United States|United States', 28, 'Actin Cytoskeleton|Actins|Animals|Binding Sites|Chickens|Focal Adhesions|Humans|Molecular Dynamics Simulation|Protein Binding|Protein Structure, Tertiary|Vinculin', 'Journal Article', '10.1371/journal.pcbi.1002995', '23633939', 'Vinculin can interact with F-actin both in recruitment of actin filaments to the growing focal adhesions and also in capping of actin filaments to regulate actin dynamics. Using molecular dynamics, both interactions are simulated using different vinculin conformations. Vinculin is simulated either with only its vinculin tail domain (Vt), with all residues in its closed conformation, with all residues in an open I conformation, and with all residues in an open II conformation. The open I conformation results from movement of domain 1 away from Vt, the open II conformation results from complete dissociation of Vt from the vinculin head domains. Simulation of vinculin binding along the actin filament showed that Vt alone can bind along the actin filaments, that vinculin in its closed conformation cannot bind along the actin filaments, and that vinculin in its open I conformation can bind along the actin filaments. The simulations confirm that movement of domain 1 away from Vt in formation of vinculin 1 is sufficient for allowing Vt to bind along the actin filament. Simulation of Vt capping actin filaments probe six possible bound structures and suggest that vinculin would cap actin filaments by interacting with both S1 and S3 of the barbed-end, using the surface of Vt normally occluded by D4 and nearby vinculin head domain residues. Simulation of D4 separation from Vt after D1 separation formed the open II conformation. Binding of open II vinculin to the barbed-end suggests this conformation allows for vinculin capping. Three binding sites on F-actin are suggested as regions that could link to vinculin. Vinculin is suggested to function as a variable switch at the focal adhesions. The conformation of vinculin and the precise F-actin binding conformation is dependent on the level of mechanical load on the focal adhesion.'),
(85998, 2013, 'plos', 'Distinct types of disorder in the human proteome: functional implications for alternative splicing', 'Colak, Recep|Kim, TaeHyung|Michaut, Magali|Sun, Mark|Irimia, Manuel|Bellay, Jeremy|Myers, Chad L|Blencowe, Benjamin J|Kim, Philip M', 'The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.', 'Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada', 39, 'Algorithms|Alternative Splicing|Amino Acid Motifs|Computational Biology|Evolution, Molecular|Exons|Humans|Muscles|Mutation|Neoplasms|Phosphorylation|Protein Folding|Protein Interaction Mapping|Protein Interaction Maps|Proteome|Proteomics|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1003030', '23633940', 'Intrinsically disordered regions have been associated with various cellular processes and are implicated in several human diseases, but their exact roles remain unclear. We previously defined two classes of conserved disordered regions in budding yeast, referred to as flexible and constrained conserved disorder. In flexible disorder, the property of disorder has been positionally conserved during evolution, whereas in constrained disorder, both the amino acid sequence and the property of disorder have been conserved. Here, we show that flexible and constrained disorder are widespread in the human proteome, and are particularly common in proteins with regulatory functions. Both classes of disordered sequences are highly enriched in regions of proteins that undergo tissue-specific (TS) alternative splicing (AS), but not in regions of proteins that undergo general (i.e., not tissue-regulated) AS. Flexible disorder is more highly enriched in TS alternative exons, whereas constrained disorder is more highly enriched in exons that flank TS alternative exons. These latter regions are also significantly more enriched in potential phosphosites and other short linear motifs associated with cell signaling. We further show that cancer driver mutations are significantly enriched in regions of proteins associated with TS and general AS. Collectively, our results point to distinct roles for TS alternative exons and flanking exons in the dynamic regulation of protein interaction networks in response to signaling activity, and they further suggest that alternatively spliced regions of proteins are often functionally altered by mutations responsible for cancer.'),
(85999, 2013, 'plos', 'Bayesian computation emerges in generic cortical microcircuits through spike-timing-dependent plasticity', 'Nessler, Bernhard|Pfeiffer, Michael|Buesing, Lars|Maass, Wolfgang', 'Institute for Theoretical Computer Science, Graz University of Technology, Graz, Austria. nessler@igi.tugraz.at|Institute for Theoretical Computer Science, Graz University of Technology, Graz, Austria. nessler@igi.tugraz.at|Institute for Theoretical Computer Science, Graz University of Technology, Graz, Austria. nessler@igi.tugraz.at|Institute for Theoretical Computer Science, Graz University of Technology, Graz, Austria. nessler@igi.tugraz.at', 'Austria|Austria|Austria|Austria', 0, 'Action Potentials|Animals|Bayes Theorem|Brain|Computational Biology|Computer Simulation|Humans|Models, Neurological|Nerve Net|Neuronal Plasticity|Neurons|Probability|Synapses|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1003037', '23633941', 'The principles by which networks of neurons compute, and how spike-timing dependent plasticity (STDP) of synaptic weights generates and maintains their computational function, are unknown. Preceding work has shown that soft winner-take-all (WTA) circuits, where pyramidal neurons inhibit each other via interneurons, are a common motif of cortical microcircuits. We show through theoretical analysis and computer simulations that Bayesian computation is induced in these network motifs through STDP in combination with activity-dependent changes in the excitability of neurons. The fundamental components of this emergent Bayesian computation are priors that result from adaptation of neuronal excitability and implicit generative models for hidden causes that are created in the synaptic weights through STDP. In fact, a surprising result is that STDP is able to approximate a powerful principle for fitting such implicit generative models to high-dimensional spike inputs: Expectation Maximization. Our results suggest that the experimentally observed spontaneous activity and trial-to-trial variability of cortical neurons are essential features of their information processing capability, since their functional role is to represent probability distributions rather than static neural codes. Furthermore it suggests networks of Bayesian computation modules as a new model for distributed information processing in the cortex.'),
(86000, 2013, 'plos', 'Localization of protein aggregation in Escherichia coli is governed by diffusion and nucleoid macromolecular crowding effect', 'Coquel, Anne-Sophie|Jacob, Jean-Pascal|Primet, Mael|Demarez, Alice|Dimiccoli, Mariella|Julou, Thomas|Moisan, Lionel|Lindner, Ariel B|Berry, Hugues', 'Institut National de la Santé et de la Recherche Médicale, Unité 1001, Paris, France.|Institut National de la Santé et de la Recherche Médicale, Unité 1001, Paris, France.|Institut National de la Santé et de la Recherche Médicale, Unité 1001, Paris, France.|Institut National de la Santé et de la Recherche Médicale, Unité 1001, Paris, France.|Institut National de la Santé et de la Recherche Médicale, Unité 1001, Paris, France.|Institut National de la Santé et de la Recherche Médicale, Unité 1001, Paris, France.|Institut National de la Santé et de la Recherche Médicale, Unité 1001, Paris, France.|Institut National de la Santé et de la Recherche Médicale, Unité 1001, Paris, France.|Institut National de la Santé et de la Recherche Médicale, Unité 1001, Paris, France.', 'France|France|France|France|France|France|France|France|France', 0, 'Cell Nucleus|Computational Biology|Computer Simulation|Diffusion|Escherichia coli|Escherichia coli Proteins|Image Processing, Computer-Assisted|Microscopy, Fluorescence|Organelles|Protein Binding|Protein Folding|Protein Transport', 'Journal Article', '10.1371/journal.pcbi.1003038', '23633942', 'Aggregates of misfolded proteins are a hallmark of many age-related diseases. Recently, they have been linked to aging of Escherichia coli (E. coli) where protein aggregates accumulate at the old pole region of the aging bacterium. Because of the potential of E. coli as a model organism, elucidating aging and protein aggregation in this bacterium may pave the way to significant advances in our global understanding of aging. A first obstacle along this path is to decipher the mechanisms by which protein aggregates are targeted to specific intercellular locations. Here, using an integrated approach based on individual-based modeling, time-lapse fluorescence microscopy and automated image analysis, we show that the movement of aging-related protein aggregates in E. coli is purely diffusive (Brownian). Using single-particle tracking of protein aggregates in live E. coli cells, we estimated the average size and diffusion constant of the aggregates. Our results provide evidence that the aggregates passively diffuse within the cell, with diffusion constants that depend on their size in agreement with the Stokes-Einstein law. However, the aggregate displacements along the cell long axis are confined to a region that roughly corresponds to the nucleoid-free space in the cell pole, thus confirming the importance of increased macromolecular crowding in the nucleoids. We thus used 3D individual-based modeling to show that these three ingredients (diffusion, aggregation and diffusion hindrance in the nucleoids) are sufficient and necessary to reproduce the available experimental data on aggregate localization in the cells. Taken together, our results strongly support the hypothesis that the localization of aging-related protein aggregates in the poles of E. coli results from the coupling of passive diffusion-aggregation with spatially non-homogeneous macromolecular crowding. They further support the importance of soft intracellular structuring (based on macromolecular crowding) in diffusion-based protein localization in E. coli.'),
(86001, 2013, 'plos', 'Chapter 17: bioimage informatics for systems pharmacology', 'Li, Fuhai|Yin, Zheng|Jin, Guangxu|Zhao, Hong|Wong, Stephen T C', 'NCI Center for Modeling Cancer Development, Department of Systems Medicine and Bioengineering, The Methodist Hospital Research Institute, Weil Medical College of Cornell University, Houston, Texas, USA.|NCI Center for Modeling Cancer Development, Department of Systems Medicine and Bioengineering, The Methodist Hospital Research Institute, Weil Medical College of Cornell University, Houston, Texas, USA.|NCI Center for Modeling Cancer Development, Department of Systems Medicine and Bioengineering, The Methodist Hospital Research Institute, Weil Medical College of Cornell University, Houston, Texas, USA.|NCI Center for Modeling Cancer Development, Department of Systems Medicine and Bioengineering, The Methodist Hospital Research Institute, Weil Medical College of Cornell University, Houston, Texas, USA.|NCI Center for Modeling Cancer Development, Department of Systems Medicine and Bioengineering, The Methodist Hospital Research Institute, Weil Medical College of Cornell University, Houston, Texas, USA.', 'United States|United States|United States|United States|United States', 0, 'Animals|Artificial Intelligence|Automation|Computational Biology|Drug Design|Drug Industry|Humans|Image Processing, Computer-Assisted|Microscopy, Fluorescence|Pharmaceutical Preparations|Pharmacology|Phenotype|RNA Interference|Software|Technology, Pharmaceutical', 'Journal Article', '10.1371/journal.pcbi.1003043', '23633943', 'Recent advances in automated high-resolution fluorescence microscopy and robotic handling have made the systematic and cost effective study of diverse morphological changes within a large population of cells possible under a variety of perturbations, e.g., drugs, compounds, metal catalysts, RNA interference (RNAi). Cell population-based studies deviate from conventional microscopy studies on a few cells, and could provide stronger statistical power for drawing experimental observations and conclusions. However, it is challenging to manually extract and quantify phenotypic changes from the large amounts of complex image data generated. Thus, bioimage informatics approaches are needed to rapidly and objectively quantify and analyze the image data. This paper provides an overview of the bioimage informatics challenges and approaches in image-based studies for drug and target discovery. The concepts and capabilities of image-based screening are first illustrated by a few practical examples investigating different kinds of phenotypic changes caEditorsused by drugs, compounds, or RNAi. The bioimage analysis approaches, including object detection, segmentation, and tracking, are then described. Subsequently, the quantitative features, phenotype identification, and multidimensional profile analysis for profiling the effects of drugs and targets are summarized. Moreover, a number of publicly available software packages for bioimage informatics are listed for further reference. It is expected that this review will help readers, including those without bioimage informatics expertise, understand the capabilities, approaches, and tools of bioimage informatics and apply them to advance their own studies.'),
(86002, 2013, 'plos', 'Chapter 16: text mining for translational bioinformatics', 'Cohen, K Bretonnel|Hunter, Lawrence E', 'Computational Bioscience Program, University of Colorado School of Medicine, Aurora, Colorado, USA. kevin.cohen@gmail.com|Computational Bioscience Program, University of Colorado School of Medicine, Aurora, Colorado, USA. kevin.cohen@gmail.com', 'United States|United States', 14, 'Algorithms|Animals|Artificial Intelligence|Computational Biology|Computer Simulation|Data Mining|Humans|Phenotype|Programming Languages|Software|Translational Medical Research', 'Journal Article', '10.1371/journal.pcbi.1003044', '23633944', 'Text mining for translational bioinformatics is a new field with tremendous research potential. It is a subfield of biomedical natural language processing that concerns itself directly with the problem of relating basic biomedical research to clinical practice, and vice versa. Applications of text mining fall both into the category of T1 translational research-translating basic science results into new interventions-and T2 translational research, or translational research for public health. Potential use cases include better phenotyping of research subjects, and pharmacogenomic research. A variety of methods for evaluating text mining applications exist, including corpora, structured test suites, and post hoc judging. Two basic principles of linguistic structure are relevant for building text mining applications. One is that linguistic structure consists of multiple levels. The other is that every level of linguistic structure is characterized by ambiguity. There are two basic approaches to text mining: rule-based, also known as knowledge-based, and machine-learning-based, also known as statistical. Many systems are hybrids of the two approaches. Shared tasks have had a strong effect on the direction of the field. Like all translational bioinformatics software, text mining software for translational bioinformatics can be considered health-critical and should be subject to the strictest standards of quality assurance and software testing.'),
(86003, 2013, 'plos', 'Lifespan differences in hematopoietic stem cells are due to imperfect repair and unstable mean-reversion', 'Sieburg, Hans B|Cattarossi, Giulio|Muller-Sieburg, Christa E', 'Stem Cell and Regenerative Medicine Program, The Sanford-Burnham Medical Research Institute, La Jolla, California, USA. hsieburg@sanfordburnham.org|Stem Cell and Regenerative Medicine Program, The Sanford-Burnham Medical Research Institute, La Jolla, California, USA. hsieburg@sanfordburnham.org|Stem Cell and Regenerative Medicine Program, The Sanford-Burnham Medical Research Institute, La Jolla, California, USA. hsieburg@sanfordburnham.org', 'United States|United States|United States', 0, 'Algorithms|Animals|Blood Cells|Computer Simulation|Epigenesis, Genetic|Flow Cytometry|Genome|Hematopoietic Stem Cell Transplantation|Hematopoietic Stem Cells|Mice|Models, Biological|Nonlinear Dynamics|Programming Languages|Reproducibility of Results|Software', 'Journal Article', '10.1371/journal.pcbi.1003006', '23637582', 'The life-long supply of blood cells depends on the long-term function of hematopoietic stem cells (HSCs). HSCs are functionally defined by their multi-potency and self-renewal capacity. Because of their self-renewal capacity, HSCs were thought to have indefinite lifespans. However, there is increasing evidence that genetically identical HSCs differ in lifespan and that the lifespan of a HSC is predetermined and HSC-intrinsic. Lifespan is here defined as the time a HSC gives rise to all mature blood cells. This raises the intriguing question: what controls the lifespan of HSCs within the same animal, exposed to the same environment? We present here a new model based on reliability theory to account for the diversity of lifespans of HSCs. Using clonal repopulation experiments and computational-mathematical modeling, we tested how small-scale, molecular level, failures are dissipated at the HSC population level. We found that the best fit of the experimental data is provided by a model, where the repopulation failure kinetics of each HSC are largely anti-persistent, or mean-reverting, processes. Thus, failure rates repeatedly increase during population-wide division events and are counteracted and decreased by repair processes. In the long-run, a crossover from anti-persistent to persistent behavior occurs. The cross-over is due to a slow increase in the mean failure rate of self-renewal and leads to rapid clonal extinction. This suggests that the repair capacity of HSCs is self-limiting. Furthermore, we show that the lifespan of each HSC depends on the amplitudes and frequencies of fluctuations in the failure rate kinetics. Shorter and longer lived HSCs differ significantly in their pre-programmed ability to dissipate perturbations. A likely interpretation of these findings is that the lifespan of HSCs is determined by preprogrammed differences in repair capacity.'),
(86004, 2013, 'plos', 'Cleavage entropy as quantitative measure of protease specificity', 'Fuchs, Julian E|von Grafenstein, Susanne|Huber, Roland G|Margreiter, Michael A|Spitzer, Gudrun M|Wallnoefer, Hannes G|Liedl, Klaus R', 'Institute of General, Inorganic and Theoretical Chemistry, and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria.|Institute of General, Inorganic and Theoretical Chemistry, and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria.|Institute of General, Inorganic and Theoretical Chemistry, and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria.|Institute of General, Inorganic and Theoretical Chemistry, and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria.|Institute of General, Inorganic and Theoretical Chemistry, and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria.|Institute of General, Inorganic and Theoretical Chemistry, and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria.|Institute of General, Inorganic and Theoretical Chemistry, and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria.', 'Austria|Austria|Austria|Austria|Austria|Austria|Austria', 0, 'Algorithms|Animals|Cattle|Computational Biology|Endopeptidases|Entropy|Evolution, Molecular|Humans|Mutation|Peptide Hydrolases|Phylogeny|Serine Proteases|Signal Transduction|Substrate Specificity|Thrombin|Trypsin', 'Journal Article', '10.1371/journal.pcbi.1003007', '23637583', 'A purely information theory-guided approach to quantitatively characterize protease specificity is established. We calculate an entropy value for each protease subpocket based on sequences of cleaved substrates extracted from the MEROPS database. We compare our results with known subpocket specificity profiles for individual proteases and protease groups (e.g. serine proteases, metallo proteases) and reflect them quantitatively. Summation of subpocket-wise cleavage entropy contributions yields a measure for overall protease substrate specificity. This total cleavage entropy allows ranking of different proteases with respect to their specificity, separating unspecific digestive enzymes showing high total cleavage entropy from specific proteases involved in signaling cascades. The development of a quantitative cleavage entropy score allows an unbiased comparison of subpocket-wise and overall protease specificity. Thus, it enables assessment of relative importance of physicochemical and structural descriptors in protease recognition. We present an exemplary application of cleavage entropy in tracing substrate specificity in protease evolution. This highlights the wide range of substrate promiscuity within homologue proteases and hence the heavy impact of a limited number of mutations on individual substrate specificity.');
