INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(88924, 2018, 'plos', 'Population-specific design of de-immunized protein biotherapeutics', 'Schubert, Benjamin|Schärfe, Charlotta|Dönnes, Pierre|Hopf, Thomas|Marks, Debora|Kohlbacher, Oliver', 'Center for Bioinformatics, University of Tübingen, Tübingen, Germany.|Center for Bioinformatics, University of Tübingen, Tübingen, Germany.|Center for Bioinformatics, University of Tübingen, Tübingen, Germany.|Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America.|Center for Bioinformatics, University of Tübingen, Tübingen, Germany.', 'Germany|Germany|Germany|United States|United States|Germany', 4, 'Amino Acid Sequence|Antibodies, Monoclonal|Computational Biology|Humans|Protein Engineering|Recombinant Proteins', 'Journal Article', '10.1371/journal.pcbi.1005983', '29499035', 'Immunogenicity is a major problem during the development of biotherapeutics since it can lead to rapid clearance of the drug and adverse reactions. The challenge for biotherapeutic design is therefore to identify mutants of the protein sequence that minimize immunogenicity in a target population whilst retaining pharmaceutical activity and protein function. Current approaches are moderately successful in designing sequences with reduced immunogenicity, but do not account for the varying frequencies of different human leucocyte antigen alleles in a specific population and in addition, since many designs are non-functional, require costly experimental post-screening. Here, we report a new method for de-immunization design using multi-objective combinatorial optimization. The method simultaneously optimizes the likelihood of a functional protein sequence at the same time as minimizing its immunogenicity tailored to a target population. We bypass the need for three-dimensional protein structure or molecular simulations to identify functional designs by automatically generating sequences using probabilistic models that have been used previously for mutation effect prediction and structure prediction. As proof-of-principle we designed sequences of the C2 domain of Factor VIII and tested them experimentally, resulting in a good correlation with the predicted immunogenicity of our model.'),
(88925, 2018, 'plos', 'An entropic barriers diffusion theory of decision-making in multiple alternative tasks', 'Fernandez Slezak, Diego|Sigman, Mariano|Cecchi, Guillermo A', 'Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Computación, Buenos Aires, Argentina.|Universidad Torcuato Di Tella, Alte, Buenos Aires, Argentina.|Computational Biology Center, T.J. Watson Research Center, IBM, Yorktown Heights, NY, USA.', 'Argentina|Argentina|United States', 0, 'Decision Making|Entropy|Humans|Models, Psychological|Problem Solving|Reaction Time', 'Journal Article', '10.1371/journal.pcbi.1005961', '29499036', 'We present a theory of decision-making in the presence of multiple choices that departs from traditional approaches by explicitly incorporating entropic barriers in a stochastic search process. We analyze response time data from an on-line repository of 15 million blitz chess games, and show that our model fits not just the mean and variance, but the entire response time distribution (over several response-time orders of magnitude) at every stage of the game. We apply the model to show that (a) higher cognitive expertise corresponds to the exploration of more complex solution spaces, and (b) reaction times of users at an on-line buying website can be similarly explained. Our model can be seen as a synergy between diffusion models used to model simple two-choice decision-making and planning agents in complex problem solving.'),
(88926, 2018, 'plos', 'Classifying dynamic transitions in high dimensional neural mass models: A random forest approach', 'Ferrat, Lauric A|Goodfellow, Marc|Terry, John R', 'College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, UK.|College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, UK.|College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, UK.', 'United Kingdom|United Kingdom|United Kingdom', 3, 'Brain|Computational Biology|Computer Simulation|Humans|Models, Neurological|Neural Networks (Computer)|Neurons', 'Journal Article', '10.1371/journal.pcbi.1006009', '29499044', 'Neural mass models (NMMs) are increasingly used to uncover the large-scale mechanisms of brain rhythms in health and disease. The dynamics of these models is dependent upon the choice of parameters, and therefore it is crucial to be able to understand how dynamics change when parameters are varied. Despite being considered low dimensional in comparison to micro-scale, neuronal network models, with regards to understanding the relationship between parameters and dynamics, NMMs are still prohibitively high dimensional for classical approaches such as numerical continuation. Therefore, we need alternative methods to characterise dynamics of NMMs in high dimensional parameter spaces. Here, we introduce a statistical framework that enables the efficient exploration of the relationship between model parameters and selected features of the simulated, emergent model dynamics of NMMs. We combine the classical machine learning approaches of trees and random forests to enable studying the effect that varying multiple parameters has on the dynamics of a model. The method proceeds by using simulations to transform the mathematical model into a database. This database is then used to partition parameter space with respect to dynamic features of interest, using random forests. This allows us to rapidly explore dynamics in high dimensional parameter space, capture the approximate location of qualitative transitions in dynamics and assess the relative importance of all parameters in the model in all dimensions simultaneously. We apply this method to a commonly used NMM in the context of transitions to seizure dynamics. We find that the inhibitory sub-system is most crucial for the generation of seizure dynamics, confirm and expand previous findings regarding the ratio of excitation and inhibition, and demonstrate that previously overlooked parameters can have a significant impact on model dynamics. We advocate the use of this method in future to constrain high dimensional parameter spaces enabling more efficient, person-specific, model calibration.'),
(88927, 2018, 'plos', 'Increased T cell trafficking as adjunct therapy for HIV-1', 'Fryer, Helen R|Wolinsky, Steven M|McLean, Angela R', 'Institute for Emerging Infections, Department of Zoology, University of Oxford, The Peter Medawar Building for Pathogen Research, South Parks Road, Oxford, United Kingdom.|Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.|Institute for Emerging Infections, Department of Zoology, University of Oxford, The Peter Medawar Building for Pathogen Research, South Parks Road, Oxford, United Kingdom.', 'United Kingdom|United States|United Kingdom', 1, 'CD4 Lymphocyte Count|CD4-Positive T-Lymphocytes|Computer Simulation|Disease Reservoirs|HIV Infections|HIV-1|Humans|Models, Theoretical|T-Lymphocytes|Viral Load|Virus Latency|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.1006028', '29499057', 'Although antiretroviral drug therapy suppresses human immunodeficiency virus-type 1 (HIV-1) to undetectable levels in the blood of treated individuals, reservoirs of replication competent HIV-1 endure. Upon cessation of antiretroviral therapy, the reservoir usually allows outgrowth of virus and approaches to targeting the reservoir have had limited success. Ongoing cycles of viral replication in regions with low drug penetration contribute to this persistence. Here, we use a mathematical model to illustrate a new approach to eliminating the part of the reservoir attributable to persistent replication in drug sanctuaries. Reducing the residency time of CD4 T cells in drug sanctuaries renders ongoing replication unsustainable in those sanctuaries. We hypothesize that, in combination with antiretroviral drugs, a strategy to orchestrate CD4 T cell trafficking could contribute to a functional cure for HIV-1 infection.'),
(88928, 2018, 'plos', 'Cytosolic proteins can exploit membrane localization to trigger functional assembly', 'Yogurtcu, Osman N|Johnson, Margaret E', 'Department of Biophysics, Johns Hopkins University, Baltimore, MD, United States of America.|Department of Biophysics, Johns Hopkins University, Baltimore, MD, United States of America.', 'United States|United States', 13, 'Cell Membrane|Computer Simulation|Cytoplasm|Cytosol|Diffusion|Endocytosis|Membrane Proteins|Models, Biological|Multiprotein Complexes|Protein Binding', 'Journal Article', '10.1371/journal.pcbi.1006031', '29505559', 'Cell division, endocytosis, and viral budding would not function without the localization and assembly of protein complexes on membranes. What is poorly appreciated, however, is that by localizing to membranes, proteins search in a reduced space that effectively drives up concentration. Here we derive an accurate and practical analytical theory to quantify the significance of this dimensionality reduction in regulating protein assembly on membranes. We define a simple metric, an effective equilibrium constant, that allows for quantitative comparison of protein-protein interactions with and without membrane present. To test the importance of membrane localization for driving protein assembly, we collected the protein-protein and protein-lipid affinities, protein and lipid concentrations, and volume-to-surface-area ratios for 46 interactions between 37 membrane-targeting proteins in human and yeast cells. We find that many of the protein-protein interactions between pairs of proteins involved in clathrin-mediated endocytosis in human and yeast cells can experience enormous increases in effective protein-protein affinity (10-1000 fold) due to membrane localization. Localization of binding partners thus triggers robust protein complexation, suggesting that it can play an important role in controlling the timing of endocytic protein coat formation. Our analysis shows that several other proteins involved in membrane remodeling at various organelles have similar potential to exploit localization. The theory highlights the master role of phosphoinositide lipid concentration, the volume-to-surface-area ratio, and the ratio of 3D to 2D equilibrium constants in triggering (or preventing) constitutive assembly on membranes. Our simple model provides a novel quantitative framework for interpreting or designing in vitro experiments of protein complexation influenced by membrane binding.'),
(88929, 2018, 'plos', 'Free energy profiles for unwrapping the outer superhelical turn of nucleosomal DNA', 'Kono, Hidetoshi|Sakuraba, Shun|Ishida, Hisashi', 'Molecular Modeling and Simulation Group, Department of Quantum Beam Life Science, National Institutes for Quantum and Radiological Science and Technology, Umemidai, Kizugawa, Kyoto, Japan.|Graduate School of Frontier Sciences, The University of Tokyo, Kashiwanoha, Kashiwa, Chiba, Japan.|Molecular Modeling and Simulation Group, Department of Quantum Beam Life Science, National Institutes for Quantum and Radiological Science and Technology, Umemidai, Kizugawa, Kyoto, Japan.', 'Japan|Japan|Japan', 5, 'Chromatin|Computer Simulation|DNA|DNA-Binding Proteins|Energy Metabolism|Entropy|Fluorescence Resonance Energy Transfer|Histones|Molecular Dynamics Simulation|Nucleic Acid Conformation|Nucleosomes', 'Journal Article', '10.1371/journal.pcbi.1006024', '29505570', 'The eukaryotic genome is packaged into a nucleus in the form of chromatin. The fundamental structural unit of chromatin is a protein-DNA complex, the nucleosome, where 146 or 147 base pairs of DNA wrap 1.75 times around a histone core. To function in cellular processes, however, nucleosomal DNA must be unwrapped. Although this unwrapping has been experimentally investigated, details of the process at an atomic level are not yet well understood. Here, we used molecular dynamics simulation with an enhanced sampling method to calculate the free energy profiles for unwrapping the outer superhelical turn of nucleosomal DNA. A free energy change of about 11.5 kcal/mol for the unwrapping agrees well with values obtained in single molecule experiments. This simulation revealed a variety of conformational states, indicating there are many potential paths to outer superhelicdal turn unwrapping, but the dominant path is likely asymmetric. At one end of the DNA, the first five bps unwrap, after which a second five bps unwrap at the same end with no increase in free energy. The unwrapping then starts at the other end of the DNA, where 10 bps are unwrapped. During further unwrapping of 15 bps, the unwrapping advances at one of the ends, after which the other end of the DNA unwraps to complete the unwrapping of the outer superhelical turn. These results provide insight into the construction, disruption, and repositioning of nucleosomes, which are continuously ongoing during cellular processes.'),
(88930, 2018, 'plos', 'A computational model for how cells choose temporal or spatial sensing during chemotaxis', 'Tan, Rui Zhen|Chiam, Keng-Hwee', 'Singapore Institute of Technology, Singapore.|Bioinformatics Institute, A*STAR, Singapore.', 'Singapore|Singapore', 2, 'Chemotaxis|Computational Biology|Computer Simulation|Escherichia coli|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1005966', '29505572', 'Cell size is thought to play an important role in choosing between temporal and spatial sensing in chemotaxis. Large cells are thought to use spatial sensing due to large chemical difference at its ends whereas small cells are incapable of spatial sensing due to rapid homogenization of proteins within the cell. However, small cells have been found to polarize and large cells like sperm cells undergo temporal sensing. Thus, it remains an open question what exactly governs spatial versus temporal sensing. Here, we identify the factors that determines sensing choices through mathematical modeling of chemotactic circuits. Comprehensive computational search of three-node signaling circuits has identified the negative integral feedback (NFB) and incoherent feedforward (IFF) circuits as capable of adaptation, an important property for chemotaxis. Cells are modeled as one-dimensional circular system consisting of diffusible activator, inactivator and output proteins, traveling across a chemical gradient. From our simulations, we find that sensing outcomes are similar for NFB or IFF circuits. Rather than cell size, the relevant parameters are the 1) ratio of cell speed to the product of cell diameter and rate of signaling, 2) diffusivity of the output protein and 3) ratio of the diffusivities of the activator to inactivator protein. Spatial sensing is favored when all three parameters are low. This corresponds to a cell moving slower than the time it takes for signaling to propagate across the cell diameter, has an output protein that is polarizable and has a local-excitation global-inhibition system to amplify the chemical gradient. Temporal sensing is favored otherwise. We also find that temporal sensing is more robust to noise. By performing extensive literature search, we find that our prediction agrees with observation in a wide range of species and cell types ranging from E. coli to human Fibroblast cells and propose that our result is universally applicable.'),
(88931, 2018, 'plos', 'Factors affecting basket catheter detection of real and phantom rotors in the atria: A computational study', 'Martinez-Mateu, Laura|Romero, Lucia|Ferrer-Albero, Ana|Sebastian, Rafael|Rodríguez Matas, José F|Jalife, José|Berenfeld, Omer|Saiz, Javier', 'Centro de Investigación e Innovación en Bioingeniería, Universitat Politècnica de València, Valencia, Spain.|Centro de Investigación e Innovación en Bioingeniería, Universitat Politècnica de València, Valencia, Spain.|Centro de Investigación e Innovación en Bioingeniería, Universitat Politècnica de València, Valencia, Spain.|Computational Multiscale Simulation Lab, Department of Computer Science, Universitat de València, Valencia, Spain.|Dipartimento di Chimica, Materiali e Ingegneria Chimica Giulio Natta, Politecnico di Milano, Milano, Italy.|Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, United States of America.|Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, United States of America.|Centro de Investigación e Innovación en Bioingeniería, Universitat Politècnica de València, Valencia, Spain.', 'Spain|Spain|Spain|Spain|Italy|United States|United States|Spain', 11, 'Ablation Techniques|Action Potentials|Atrial Fibrillation|Computational Biology|Computer Simulation|Heart Atria|Heart Conduction System|Heart Rate|Humans|Models, Biological|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1006017', '29505583', 'Anatomically based procedures to ablate atrial fibrillation (AF) are often successful in terminating paroxysmal AF. However, the ability to terminate persistent AF remains disappointing. New mechanistic approaches use multiple-electrode basket catheter mapping to localize and target AF drivers in the form of rotors but significant concerns remain about their accuracy. We aimed to evaluate how electrode-endocardium distance, far-field sources and inter-electrode distance affect the accuracy of localizing rotors. Sustained rotor activation of the atria was simulated numerically and mapped using a virtual basket catheter with varying electrode densities placed at different positions within the atrial cavity. Unipolar electrograms were calculated on the entire endocardial surface and at each of the electrodes. Rotors were tracked on the interpolated basket phase maps and compared with the respective atrial voltage and endocardial phase maps, which served as references. Rotor detection by the basket maps varied between 35-94% of the simulation time, depending on the baskets position and the electrode-to-endocardial wall distance. However, two different types of phantom rotors appeared also on the basket maps. The first type was due to the far-field sources and the second type was due to interpolation between the electrodes, increasing electrode density decreased the incidence of the second but not the first type of phantom rotors. In the simulations study, basket catheter-based phase mapping detected rotors even when the basket was not in full contact with the endocardial wall, but always generated a number of phantom rotors in the presence of only a single real rotor, which would be the desired ablation target. Phantom rotors may mislead and contribute to failure in AF ablation procedures.'),
(88932, 2018, 'plos', 'Deploying digital health data to optimize influenza surveillance at national and local scales', 'Lee, Elizabeth C|Arab, Ali|Goldlust, Sandra M|Viboud, Cécile|Grenfell, Bryan T|Bansal, Shweta', 'Department of Biology, Georgetown University, Washington, DC, United States of America.|Department of Mathematics & Statistics, Georgetown University, Washington, DC, United States of America.|Department of Biology, Georgetown University, Washington, DC, United States of America.|Fogarty International Center, National Institutes of Health, Bethesda, Maryland, United States of America.|Fogarty International Center, National Institutes of Health, Bethesda, Maryland, United States of America.|Department of Biology, Georgetown University, Washington, DC, United States of America.', 'United States|United States|United States|United States|United States|United States', 8, 'Bayes Theorem|Computer Simulation|Databases, Factual|Humans|Influenza A Virus, H1N1 Subtype|Influenza, Human|Medical Records|Models, Theoretical|Online Systems|Pandemics|Population Surveillance|Selection Bias|Sentinel Surveillance|United States', 'Journal Article', '10.1371/journal.pcbi.1006020', '29513661', 'The surveillance of influenza activity is critical to early detection of epidemics and pandemics and the design of disease control strategies. Case reporting through a voluntary network of sentinel physicians is a commonly used method of passive surveillance for monitoring rates of influenza-like illness (ILI) worldwide. Despite its ubiquity, little attention has been given to the processes underlying the observation, collection, and spatial aggregation of sentinel surveillance data, and its subsequent effects on epidemiological understanding. We harnessed the high specificity of diagnosis codes in medical claims from a database that represented 2.5 billion visits from upwards of 120,000 United States healthcare providers each year. Among influenza seasons from 2002-2009 and the 2009 pandemic, we simulated limitations of sentinel surveillance systems such as low coverage and coarse spatial resolution, and performed Bayesian inference to probe the robustness of ecological inference and spatial prediction of disease burden. Our models suggest that a number of socio-environmental factors, in addition to local population interactions, state-specific health policies, as well as sampling effort may be responsible for the spatial patterns in U.S. sentinel ILI surveillance. In addition, we find that biases related to spatial aggregation were accentuated among areas with more heterogeneous disease risk, and sentinel systems designed with fixed reporting locations across seasons provided robust inference and prediction. With the growing availability of health-associated big data worldwide, our results suggest mechanisms for optimizing digital data streams to complement traditional surveillance in developed settings and enhance surveillance opportunities in developing countries.'),
(88933, 2018, 'plos', 'Correction: Effect of Ionic Diffusion on Extracellular Potentials in Neural Tissue', 'PLOS Computational Biology Staff', 'Department of Biology, Georgetown University, Washington, DC, United States of America.', 'United States', 0, '-', 'Journal Article', '10.1371/journal.pcbi.1006050', '29513665', '[This corrects the article DOI: 10.1371/journal.pcbi.1005193.].'),
(88934, 2018, 'plos', 'Stoichiometric balance of protein copy numbers is measurable and functionally significant in a protein-protein interaction network for yeast endocytosis', 'Holland, David O|Johnson, Margaret E', 'Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Biophysics, Johns Hopkins University, Baltimore, Maryland, United States of America.', 'United States|United States', 4, 'Clathrin|Clathrin-Coated Vesicles|Endocytosis|Gene Dosage|Gene Expression Profiling|Kinetics|Models, Biological|Protein Binding|Protein Interaction Mapping|Protein Interaction Maps|Proteostasis|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins', 'Journal Article', '10.1371/journal.pcbi.1006022', '29518071', 'Stoichiometric balance, or dosage balance, implies that proteins that are subunits of obligate complexes (e.g. the ribosome) should have copy numbers expressed to match their stoichiometry in that complex. Establishing balance (or imbalance) is an important tool for inferring subunit function and assembly bottlenecks. We show here that these correlations in protein copy numbers can extend beyond complex subunits to larger protein-protein interactions networks (PPIN) involving a range of reversible binding interactions. We develop a simple method for quantifying balance in any interface-resolved PPINs based on network structure and experimentally observed protein copy numbers. By analyzing such a network for the clathrin-mediated endocytosis (CME) system in yeast, we found that the real protein copy numbers were significantly more balanced in relation to their binding partners compared to randomly sampled sets of yeast copy numbers. The observed balance is not perfect, highlighting both under and overexpressed proteins. We evaluate the potential cost and benefits of imbalance using two criteria. First, a potential cost to imbalance is that leftover proteins without remaining functional partners are free to misinteract. We systematically quantify how this misinteraction cost is most dangerous for strong-binding protein interactions and for network topologies observed in biological PPINs. Second, a more direct consequence of imbalance is that the formation of specific functional complexes depends on relative copy numbers. We therefore construct simple kinetic models of two sub-networks in the CME network to assess multi-protein assembly of the ARP2/3 complex and a minimal, nine-protein clathrin-coated vesicle forming module. We find that the observed, imperfectly balanced copy numbers are less effective than balanced copy numbers in producing fast and complete multi-protein assemblies. However, we speculate that strategic imbalance in the vesicle forming module allows cells to tune where endocytosis occurs, providing sensitive control over cargo uptake via clathrin-coated vesicles.'),
(88935, 2018, 'plos', 'Ten simple rules to create a serious game, illustrated with examples from structural biology', 'Baaden, Marc|Delalande, Olivier|Ferey, Nicolas|Pasquali, Samuela|Waldispühl, Jérôme|Taly, Antoine', 'Laboratoire de Biochimie Théorique, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Institut de Génétique et Développement de Rennes, Univ. Rennes 1, Rennes, France.|VENISE group, CNRS-LIMSI, Orsay, France.|Laboratoire de Cristallographie et RMN Biologiques, Faculté des sciences pharmaceutiques et biologiques, Université Paris Descartes et Université Sorbonne Paris Cité, Paris, France.|School of Computer Science, McGill University, Montréal, Canada.|Laboratoire de Biochimie Théorique, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.', 'France|France|France|France|Canada|France', 7, 'Computational Biology|Goals|Humans|Models, Molecular|Molecular Biology|User-Computer Interface|Video Games', 'Editorial', '10.1371/journal.pcbi.1005955', '29518072', '-'),
(88936, 2018, 'plos', 'Method for the simulation of blood platelet shape and its evolution during activation', 'Moskalensky, Alexander E|Yurkin, Maxim A|Muliukov, Artem R|Litvinenko, Alena L|Nekrasov, Vyacheslav M|Chernyshev, Andrei V|Maltsev, Valeri P', 'Novosibirsk State University, Novosibirsk, Russia.|Novosibirsk State University, Novosibirsk, Russia.|Novosibirsk State University, Novosibirsk, Russia.|Novosibirsk State University, Novosibirsk, Russia.|Novosibirsk State University, Novosibirsk, Russia.|Novosibirsk State University, Novosibirsk, Russia.|Novosibirsk State University, Novosibirsk, Russia.', '-|-|-|-|-|-|-', 5, 'Algorithms|Blood Platelets|Cell Shape|Computational Biology|Computer Simulation|Humans|Platelet Activation', 'Journal Article', '10.1371/journal.pcbi.1005899', '29518073', 'We present a simple physically based quantitative model of blood platelet shape and its evolution during agonist-induced activation. The model is based on the consideration of two major cytoskeletal elements: the marginal band of microtubules and the submembrane cortex. Mathematically, we consider the problem of minimization of surface area constrained to confine the marginal band and a certain cellular volume. For resting platelets, the marginal band appears as a peripheral ring, allowing for the analytical solution of the minimization problem. Upon activation, the marginal band coils out of plane and forms 3D convoluted structure. We show that its shape is well approximated by an overcurved circle, a mathematical concept of closed curve with constant excessive curvature. Possible mechanisms leading to such marginal band coiling are discussed, resulting in simple parametric expression for the marginal band shape during platelet activation. The excessive curvature of marginal band is a convenient state variable which tracks the progress of activation. The cell surface is determined using numerical optimization. The shapes are strictly mathematically defined by only three parameters and show good agreement with literature data. They can be utilized in simulation of platelets interaction with different physical fields, e.g. for the description of hydrodynamic and mechanical properties of platelets, leading to better understanding of platelets margination and adhesion and thrombus formation in blood flow. It would also facilitate precise characterization of platelets in clinical diagnosis, where a novel optical model is needed for the correct solution of inverse light-scattering problem.'),
(88937, 2018, 'plos', 'Bat detective-Deep learning tools for bat acoustic signal detection', 'Mac Aodha, Oisin|Gibb, Rory|Barlow, Kate E|Browning, Ella|Firman, Michael|Freeman, Robin|Harder, Briana|Kinsey, Libby|Mead, Gary R|Newson, Stuart E|Pandourski, Ivan|Parsons, Stuart|Russ, Jon|Szodoray-Paradi, Abigel|Szodoray-Paradi, Farkas|Tilova, Elena|Girolami, Mark|Brostow, Gabriel|Jones, Kate E', 'Department of Computer Science, University College London, London, United Kingdom.|Centre for Biodiversity and Environment Research, Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.|Bat Conservation Trust, Quadrant House, London, United Kingdom.|Centre for Biodiversity and Environment Research, Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.|Department of Computer Science, University College London, London, United Kingdom.|Institute of Zoology, Zoological Society of London, Regents Park, London, United Kingdom.|Bellevue, Washington, United States of America.|Department of Computer Science, University College London, London, United Kingdom.|Wickford, Essex, United Kingdom.|British Trust for Ornithology, The Nunnery, Thetford, Norfolk, United Kingdom.|Institute of Biodiversity and Ecosystem Research, Bulgaria Academy of Sciences, Sofia, Bulgaria.|School of Earth, Environmental and Biological Sciences, Queensland University of Technology (QUT), Brisbane, QLD, Australia.|Ridgeway Ecology, Warwick, United Kingdom.|Romanian Bat Protection Association, Satu Mare, Romania.|Romanian Bat Protection Association, Satu Mare, Romania.|Green Balkans-Stara Zagora, Stara Zagora, Bulgaria.|Department of Mathematics, Imperial College London, London, United Kingdom.|Department of Computer Science, University College London, London, United Kingdom.|Centre for Biodiversity and Environment Research, Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Sta', 42, 'Algorithms|Animals|Chiroptera|Computational Biology|Echolocation|Endangered Species|Environmental Monitoring|Machine Learning|Neural Networks (Computer)|Signal Processing, Computer-Assisted|Zoology', 'Journal Article', '10.1371/journal.pcbi.1005995', '29518076', 'Passive acoustic sensing has emerged as a powerful tool for quantifying anthropogenic impacts on biodiversity, especially for echolocating bat species. To better assess bat population trends there is a critical need for accurate, reliable, and open source tools that allow the detection and classification of bat calls in large collections of audio recordings. The majority of existing tools are commercial or have focused on the species classification task, neglecting the important problem of first localizing echolocation calls in audio which is particularly problematic in noisy recordings. We developed a convolutional neural network based open-source pipeline for detecting ultrasonic, full-spectrum, search-phase calls produced by echolocating bats. Our deep learning algorithms were trained on full-spectrum ultrasonic audio collected along road-transects across Europe and labelled by citizen scientists from www.batdetective.org. When compared to other existing algorithms and commercial systems, we show significantly higher detection performance of search-phase echolocation calls with our test sets. As an example application, we ran our detection pipeline on bat monitoring data collected over five years from Jersey (UK), and compared results to a widely-used commercial system. Our detection pipeline can be used for the automatic detection and monitoring of bat populations, and further facilitates their use as indicator species on a large scale. Our proposed pipeline makes only a small number of bat specific design decisions, and with appropriate training data it could be applied to detecting other species in audio. A crucial novelty of our work is showing that with careful, non-trivial, design and implementation considerations, state-of-the-art deep learning methods can be used for accurate and efficient monitoring in audio.'),
(88938, 2018, 'plos', 'ChromoTrace: Computational reconstruction of 3D chromosome configurations for super-resolution microscopy', 'Barton, Carl|Morganella, Sandro|Ødegård-Fougner, Øyvind|Alexander, Stephanie|Ries, Jonas|Fitzgerald, Tomas|Ellenberg, Jan|Birney, Ewan', 'European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.|European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.|European Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics Unit, Heidelberg, Heidelberg, Germany.|European Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics Unit, Heidelberg, Heidelberg, Germany.|European Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics Unit, Heidelberg, Heidelberg, Germany.|European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.|European Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics Unit, Heidelberg, Heidelberg, Germany.|European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.', 'United Kingdom|United Kingdom|Germany|Germany|Germany|United Kingdom|Germany|United Kingdom', 0, 'Algorithms|Cell Nucleus|Chromatin|Chromosomes|Computational Biology|DNA|DNA Replication|Fluorescent Dyes|Genome|Humans|Image Processing, Computer-Assisted|Imaging, Three-Dimensional|In Situ Hybridization, Fluorescence|Microscopy, Fluorescence|Nucleic Acid Conformation', 'Journal Article', '10.1371/journal.pcbi.1006002', '29522506', 'The 3D structure of chromatin plays a key role in genome function, including gene expression, DNA replication, chromosome segregation, and DNA repair. Furthermore the location of genomic loci within the nucleus, especially relative to each other and nuclear structures such as the nuclear envelope and nuclear bodies strongly correlates with aspects of function such as gene expression. Therefore, determining the 3D position of the 6 billion DNA base pairs in each of the 23 chromosomes inside the nucleus of a human cell is a central challenge of biology. Recent advances of super-resolution microscopy in principle enable the mapping of specific molecular features with nanometer precision inside cells. Combined with highly specific, sensitive and multiplexed fluorescence labeling of DNA sequences this opens up the possibility of mapping the 3D path of the genome sequence in situ. Here we develop computational methodologies to reconstruct the sequence configuration of all human chromosomes in the nucleus from a super-resolution image of a set of fluorescent in situ probes hybridized to the genome in a cell. To test our approach, we develop a method for the simulation of DNA in an idealized human nucleus. Our reconstruction method, ChromoTrace, uses suffix trees to assign a known linear ordering of in situ probes on the genome to an unknown set of 3D in-situ probe positions in the nucleus from super-resolved images using the known genomic probe spacing as a set of physical distance constraints between probes. We find that ChromoTrace can assign the 3D positions of the majority of loci with high accuracy and reasonable sensitivity to specific genome sequences. By simulating appropriate spatial resolution, label multiplexing and noise scenarios we assess our algorithms performance. Our study shows that it is feasible to achieve genome-wide reconstruction of the 3D DNA path based on super-resolution microscopy images.'),
(88939, 2018, 'plos', 'Neuronal gain modulability is determined by dendritic morphology: A computational optogenetic study', 'Jarvis, Sarah|Nikolic, Konstantin|Schultz, Simon R', 'Centre for Neurotechnology and Department of Bioengineering, Imperial College London, London, United Kingdom.|Centre for Bio-Inspired Technology and Department of Electrical & Electronic Engineering, Imperial College London, London, United Kingdom.|Centre for Neurotechnology and Department of Bioengineering, Imperial College London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 7, 'Computational Biology|Computer Simulation|Dendrites|Kinetics|Models, Neurological|Neurons|Opsins|Optogenetics|Pyramidal Cells|Synapses', 'Journal Article', '10.1371/journal.pcbi.1006027', '29522509', 'The mechanisms by which the gain of the neuronal input-output function may be modulated have been the subject of much investigation. However, little is known of the role of dendrites in neuronal gain control. New optogenetic experimental paradigms based on spatial profiles or patterns of light stimulation offer the prospect of elucidating many aspects of single cell function, including the role of dendrites in gain control. We thus developed a model to investigate how competing excitatory and inhibitory input within the dendritic arbor alters neuronal gain, incorporating kinetic models of opsins into our modeling to ensure it is experimentally testable. To investigate how different topologies of the neuronal dendritic tree affect the neurons input-output characteristics we generate branching geometries which replicate morphological features of most common neurons, but keep the number of branches and overall area of dendrites approximately constant. We found a relationship between a neurons gain modulability and its dendritic morphology, with neurons with bipolar dendrites with a moderate degree of branching being most receptive to control of the gain of their input-output relationship. The theory was then tested and confirmed on two examples of realistic neurons: 1) layer V pyramidal cells-confirming their role in neural circuits as a regulator of the gain in the circuit in addition to acting as the primary excitatory neurons, and 2) stellate cells. In addition to providing testable predictions and a novel application of dual-opsins, our model suggests that innervation of all dendritic subdomains is required for full gain modulation, revealing the importance of dendritic targeting in the generation of neuronal gain control and the functions that it subserves. Finally, our study also demonstrates that neurophysiological investigations which use direct current injection into the soma and bypass the dendrites may miss some important neuronal functions, such as gain modulation.'),
(88940, 2018, 'plos', '4Cin: A computational pipeline for 3D genome modeling and virtual Hi-C analyses from 4C data', 'Irastorza-Azcarate, Ibai|Acemel, Rafael D|Tena, Juan J|Maeso, Ignacio|Gómez-Skarmeta, José Luis|Devos, Damien P', 'Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, Seville, Spain.|Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, Seville, Spain.|Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, Seville, Spain.|Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, Seville, Spain.|Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, Seville, Spain.|Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, Seville, Spain.', 'Spain|Spain|Spain|Spain|Spain|Spain', 0, 'Chromatin|Chromosome Mapping|Chromosomes|Computational Biology|Computer Simulation|Genome|Genomics|Imaging, Three-Dimensional|Nucleic Acid Conformation|Sequence Analysis, DNA|Software', 'Journal Article', '10.1371/journal.pcbi.1006030', '29522512', 'The use of 3C-based methods has revealed the importance of the 3D organization of the chromatin for key aspects of genome biology. However, the different caveats of the variants of 3C techniques have limited their scope and the range of scientific fields that could benefit from these approaches. To address these limitations, we present 4Cin, a method to generate 3D models and derive virtual Hi-C (vHi-C) heat maps of genomic loci based on 4C-seq or any kind of 4C-seq-like data, such as those derived from NG Capture-C. 3D genome organization is determined by integrative consideration of the spatial distances derived from as few as four 4C-seq experiments. The 3D models obtained from 4C-seq data, together with their associated vHi-C maps, allow the inference of all chromosomal contacts within a given genomic region, facilitating the identification of Topological Associating Domains (TAD) boundaries. Thus, 4Cin offers a much cheaper, accessible and versatile alternative to other available techniques while providing a comprehensive 3D topological profiling. By studying TAD modifications in genomic structural variants associated to disease phenotypes and performing cross-species evolutionary comparisons of 3D chromatin structures in a quantitative manner, we demonstrate the broad potential and novel range of applications of our method.'),
(88941, 2018, 'plos', 'Use of temperature to improve West Nile virus forecasts', 'DeFelice, Nicholas B|Schneider, Zachary D|Little, Eliza|Barker, Christopher|Caillouet, Kevin A|Campbell, Scott R|Damian, Dan|Irwin, Patrick|Jones, Herff M P|Townsend, John|Shaman, Jeffrey', 'Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, United States of America.|Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, United States of America.|Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, United States of America.|Center for Vectorborne Diseases, University of California Davis, Davis, California.|St. Tammany Parish Mosquito Abatement District, St. Tammany Parish, Slidell, Louisiana, United States of America.|Arthropod-Borne Disease Laboratory, Suffolk County Department of Health Services, Yaphank, New York, United States of America.|Vector Control Division, Maricopa County Environmental Services Department, Phoenix, Arizona, United States of America.|Northwest Mosquito Abatement District, Wheeling, Illinois, United States of America.|Iberia Parish Mosquito Abatement District, Iberia Parish, New Iberia, Louisiana, United States of America.|Vector Control Division, Maricopa County Environmental Services Department, Phoenix, Arizona, United States of America.|Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, United States of America.', 'United States|United States|United States|-|United States|United States|United States|United States|', 0, 'Animals|Culicidae|Disease Outbreaks|Forecasting|Humans|Insect Vectors|Models, Theoretical|Mosquito Control|Public Health|Retrospective Studies|Seasons|Temperature|West Nile Fever|West Nile virus', 'Journal Article', '10.1371/journal.pcbi.1006047', '29522514', 'Ecological and laboratory studies have demonstrated that temperature modulates West Nile virus (WNV) transmission dynamics and spillover infection to humans. Here we explore whether inclusion of temperature forcing in a model depicting WNV transmission improves WNV forecast accuracy relative to a baseline model depicting WNV transmission without temperature forcing. Both models are optimized using a data assimilation method and two observed data streams: mosquito infection rates and reported human WNV cases. Each coupled model-inference framework is then used to generate retrospective ensemble forecasts of WNV for 110 outbreak years from among 12 geographically diverse United States counties. The temperature-forced model improves forecast accuracy for much of the outbreak season. From the end of July until the beginning of October, a timespan during which 70% of human cases are reported, the temperature-forced model generated forecasts of the total number of human cases over the next 3 weeks, total number of human cases over the season, the week with the highest percentage of infectious mosquitoes, and the peak percentage of infectious mosquitoes that on average increased absolute forecast accuracy 5%, 10%, 12%, and 6%, respectively, over the non-temperature forced baseline model. These results indicate that use of temperature forcing improves WNV forecast accuracy and provide further evidence that temperature influences rates of WNV transmission. The findings provide a foundation for implementation of a statistically rigorous system for real-time forecast of seasonal WNV outbreaks and their use as a quantitative decision support tool for public health officials and mosquito control programs.'),
(88942, 2018, 'plos', 'The importance of geometry in the corneal micropocket angiogenesis assay', 'Grogan, James A|Connor, Anthony J|Pitt-Francis, Joe M|Maini, Philip K|Byrne, Helen M', 'Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, United Kingdom.|Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, United Kingdom.|Department of Computer Science, University of Oxford, Oxford, United Kingdom.|Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, United Kingdom.|Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 1, 'Animals|Biological Assay|Computer Simulation|Cornea|Corneal Neovascularization|Models, Spatial Interaction|Models, Theoretical|Molecular Dynamics Simulation|Neovascularization, Pathologic|Neovascularization, Physiologic|Vascular Endothelial Growth Factor A', 'Journal Article', '10.1371/journal.pcbi.1006049', '29522527', 'The corneal micropocket angiogenesis assay is an experimental protocol for studying vessel network formation, or neovascularization, in vivo. The assay is attractive due to the ease with which the developing vessel network can be observed in the same animal over time. Measurements from the assay have been used in combination with mathematical modeling to gain insights into the mechanisms of angiogenesis. While previous modeling studies have adopted planar domains to represent the assay, the hemispherical shape of the cornea and asymmetric positioning of the angiogenic source can be seen to affect vascular patterning in experimental images. As such, we aim to better understand: i) how the geometry of the assay influences vessel network formation and ii) how to relate observations from planar domains to those in the hemispherical cornea. To do so, we develop a three-dimensional, off-lattice mathematical model of neovascularization in the cornea, using a spatially resolved representation of the assay for the first time. Relative to the detailed model, we predict that the adoption of planar geometries has a noticeable impact on vascular patterning, leading to increased vessel merging, or anastomosis, in particular when circular geometries are adopted. Significant differences in the dynamics of diffusible aniogenesis simulators are also predicted between different domains. In terms of comparing predictions across domains, the distance of the vascular front to the limbus metric is found to have low sensitivity to domain choice, while metrics such as densities of tip cells and vessels and vascularized fraction are sensitive to domain choice. Given the widespread adoption and attractive simplicity of planar tissue domains, both in silico and in vitro, the differences identified in the present study should prove useful in relating the results of previous and future theoretical studies of neovascularization to in vivo observations in the cornea.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(88943, 2018, 'plos', 'Particle-based simulations of polarity establishment reveal stochastic promotion of Turing pattern formation', 'Pablo, Michael|Ramirez, Samuel A|Elston, Timothy C', 'Department of Chemistry, The University of North Carolina, Chapel Hill, NC, United States of America.|Department of Pharmacology, The University of North Carolina, Chapel Hill, NC, United States of America.|Department of Pharmacology, The University of North Carolina, Chapel Hill, NC, United States of America.', 'United States|United States|United States', 4, 'Cell Division|Cell Membrane|Cell Membrane Permeability|Cell Polarity|Computational Biology|Computer Simulation|Cytosol|Diffusion|Models, Biological|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Stochastic Processes|cdc42 GTP-Binding Protein, Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1006016', '29529021', 'Polarity establishment, the spontaneous generation of asymmetric molecular distributions, is a crucial component of many cellular functions. Saccharomyces cerevisiae (yeast) undergoes directed growth during budding and mating, and is an ideal model organism for studying polarization. In yeast and many other cell types, the Rho GTPase Cdc42 is the key molecular player in polarity establishment. During yeast polarization, multiple patches of Cdc42 initially form, then resolve into a single front. Because polarization relies on strong positive feedback, it is likely that the amplification of molecular-level fluctuations underlies the generation of multiple nascent patches. In the absence of spatial cues, these fluctuations may be key to driving polarization. Here we used particle-based simulations to investigate the role of stochastic effects in a Turing-type model of yeast polarity establishment. In the model, reactions take place either between two molecules on the membrane, or between a cytosolic and a membrane-bound molecule. Thus, we developed a computational platform that explicitly simulates molecules at and near the cell membrane, and implicitly handles molecules away from the membrane. To evaluate stochastic effects, we compared particle simulations to deterministic reaction-diffusion equation simulations. Defining macroscopic rate constants that are consistent with the microscopic parameters for this system is challenging, because diffusion occurs in two dimensions and particles exchange between the membrane and cytoplasm. We address this problem by empirically estimating macroscopic rate constants from appropriately designed particle-based simulations. Ultimately, we find that stochastic fluctuations speed polarity establishment and permit polarization in parameter regions predicted to be Turing stable. These effects can operate at Cdc42 abundances expected of yeast cells, and promote polarization on timescales consistent with experimental results. To our knowledge, our work represents the first particle-based simulations of a model for yeast polarization that is based on a Turing mechanism.'),
(88944, 2018, 'plos', 'In silico study of multicellular automaticity of heterogeneous cardiac cell monolayers: Effects of automaticity strength and structural linear anisotropy', 'Duverger, James Elber|Jacquemet, Vincent|Vinet, Alain|Comtois, Philippe', 'Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada.|Department of Pharmacology and Physiology / Institute of Biomedical Engineering, Université de Montréal, Montreal, Quebec, Canada.|Department of Pharmacology and Physiology / Institute of Biomedical Engineering, Université de Montréal, Montreal, Quebec, Canada.|Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada.', 'Canada|Canada|Canada|Canada', 0, 'Algorithms|Anisotropy|Biological Clocks|Computational Biology|Computer Simulation|Humans|Models, Cardiovascular|Myocytes, Cardiac', 'Journal Article', '10.1371/journal.pcbi.1005978', '29529023', 'The biological pacemaker approach is an alternative to cardiac electronic pacemakers. Its main objective is to create pacemaking activity from added or modified distribution of spontaneous cells in the myocardium. This paper aims to assess how automaticity strength of pacemaker cells (i.e. their ability to maintain robust spontaneous activity with fast rate and to drive neighboring quiescent cells) and structural linear anisotropy, combined with density and spatial distribution of pacemaker cells, may affect the macroscopic behavior of the biological pacemaker. A stochastic algorithm was used to randomly distribute pacemaker cells, with various densities and spatial distributions, in a semi-continuous mathematical model. Simulations of the model showed that stronger automaticity allows onset of spontaneous activity for lower densities and more homogeneous spatial distributions, displayed more central foci, less variability in cycle lengths and synchronization of electrical activation for similar spatial patterns, but more variability in those same variables for dissimilar spatial patterns. Compared to their isotropic counterparts, in silico anisotropic monolayers had less central foci and displayed more variability in cycle lengths and synchronization of electrical activation for both similar and dissimilar spatial patterns. The present study established a link between microscopic structure and macroscopic behavior of the biological pacemaker, and may provide crucial information for optimized biological pacemaker therapies.'),
(88945, 2018, 'plos', 'LAILAPS-QSM: A RESTful API and JAVA library for semantic query suggestions', 'Chen, Jinbo|Scholz, Uwe|Zhou, Ruonan|Lange, Matthias', 'Research Group Bioinformatics and Information Technology, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, Seeland OT Gatersleben, Germany.|Research Group Bioinformatics and Information Technology, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, Seeland OT Gatersleben, Germany.|Research Group Bioinformatics and Information Technology, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, Seeland OT Gatersleben, Germany.|Research Group Bioinformatics and Information Technology, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, Seeland OT Gatersleben, Germany.', 'Germany|Germany|Germany|Germany', 0, 'Algorithms|Biochemical Phenomena|Biological Science Disciplines|Computational Biology|Databases, Factual|Gene Library|Humans|Information Storage and Retrieval|Internet|Linguistics|Machine Learning|Search Engine|Semantics|Software|User-Computer Interface|Vocabulary, Controlled', 'Journal Article', '10.1371/journal.pcbi.1006058', '29529024', 'In order to access and filter content of life-science databases, full text search is a widely applied query interface. But its high flexibility and intuitiveness is paid for with potentially imprecise and incomplete query results. To reduce this drawback, query assistance systems suggest those combinations of keywords with the highest potential to match most of the relevant data records. Widespread approaches are syntactic query corrections that avoid misspelling and support expansion of words by suffixes and prefixes. Synonym expansion approaches apply thesauri, ontologies, and query logs. All need laborious curation and maintenance. Furthermore, access to query logs is in general restricted. Approaches that infer related queries by their query profile like research field, geographic location, co-authorship, affiliation etc. require users registration and its public accessibility that contradict privacy concerns. To overcome these drawbacks, we implemented LAILAPS-QSM, a machine learning approach that reconstruct possible linguistic contexts of a given keyword query. The context is referred from the text records that are stored in the databases that are going to be queried or extracted for a general purpose query suggestion from PubMed abstracts and UniProt data. The supplied tool suite enables the pre-processing of these text records and the further computation of customized distributed word vectors. The latter are used to suggest alternative keyword queries. An evaluated of the query suggestion quality was done for plant science use cases. Locally present experts enable a cost-efficient quality assessment in the categories trait, biological entity, taxonomy, affiliation, and metabolic function which has been performed using ontology term similarities. LAILAPS-QSM mean information content similarity for 15 representative queries is 0.70, whereas 34% have a score above 0.80. In comparison, the information content similarity for human expert made query suggestions is 0.90. The software is either available as tool set to build and train dedicated query suggestion services or as already trained general purpose RESTful web service. The service uses open interfaces to be seamless embeddable into database frontends. The JAVA implementation uses highly optimized data structures and streamlined code to provide fast and scalable response for web service calls. The source code of LAILAPS-QSM is available under GNU General Public License version 2 in Bitbucket GIT repository: https://bitbucket.org/ipk_bit_team/bioescorte-suggestion.'),
(88946, 2018, 'plos', 'Closely related, yet unique: Distinct homo- and heterodimerization patterns of G protein coupled chemokine receptors and their fine-tuning by cholesterol', 'Gahbauer, Stefan|Pluhackova, Kristyna|Böckmann, Rainer A', 'Computational Biology, Department of Biology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.|Computational Biology, Department of Biology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.|Computational Biology, Department of Biology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.', 'Germany|Germany|Germany', 13, 'Animals|Chemokines|Cholesterol|Computer Simulation|Dimerization|Humans|Molecular Dynamics Simulation|Receptors, CCR2|Receptors, CCR5|Receptors, CXCR4|Receptors, Chemokine|Receptors, G-Protein-Coupled|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1006062', '29529028', 'Chemokine receptors, a subclass of G protein coupled receptors (GPCRs), play essential roles in the human immune system, they are involved in cancer metastasis as well as in HIV-infection. A plethora of studies show that homo- and heterodimers or even higher order oligomers of the chemokine receptors CXCR4, CCR5, and CCR2 modulate receptor function. In addition, membrane cholesterol affects chemokine receptor activity. However, structural information about homo- and heterodimers formed by chemokine receptors and their interplay with cholesterol is limited. Here, we report homo- and heterodimer configurations of the chemokine receptors CXCR4, CCR5, and CCR2 at atomistic detail, as obtained from thousands of molecular dynamics simulations. The observed homodimerization patterns were similar for the closely related CC chemokine receptors, yet they differed significantly between the CC receptors and CXCR4. Despite their high sequence identity, cholesterol modulated the CC homodimer interfaces in a subtype-specific manner. Chemokine receptor heterodimers display distinct dimerization patterns for CXCR4/CCR5 and CXCR4/CCR2. Furthermore, associations between CXCR4 and CCR5 reveal an increased cholesterol-sensitivity as compared to CXCR4/CCR2 heterodimerization patterns. This work provides a first comprehensive structural overview over the complex interaction network between chemokine receptors and indicates how heterodimerization and the interaction with the membrane environment diversifies the function of closely related GPCRs.'),
(88947, 2018, 'plos', 'Gap junction plasticity as a mechanism to regulate network-wide oscillations', 'Pernelle, Guillaume|Nicola, Wilten|Clopath, Claudia', 'Bioengineering Department, Imperial College London, London, United Kingdom.|Bioengineering Department, Imperial College London, London, United Kingdom.|Bioengineering Department, Imperial College London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 12, 'Action Potentials|Animals|Computational Biology|Computer Simulation|Cortical Synchronization|Electrical Synapses|Gap Junctions|Humans|Interneurons|Nerve Net|Neuronal Plasticity|Neurons|Synapses|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1006025', '29529034', 'Cortical oscillations are thought to be involved in many cognitive functions and processes. Several mechanisms have been proposed to regulate oscillations. One prominent but understudied mechanism is gap junction coupling. Gap junctions are ubiquitous in cortex between GABAergic interneurons. Moreover, recent experiments indicate their strength can be modified in an activity-dependent manner, similar to chemical synapses. We hypothesized that activity-dependent gap junction plasticity acts as a mechanism to regulate oscillations in the cortex. We developed a computational model of gap junction plasticity in a recurrent cortical network based on recent experimental findings. We showed that gap junction plasticity can serve as a homeostatic mechanism for oscillations by maintaining a tight balance between two network states: asynchronous irregular activity and synchronized oscillations. This homeostatic mechanism allows for robust communication between neuronal assemblies through two different mechanisms: transient oscillations and frequency modulation. This implies a direct functional role for gap junction plasticity in information transmission in cortex.'),
(88948, 2018, 'plos', 'Relatively slow stochastic gene-state switching in the presence of positive feedback significantly broadens the region of bimodality through stabilizing the uninduced phenotypic state', 'Ge, Hao|Wu, Pingping|Qian, Hong|Xie, Xiaoliang Sunney', 'Biodynamic Optical Imaging Center (BIOPIC), Peking University, Beijing, P.R.China.|School of Mathematical Sciences and Centre for Computational Systems Biology, Fudan University, Shanghai, P.R.China.|Department of Applied Mathematics, University of Washington, Seattle, Washington, United States of America.|Biodynamic Optical Imaging Center (BIOPIC), Peking University, Beijing, P.R.China.', 'China|China|United States|China', 4, 'Computer Simulation|Escherichia coli|Feedback|Gene Expression Regulation|Gene Expression Regulation, Bacterial|Gene Regulatory Networks|Kinetics|Lac Operon|Models, Biological|Operon|Phenotype|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1006051', '29529037', 'Within an isogenic population, even in the same extracellular environment, individual cells can exhibit various phenotypic states. The exact role of stochastic gene-state switching regulating the transition among these phenotypic states in a single cell is not fully understood, especially in the presence of positive feedback. Recent high-precision single-cell measurements showed that, at least in bacteria, switching in gene states is slow relative to the typical rates of active transcription and translation. Hence using the lac operon as an archetype, in such a region of operon-state switching, we present a fluctuating-rate model for this classical gene regulation module, incorporating the more realistic operon-state switching mechanism that was recently elucidated. We found that the positive feedback mechanism induces bistability (referred to as deterministic bistability), and that the parameter range for its occurrence is significantly broadened by stochastic operon-state switching. We further show that in the absence of positive feedback, operon-state switching must be extremely slow to trigger bistability by itself. However, in the presence of positive feedback, which stabilizes the induced state, the relatively slow operon-state switching kinetics within the physiological region are sufficient to stabilize the uninduced state, together generating a broadened parameter region of bistability (referred to as stochastic bistability). We illustrate the opposite phenotype-transition rate dependence upon the operon-state switching rates in the two types of bistability, with the aid of a recently proposed rate formula for fluctuating-rate models. The rate formula also predicts a maximal transition rate in the intermediate region of operon-state switching, which is validated by numerical simulations in our model. Overall, our findings suggest a biological function of transcriptional variations among genetically identical cells, for the emergence of bistability and transition between phenotypic states.'),
(88949, 2018, 'plos', 'Across-subjects classification of stimulus modality from human MEG high frequency activity', 'Westner, Britta U|Dalal, Sarang S|Hanslmayr, Simon|Staudigl, Tobias', 'Department of Psychology, University of Konstanz, Konstanz, Germany.|Center of Functionally Integrative Neuroscience, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.|School of Psychology, University of Birmingham, Birmingham, United Kingdom.|Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.', 'Germany|Denmark|United Kingdom|Netherlands', 8, 'Acoustic Stimulation|Adult|Auditory Cortex|Brain|Female|Humans|Magnetoencephalography|Male|Photic Stimulation|Signal Processing, Computer-Assisted|Signal-To-Noise Ratio|Support Vector Machine|Visual Cortex|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1005938', '29529062', 'Single-trial analyses have the potential to uncover meaningful brain dynamics that are obscured when averaging across trials. However, low signal-to-noise ratio (SNR) can impede the use of single-trial analyses and decoding methods. In this study, we investigate the applicability of a single-trial approach to decode stimulus modality from magnetoencephalographic (MEG) high frequency activity. In order to classify the auditory versus visual presentation of words, we combine beamformer source reconstruction with the random forest classification method. To enable group level inference, the classification is embedded in an across-subjects framework. We show that single-trial gamma SNR allows for good classification performance (accuracy across subjects: 66.44%). This implies that the characteristics of high frequency activity have a high consistency across trials and subjects. The random forest classifier assigned informational value to activity in both auditory and visual cortex with high spatial specificity. Across time, gamma power was most informative during stimulus presentation. Among all frequency bands, the 75 Hz to 95 Hz band was the most informative frequency band in visual as well as in auditory areas. Especially in visual areas, a broad range of gamma frequencies (55 Hz to 125 Hz) contributed to the successful classification. Thus, we demonstrate the feasibility of single-trial approaches for decoding the stimulus modality across subjects from high frequency activity and describe the discriminative gamma activity in time, frequency, and space.'),
(88950, 2018, 'plos', 'iDREM: Interactive visualization of dynamic regulatory networks', 'Ding, Jun|Hagood, James S|Ambalavanan, Namasivayam|Kaminski, Naftali|Bar-Joseph, Ziv', 'Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego and Rady Childrens Hospital, La Jolla, California, United States of America.|Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.|Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America.|Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.', 'United States|United States|United States|United States|United States', 5, 'Computational Biology|Computers|DNA-Binding Proteins|Gene Expression Profiling|Gene Regulatory Networks|Humans|MicroRNAs|Molecular Dynamics Simulation|Protein Binding|Proteomics|Software', 'Journal Article', '10.1371/journal.pcbi.1006019', '29538379', 'The Dynamic Regulatory Events Miner (DREM) software reconstructs dynamic regulatory networks by integrating static protein-DNA interaction data with time series gene expression data. In recent years, several additional types of high-throughput time series data have been profiled when studying biological processes including time series miRNA expression, proteomics, epigenomics and single cell RNA-Seq. Combining all available time series and static datasets in a unified model remains an important challenge and goal. To address this challenge we have developed a new version of DREM termed interactive DREM (iDREM). iDREM provides support for all data types mentioned above and combines them with existing interaction data to reconstruct networks that can lead to novel hypotheses on the function and timing of regulators. Users can interactively visualize and query the resulting model. We showcase the functionality of the new tool by applying it to microglia developmental data from multiple labs.'),
(88951, 2018, 'plos', 'A FAIR guide for data providers to maximise sharing of human genomic data', 'Corpas, Manuel|Kovalevskaya, Nadezda V|McMurray, Amanda|Nielsen, Fiona G G', 'Repositive Ltd, Betjeman House, Cambridge, United Kingdom.|Repositive Ltd, Betjeman House, Cambridge, United Kingdom.|Repositive Ltd, Betjeman House, Cambridge, United Kingdom.|Repositive Ltd, Betjeman House, Cambridge, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 5, 'Databases, Genetic|Genome, Human|Genomics|Humans|Information Dissemination', 'Journal Article', '10.1371/journal.pcbi.1005873', '29543799', 'It is generally acknowledged that, for reproducibility and progress of human genomic research, data sharing is critical. For every sharing transaction, a successful data exchange is produced between a data consumer and a data provider. Providers of human genomic data (e.g., publicly or privately funded repositories and data archives) fulfil their social contract with data donors when their shareable data conforms to FAIR (findable, accessible, interoperable, reusable) principles. Based on our experiences via Repositive (https://repositive.io), a leading discovery platform cataloguing all shared human genomic datasets, we propose guidelines for data providers wishing to maximise their shared datas FAIRness.'),
(88952, 2018, 'plos', 'Epigenetic regulation of cell fate reprogramming in aging and disease: A predictive computational model', 'Folguera-Blasco, Núria|Cuyàs, Elisabet|Menéndez, Javier A|Alarcón, Tomás', 'Centre de Recerca Matemàtica, Edifici C, Campus de Bellaterra, Bellaterra (Barcelona), Spain.|Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain.|Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain.|Centre de Recerca Matemàtica, Edifici C, Campus de Bellaterra, Bellaterra (Barcelona), Spain.', 'Spain|Spain|Spain|Spain', 7, 'Aging|Animals|Bayes Theorem|Cell Differentiation|Cellular Reprogramming|Cellular Senescence|Chromatin|Computational Biology|Computer Simulation|DNA Methylation|Epigenesis, Genetic|Forecasting|Histone Code|Histones|Humans|Kinetics', 'Journal Article', '10.1371/journal.pcbi.1006052', '29543808', 'Understanding the control of epigenetic regulation is key to explain and modify the aging process. Because histone-modifying enzymes are sensitive to shifts in availability of cofactors (e.g. metabolites), cellular epigenetic states may be tied to changing conditions associated with cofactor variability. The aim of this study is to analyse the relationships between cofactor fluctuations, epigenetic landscapes, and cell state transitions. Using Approximate Bayesian Computation, we generate an ensemble of epigenetic regulation (ER) systems whose heterogeneity reflects variability in cofactor pools used by histone modifiers. The heterogeneity of epigenetic metabolites, which operates as regulator of the kinetic parameters promoting/preventing histone modifications, stochastically drives phenotypic variability. The ensemble of ER configurations reveals the occurrence of distinct epi-states within the ensemble. Whereas resilient states maintain large epigenetic barriers refractory to reprogramming cellular identity, plastic states lower these barriers, and increase the sensitivity to reprogramming. Moreover, fine-tuning of cofactor levels redirects plastic epigenetic states to re-enter epigenetic resilience, and vice versa. Our ensemble model agrees with a model of metabolism-responsive loss of epigenetic resilience as a cellular aging mechanism. Our findings support the notion that cellular aging, and its reversal, might result from stochastic translation of metabolic inputs into resilient/plastic cell states via ER systems.'),
(88953, 2018, 'plos', 'Meet-U: Educating through research immersion', 'Abdollahi, Nika|Albani, Alexandre|Anthony, Eric|Baud, Agnes|Cardon, Mélissa|Clerc, Robert|Czernecki, Dariusz|Conte, Romain|David, Laurent|Delaune, Agathe|Djerroud, Samia|Fourgoux, Pauline|Guiglielmoni, Nadège|Laurentie, Jeanne|Lehmann, Nathalie|Lochard, Camille|Montagne, Rémi|Myrodia, Vasiliki|Opuu, Vaitea|Parey, Elise|Polit, Lélia|Privé, Sylvain|Quignot, Chloé|Ruiz-Cuevas, Maria|Sissoko, Mariam|Sompairac, Nicolas|Vallerix, Audrey|Verrecchia, Violaine|Delarue, Marc|Guérois, Raphael|Ponty, Yann|Sacquin-Mora, Sophie|Carbone, Alessandra|Froidevaux, Christine|Le Crom, Stéphane|Lespinet, Olivier|Weigt, Martin|Abboud, Samer|Bernardes, Juliana|Bouvier, Guillaume|Dequeker, Chloé|Ferré, Arnaud|Fuchs, Patrick|Lelandais, Gaëlle|Poulain, Pierre|Richard, Hugues|Schweke, Hugo|Laine, Elodie|Lopes, Anne', 'Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Department of Biology and of Computer Science, Univ. Paris-Sud, Université Paris-Saclay (UPSay), Orsay, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Department of Biology and of Computer Science, Univ. Paris-Sud, Université Paris-Saclay (UPSay), Orsay, France.|Department of Biology and of Computer Science, Univ. Paris-Sud, Université Paris-Saclay (UPSay), Orsay, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Department of Biology and of Computer Science, Univ. Paris-Sud, Université Paris-Saclay (UPSay), Orsay, France.|Department of Biology and of Computer Science, Univ. Paris-Sud, Université Paris-Saclay (UPSay), Orsay, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Department of Biology and of Computer Science, Univ. Paris-Sud, Université Paris-Saclay (UPSay), Orsay, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Department of Biology and of Computer Science, Univ. Paris-Sud, Université Paris-Saclay (UPSay), Orsay, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Departments of Computer Science and of Life Sciences, Sorbonne Université (SU) / UPMC, Paris, France.|Department of Biology and of Computer Science, Univ. Paris-Sud, Université Paris-Saclay (UPSay), Orsay, France.|Department of Biology and of Computer Science, Univ. Paris-Sud, Université Paris-Saclay (UPSay), Orsay, France.|Unit of Structural Dynamics of Macromolecules, CNRS, Institut Pasteur, Paris, France.|Institute for Integrative Biology of the Cell (I2BC), IBITECS, CEA, CNRS, Univ. Paris-Sud, UPSay, Gif-sur-Yvette cedex, France.|AMIBio team, Laboratoire dinformatique de lÉcole polytechnique (LIX, UMR 7161) / Inria Saclay, UPSay, Palaiseau, France.|Laboratoire de Biochimie Théorique, UPR 9080 CNRS Institut de Biologie Physico-Chimique, Paris, France.|Sorbonne Université / UPMC, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB), UMR 7238, Paris, France.|LRI, Univ. Paris-Sud, CNRS, UPSay, Orsay, France.|Sorbonne Université / UPMC, Univ. Antilles, Univ. Nice Sophia Antipolis, CNRS, Evolution Paris Seine - Institut de Biologie Paris Seine (EPS - IBPS), Paris, France.|Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, UPSay, Gif-sur-Yvette cedex, France.|Sorbonne Université / UPMC, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB), UMR 7238, Paris, France.|Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, UPSay, Gif-sur-Yvette cedex, France.|Sorbonne Université / UPMC, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB), UMR 7238, Paris, France.|Department of Structural Biology and CheImistry (CNRS UMR3528) - Center of Bioinformatics, Biostatistics and Integrative Biology (CNRS USR3756) - Structural Bioinformatics Unit, Institut Pasteur, Paris, France.|Sorbonne Université / UPMC, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB), UMR 7238, Paris, France.|MaIAGE, INRA, UPSay, Jouy-en-Josas, France and LIMSI, CNRS, UPSay, Orsay, France.|Sorbonne Université / UPMC, Ecole Normale Supérieure - PLS Research University, Département de Chimie, CNRS, Laboratoire des Biomolécules, UMR 7203 - Univ. Paris Diderot, Sorbonne Paris Cité, Paris, France.|Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, UPSay, Gif-sur-Yvette cedex, France.|Mitochondria, Metals and Oxidative Stress Group, Institut Jacques Monod, UMR 7592, Univ. Paris Diderot, CNRS, Sorbonne Paris Cité, Paris, France.|Sorbonne Université / UPMC, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB), UMR 7238, Paris, France.|Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, UPSay, Gif-sur-Yvette cedex, France.|Sorbonne Université / UPMC, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB), UMR 7238, Paris, France.|Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, UPSay, Gif-sur-Yvette cedex, France.', 'France|France|France|France|France|France|France|France|France|France|France|France|France|France|Fr', 2, 'Computational Biology|Humans|Research|Research Design|Students|Universities', 'Journal Article', '10.1371/journal.pcbi.1005992', '29543809', 'We present a new educational initiative called Meet-U that aims to train students for collaborative work in computational biology and to bridge the gap between education and research. Meet-U mimics the setup of collaborative research projects and takes advantage of the most popular tools for collaborative work and of cloud computing. Students are grouped in teams of 4-5 people and have to realize a project from A to Z that answers a challenging question in biology. Meet-U promotes coopetition, as the students collaborate within and across the teams and are also in competition with each other to develop the best final product. Meet-U fosters interactions between different actors of education and research through the organization of a meeting day, open to everyone, where the students present their work to a jury of researchers and jury members give research seminars. This very unique combination of education and research is strongly motivating for the students and provides a formidable opportunity for a scientific community to unite and increase its visibility. We report on our experience with Meet-U in two French universities with masters students in bioinformatics and modeling, with protein-protein docking as the subject of the course. Meet-U is easy to implement and can be straightforwardly transferred to other fields and/or universities. All the information and data are available at www.meet-u.org.'),
(88954, 2018, 'plos', 'Imbalanced amplification: A mechanism of amplification and suppression from local imbalance of excitation and inhibition in cortical circuits', 'Ebsch, Christopher|Rosenbaum, Robert', 'Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, Indiana, United States of America.|Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, Indiana, United States of America.', 'India|India', 7, 'Action Potentials|Cerebral Cortex|Computer Simulation|Homeostasis|Models, Neurological|Models, Theoretical|Nerve Net|Neural Inhibition|Neural Pathways|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1006048', '29543827', 'Understanding the relationship between external stimuli and the spiking activity of cortical populations is a central problem in neuroscience. Dense recurrent connectivity in local cortical circuits can lead to counterintuitive response properties, raising the question of whether there are simple arithmetical rules for relating circuits connectivity structure to their response properties. One such arithmetic is provided by the mean field theory of balanced networks, which is derived in a limit where excitatory and inhibitory synaptic currents precisely balance on average. However, balanced network theory is not applicable to some biologically relevant connectivity structures. We show that cortical circuits with such structure are susceptible to an amplification mechanism arising when excitatory-inhibitory balance is broken at the level of local subpopulations, but maintained at a global level. This amplification, which can be quantified by a linear correction to the classical mean field theory of balanced networks, explains several response properties observed in cortical recordings and provides fundamental insights into the relationship between connectivity structure and neural responses in cortical circuits.'),
(88955, 2018, 'plos', 'The exclusive effects of chaperonin on the behavior of proteins with 52 knot', 'Zhao, Yani|Dabrowski-Tumanski, Pawel|Niewieczerzal, Szymon|Sulkowska, Joanna I', 'Centre of New Technologies, University of Warsaw, Warsaw, Poland.|Centre of New Technologies, University of Warsaw, Warsaw, Poland.|Centre of New Technologies, University of Warsaw, Warsaw, Poland.|Centre of New Technologies, University of Warsaw, Warsaw, Poland.', 'Poland|Poland|Poland|Poland', 12, 'Chaperonins|Computational Biology|Protein Conformation|Protein Denaturation|Protein Folding|Proteins|Ubiquitin Thiolesterase', 'Journal Article', '10.1371/journal.pcbi.1005970', '29547629', 'The folding of proteins with a complex knot is still an unresolved question. Based on representative members of Ubiquitin C-terminal Hydrolases (UCHs) that contain the 52 knot in the native state, we explain how UCHs are able to unfold and refold in vitro reversibly within the structure-based model. In particular, we identify two, topologically different folding/unfolding pathways and corroborate our results with experiment, recreating the chevron plot. We show that confinement effect of chaperonin or weak crowding greatly facilitates folding, simultaneously slowing down the unfolding process of UCHs, compared with bulk conditions. Finally, we analyze the existence of knots in the denaturated state of UCHs. The results of the work show that the crowded environment of the cell should have a positive effect on the kinetics of complex knotted proteins, especially when proteins with deeper knots are found in this family.'),
(88956, 2018, 'plos', 'The Pathway Coexpression Network: Revealing pathway relationships', 'Pita-Juárez, Yered|Altschuler, Gabriel|Kariotis, Sokratis|Wei, Wenbin|Koler, Katjuša|Green, Claire|Tanzi, Rudolph E|Hide, Winston', 'Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, United States of America.|Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom.|Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom.|Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom.|Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom.|Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom.|Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United States of America.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, United States of America.', 'United States|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Stat', 13, 'Alzheimer Disease|Biological Phenomena|Computational Biology|Databases, Chemical|Databases, Genetic|Gene Expression Profiling|Gene Regulatory Networks|Genomics|Humans|Internet|Microarray Analysis|Software', 'Journal Article', '10.1371/journal.pcbi.1006042', '29554099', 'A goal of genomics is to understand the relationships between biological processes. Pathways contribute to functional interplay within biological processes through complex but poorly understood interactions. However, limited functional references for global pathway relationships exist. Pathways from databases such as KEGG and Reactome provide discrete annotations of biological processes. Their relationships are currently either inferred from gene set enrichment within specific experiments, or by simple overlap, linking pathway annotations that have genes in common. Here, we provide a unifying interpretation of functional interaction between pathways by systematically quantifying coexpression between 1,330 canonical pathways from the Molecular Signatures Database (MSigDB) to establish the Pathway Coexpression Network (PCxN). We estimated the correlation between canonical pathways valid in a broad context using a curated collection of 3,207 microarrays from 72 normal human tissues. PCxN accounts for shared genes between annotations to estimate significant correlations between pathways with related functions rather than with similar annotations. We demonstrate that PCxN provides novel insight into mechanisms of complex diseases using an Alzheimers Disease (AD) case study. PCxN retrieved pathways significantly correlated with an expert curated AD gene list. These pathways have known associations with AD and were significantly enriched for genes independently associated with AD. As a further step, we show how PCxN complements the results of gene set enrichment methods by revealing relationships between enriched pathways, and by identifying additional highly correlated pathways. PCxN revealed that correlated pathways from an AD expression profiling study include functional clusters involved in cell adhesion and oxidative stress. PCxN provides expanded connections to pathways from the extracellular matrix. PCxN provides a powerful new framework for interrogation of global pathway relationships. Comprehensive exploration of PCxN can be performed at http://pcxn.org/.'),
(88957, 2018, 'plos', 'Integrative single-cell omics analyses reveal epigenetic heterogeneity in mouse embryonic stem cells', 'Luo, Yanting|He, Jianlin|Xu, Xiguang|Sun, Ming-An|Wu, Xiaowei|Lu, Xuemei|Xie, Hehuang', 'Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.|Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.|Epigenomics and Computational Biology Lab, Biocomplexity Institute of Virginia Tech, Blacksburg, United States of America.|University of Chinese Academy of Sciences, Beijing, China.|Department of Statistics, Virginia Tech, Blacksburg, United States of America.|Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.|Epigenomics and Computational Biology Lab, Biocomplexity Institute of Virginia Tech, Blacksburg, United States of America.', 'China|China|United States|China|United States|China|United States', 10, 'Animals|CpG Islands|DNA Methylation|Databases, Genetic|Embryonic Stem Cells|Epigenesis, Genetic|Epigenomics|Gene Expression Profiling|Gene Regulatory Networks|Genetic Heterogeneity|Genomics|Mice|Mouse Embryonic Stem Cells|Promoter Regions, Genetic|Single-Cell Analysis|Transcription Factors|Transcriptome', 'Journal Article', '10.1371/journal.pcbi.1006034', '29561833', 'Embryonic stem cells (ESCs) consist of a population of self-renewing cells displaying extensive phenotypic and functional heterogeneity. Research towards the understanding of the epigenetic mechanisms underlying the heterogeneity among ESCs is still in its initial stage. Key issues, such as how to identify cell-subset specifically methylated loci and how to interpret the biological meanings of methylation variations remain largely unexplored. To fill in the research gap, we implemented a computational pipeline to analyze single-cell methylome and to perform an integrative analysis with single-cell transcriptome data. According to the origins of variation in DNA methylation, we determined the genomic loci associated with allelic-specific methylation or asymmetric DNA methylation, and explored a beta mixture model to infer the genomic loci exhibiting cell-subset specific methylation (CSM). We observed that the putative CSM loci in ESCs are significantly enriched in CpG island (CGI) shelves and regions with histone marks for promoter and enhancer, and the genes hosting putative CSM loci show wide-ranging expression among ESCs. More interestingly, the putative CSM loci may be clustered into co-methylated modules enriching the binding motifs of distinct sets of transcription factors. Taken together, our study provided a novel tool to explore single-cell methylome and transcriptome to reveal the underlying transcriptional regulatory networks associated with epigenetic heterogeneity of ESCs.'),
(88958, 2018, 'plos', 'Role of genetic heterogeneity in determining the epidemiological severity of H1N1 influenza', 'Sambaturu, Narmada|Mukherjee, Sumanta|López-García, Martín|Molina-París, Carmen|Menon, Gautam I|Chandra, Nagasuma', 'IISc Mathematics Initiative, Indian Institute of Science, Bangalore, Karnataka, India.|IISc Mathematics Initiative, Indian Institute of Science, Bangalore, Karnataka, India.|Department of Applied Mathematics, University of Leeds, Leeds, United Kingdom.|Department of Applied Mathematics, University of Leeds, Leeds, United Kingdom.|Computational Biology and Theoretical Physics groups, The Institute of Mathematical Sciences, Chennai, Tamil Nadu, India.|IISc Mathematics Initiative, Indian Institute of Science, Bangalore, Karnataka, India.', 'India|India|United Kingdom|United Kingdom|India|India', 4, 'Computer Simulation|Disease Outbreaks|Disease Susceptibility|Epidemics|Epitopes|Ethnic Groups|Humans|Influenza A Virus, H1N1 Subtype|Influenza, Human', 'Journal Article', '10.1371/journal.pcbi.1006069', '29561846', 'Genetic differences contribute to variations in the immune response mounted by different individuals to a pathogen. Such differential response can influence the spread of infectious disease, indicating why such diseases impact some populations more than others. Here, we study the impact of population-level genetic heterogeneity on the epidemic spread of different strains of H1N1 influenza. For a population with known HLA class-I allele frequency and for a given H1N1 viral strain, we classify individuals into sub-populations according to their level of susceptibility to infection. Our core hypothesis is that the susceptibility of a given individual to a disease such as H1N1 influenza is inversely proportional to the number of high affinity viral epitopes the individual can present. This number can be extracted from the HLA genetic profile of the individual. We use ethnicity-specific HLA class-I allele frequency data, together with genome sequences of various H1N1 viral strains, to obtain susceptibility sub-populations for 61 ethnicities and 81 viral strains isolated in 2009, as well as 85 strains isolated in other years. We incorporate these data into a multi-compartment SIR model to analyse the epidemic dynamics for these (ethnicity, viral strain) epidemic pairs. Our results show that HLA allele profiles which lead to a large spread in individual susceptibility values can act as a protective barrier against the spread of influenza. We predict that populations skewed such that a small number of highly susceptible individuals coexist with a large number of less susceptible ones, should exhibit smaller outbreaks than populations with the same average susceptibility but distributed more uniformly across individuals. Our model tracks some well-known qualitative trends of influenza spread worldwide, suggesting that HLA genetic diversity plays a crucial role in determining the spreading potential of different influenza viral strains across populations.'),
(88959, 2018, 'plos', 'Haptic communication between humans is tuned by the hard or soft mechanics of interaction', 'Takagi, Atsushi|Usai, Francesco|Ganesh, Gowrishankar|Sanguineti, Vittorio|Burdet, Etienne', 'Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan.|Department of Informatics, Bioengineering, Robotics and Systems Engineering, Università degli studi di Genova, Genova, Italy.|CNRS-AIST JRL (Joint Robotics Laboratory), UMI3218/RL, Umezono, Tsukuba, Ibaraki, Japan.|Department of Informatics, Bioengineering, Robotics and Systems Engineering, Università degli studi di Genova, Genova, Italy.|Department of Bioengineering, Imperial College of Science, Technology and Medicine, South Kensington, London, United Kingdom.', 'Japan|Italy|Japan|Italy|United Kingdom', 5, 'Communication|Cooperative Behavior|Electromyography|Female|Humans|Male|Motor Skills|Perception|Robotics|Task Performance and Analysis|Touch|Wrist', 'Journal Article', '10.1371/journal.pcbi.1005971', '29565966', 'To move a hard table together, humans may coordinate by following the dominant partners motion [1-4], but this strategy is unsuitable for a soft mattress where the perceived forces are small. How do partners readily coordinate in such differing interaction dynamics? To address this, we investigated how pairs tracked a target using flexion-extension of their wrists, which were coupled by a hard, medium or soft virtual elastic band. Tracking performance monotonically increased with a stiffer band for the worse partner, who had higher tracking error, at the cost of the skilled partners muscular effort. This suggests that the worse partner followed the skilled ones lead, but simulations show that the results are better explained by a model where partners share movement goals through the forces, whilst the coupling dynamics determine the capacity of communicable information. This model elucidates the versatile mechanism by which humans can coordinate during both hard and soft physical interactions to ensure maximum performance with minimal effort.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(88960, 2018, 'plos', 'Model-based analysis of competing-endogenous pathways (MACPath) in human cancers', 'Park, Hyun Jung|Kim, Soyeon|Li, Wei', 'Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center, Houston, Texas, United States of America.|Division of Biostatistics, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America.', 'United States|United States|United States', 2, 'Cell Proliferation|Computational Biology|Computer Simulation|Databases, Genetic|Gene Expression Profiling|Gene Expression Regulation, Neoplastic|Gene Regulatory Networks|Humans|MicroRNAs|RNA, Long Noncoding|RNA, Messenger', 'Journal Article', '10.1371/journal.pcbi.1006074', '29565967', 'Competing endogenous RNA (ceRNA) has emerged as an important post-transcriptional mechanism that simultaneously alters expressions of thousands genes in cancers. However, only a few ceRNA genes have been studied for their functions to date. To understand the major biological functions of thousands ceRNA genes as a whole, we designed Model-based Analysis of Competing-endogenous Pathways (MACPath) to infer pathways co-regulated through ceRNA mechanism (cePathways). Our analysis on breast tumors suggested that NGF (nerve growth factor)-induced tumor cell proliferation might be associated with tumor-related growth factor pathways through ceRNA. MACPath also identified indirect cePathways, whose ceRNA relationship is mediated by mediating ceRNAs. Finally, MACPath identified mediating ceRNAs that connect the indirect cePathways based on efficient integer linear programming technique. Mediating ceRNAs are unexpectedly enriched in tumor suppressor genes, whose down-regulation is suspected to disrupt indirect cePathways, such as between DNA replication and WNT signaling pathways. Altogether, MACPath is the first computational method to comprehensively understand functions of thousands ceRNA genes, both direct and indirect, at the pathway level.'),
(88961, 2018, 'plos', 'Activation gating in HCN2 channels', 'Hummert, Sabine|Thon, Susanne|Eick, Thomas|Schmauder, Ralf|Schulz, Eckhard|Benndorf, Klaus', 'Institut für Physiologie II, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany.|Institut für Physiologie II, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany.|Institut für Physiologie II, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany.|Institut für Physiologie II, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany.|Fachhochschule Schmalkalden, Fakultät Elektrotechnik, Blechhammer, Schmalkalden, Germany.|Institut für Physiologie II, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany', 5, 'Animals|Cyclic AMP|Cyclic Nucleotide-Gated Cation Channels|Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels|Ion Channel Gating|Kinetics|Markov Chains|Models, Neurological|Oocytes|Patch-Clamp Techniques|Potassium Channels|Xenopus laevis', 'Journal Article', '10.1371/journal.pcbi.1006045', '29565972', 'Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels control electrical rhythmicity in specialized brain and heart cells. We quantitatively analysed voltage-dependent activation of homotetrameric HCN2 channels and its modulation by the second messenger cAMP using global fits of hidden Markovian models to complex experimental data. We show that voltage-dependent activation is essentially governed by two separable voltage-dependent steps followed by voltage-independent opening of the pore. According to this model analysis, the binding of cAMP to the channels exerts multiple effects on the voltage-dependent gating: It stabilizes the open pore, reduces the total gating charge from ~8 to ~5, makes an additional closed state outside the activation pathway accessible and strongly accelerates the ON-gating but not the OFF-gating. Furthermore, the open channel has a much slower computed OFF-gating current than the closed channel, in both the absence and presence of cAMP. Together, these results provide detailed new insight into the voltage- and cAMP-induced activation gating of HCN channels.'),
(88962, 2018, 'plos', 'Brain-state invariant thalamo-cortical coordination revealed by non-linear encoders', 'Viejo, Guillaume|Cortier, Thomas|Peyrache, Adrien', 'Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A 2B4, Canada.|Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A 2B4, Canada.|Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A 2B4, Canada.', 'Canada|Canada|Canada', 4, 'Action Potentials|Animals|Bayes Theorem|Brain|Brain Mapping|Cerebral Cortex|Mice|Models, Neurological|Neurons|Nonlinear Dynamics|Sleep|Spatio-Temporal Analysis|Supervised Machine Learning|Thalamus|Wakefulness', 'Journal Article', '10.1371/journal.pcbi.1006041', '29565979', 'Understanding how neurons cooperate to integrate sensory inputs and guide behavior is a fundamental problem in neuroscience. A large body of methods have been developed to study neuronal firing at the single cell and population levels, generally seeking interpretability as well as predictivity. However, these methods are usually confronted with the lack of ground-truth necessary to validate the approach. Here, using neuronal data from the head-direction (HD) system, we present evidence demonstrating how gradient boosted trees, a non-linear and supervised Machine Learning tool, can learn the relationship between behavioral parameters and neuronal responses with high accuracy by optimizing the information rate. Interestingly, and unlike other classes of Machine Learning methods, the intrinsic structure of the trees can be interpreted in relation to behavior (e.g. to recover the tuning curves) or to study how neurons cooperate with their peers in the network. We show how the method, unlike linear analysis, reveals that the coordination in thalamo-cortical circuits is qualitatively the same during wakefulness and sleep, indicating a brain-state independent feed-forward circuit. Machine Learning tools thus open new avenues for benchmarking model-based characterization of spike trains.'),
(88963, 2018, 'plos', 'Fluctuating Finite Element Analysis (FFEA): A continuum mechanics software tool for mesoscale simulation of biomolecules', 'Solernou, Albert|Hanson, Benjamin S|Richardson, Robin A|Welch, Robert|Read, Daniel J|Harlen, Oliver G|Harris, Sarah A', 'School of Physics and Astronomy, University of Leeds, Leeds, United Kingdom.|School of Physics and Astronomy, University of Leeds, Leeds, United Kingdom.|School of Chemistry, University College London, London, United Kingdom.|School of Physics and Astronomy, University of Leeds, Leeds, United Kingdom.|School of Mathematics, University of Leeds, Leeds, United Kingdom.|School of Mathematics, University of Leeds, Leeds, United Kingdom.|School of Physics and Astronomy, University of Leeds, Leeds, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 12, 'Computational Biology|Finite Element Analysis|Molecular Dynamics Simulation|Protein Binding|Proteins|Software', 'Journal Article', '10.1371/journal.pcbi.1005897', '29570700', 'Fluctuating Finite Element Analysis (FFEA) is a software package designed to perform continuum mechanics simulations of proteins and other globular macromolecules. It combines conventional finite element methods with stochastic thermal noise, and is appropriate for simulations of large proteins and protein complexes at the mesoscale (length-scales in the range of 5 nm to 1 xcexbcm), where there is currently a paucity of modelling tools. It requires 3D volumetric information as input, which can be low resolution structural information such as cryo-electron tomography (cryo-ET) maps or much higher resolution atomistic co-ordinates from which volumetric information can be extracted. In this article we introduce our open source software package for performing FFEA simulations which we have released under a GPLv3 license. The software package includes a C ++ implementation of FFEA, together with tools to assist the user to set up the system from Electron Microscopy Data Bank (EMDB) or Protein Data Bank (PDB) data files. We also provide a PyMOL plugin to perform basic visualisation and additional Python tools for the analysis of FFEA simulation trajectories. This manuscript provides a basic background to the FFEA method, describing the implementation of the core mechanical model and how intermolecular interactions and the solvent environment are included within this framework. We provide prospective FFEA users with a practical overview of how to set up an FFEA simulation with reference to our publicly available online tutorials and manuals that accompany this first release of the package.'),
(88964, 2018, 'plos', 'Population dynamics of engineered underdominance and killer-rescue gene drives in the control of disease vectors', 'Edgington, Matthew P|Alphey, Luke S', 'The Pirbright Institute, Pirbright, Woking, Surrey, United Kingdom.|The Pirbright Institute, Pirbright, Woking, Surrey, United Kingdom.', 'United Kingdom|United Kingdom', 7, 'Aedes|Animals|Animals, Genetically Modified|Disease Vectors|Gene Drive Technology|Genetic Engineering|Genetics, Population|Models, Genetic|Models, Theoretical|Mosquito Vectors|Population Dynamics|Transgenes', 'Journal Article', '10.1371/journal.pcbi.1006059', '29570717', 'A number of different genetics-based vector control methods have been proposed. Two approaches currently under development in Aedes aegypti mosquitoes are the two-locus engineered underdominance and killer-rescue gene drive systems. Each of these is theoretically capable of increasing in frequency within a population, thus spreading associated desirable genetic traits. Thus they have gained attention for their potential to aid in the fight against various mosquito-vectored diseases. In the case of engineered underdominance, introduced transgenes are theoretically capable of persisting indefinitely (i.e. it is self-sustaining) whilst in the killer-rescue system the rescue component should initially increase in frequency (while the lethal component (killer) is common) before eventually declining (when the killer is rare) and being eliminated (i.e. it is temporally self-limiting). The population genetics of both systems have been explored using discrete generation mathematical models. The effects of various ecological factors on these two systems have also been considered using alternative modelling methodologies. Here we formulate and analyse new mathematical models combining the population dynamics and population genetics of these two classes of gene drive that incorporate ecological factors not previously studied and are simple enough to allow the effects of each to be disentangled. In particular, we focus on the potential effects that may be obtained as a result of differing ecological factors such as strengths of larval competition, numbers of breeding sites, and the relative fitness of transgenic mosquitoes compared with their wild-type counterparts. We also extend our models to consider population dynamics in two demes in order to explore the effects of dispersal between neighbouring populations on the outcome of UD and KR gene drive systems.'),
(88965, 2018, 'plos', 'A mechanistic pan-cancer pathway model informed by multi-omics data interprets stochastic cell fate responses to drugs and mitogens', 'Bouhaddou, Mehdi|Barrette, Anne Marie|Stern, Alan D|Koch, Rick J|DiStefano, Matthew S|Riesel, Eric A|Santos, Luis C|Tan, Annie L|Mertz, Alex E|Birtwistle, Marc R', 'Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.|Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.|Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.|Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.|Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.|Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.|Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.|Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.|Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.|Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 10, 'Algorithms|Antineoplastic Agents|Cell Line, Tumor|Computational Biology|Gene Expression Profiling|Humans|Mitogens|Neoplasms|Signal Transduction|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1005985', '29579036', 'Most cancer cells harbor multiple drivers whose epistasis and interactions with expression context clouds drug and drug combination sensitivity prediction. We constructed a mechanistic computational model that is context-tailored by omics data to capture regulation of stochastic proliferation and death by pan-cancer driver pathways. Simulations and experiments explore how the coordinated dynamics of RAF/MEK/ERK and PI-3K/AKT kinase activities in response to synergistic mitogen or drug combinations control cell fate in a specific cellular context. In this MCF10A cell context, simulations suggest that synergistic ERK and AKT inhibitor-induced death is likely mediated by BIM rather than BAD, which is supported by prior experimental studies. AKT dynamics explain S-phase entry synergy between EGF and insulin, but simulations suggest that stochastic ERK, and not AKT, dynamics seem to drive cell-to-cell proliferation variability, which in simulations is predictable from pre-stimulus fluctuations in C-Raf/B-Raf levels. Simulations suggest MEK alteration negligibly influences transformation, consistent with clinical data. Tailoring the model to an alternate cell expression and mutation context, a glioma cell line, allows prediction of increased sensitivity of cell death to AKT inhibition. Our model mechanistically interprets context-specific landscapes between driver pathways and cell fates, providing a framework for designing more rational cancer combination therapy.'),
(88966, 2018, 'plos', 'Scabies in residential care homes: Modelling, inference and interventions for well-connected population sub-units', 'Kinyanjui, Timothy|Middleton, Jo|Güttel, Stefan|Cassell, Jackie|Ross, Joshua|House, Thomas', 'School of Mathematics, University of Manchester, United Kingdom.|Department of Primary Care and Public Health Medicine, Brighton and Sussex Medical School, Falmer, Brighton, United Kingdom.|School of Mathematics, University of Manchester, United Kingdom.|Department of Primary Care and Public Health Medicine, Brighton and Sussex Medical School, Falmer, Brighton, United Kingdom.|School of Mathematical Sciences, The University of Adelaide, Adelaide, Australia.|School of Mathematics, University of Manchester, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|Australia|United Kingdom', 6, 'Bayes Theorem|Communicable Disease Control|Communicable Diseases|Humans|Ivermectin|Markov Chains|Monte Carlo Method|Residential Facilities|Scabies', 'Journal Article', '10.1371/journal.pcbi.1006046', '29579037', 'In the context of an ageing population, understanding the transmission of infectious diseases such as scabies through well-connected sub-units of the population, such as residential care homes, is particularly important for the design of efficient interventions to mitigate against the effects of those diseases. Here, we present a modelling methodology based on the efficient solution of a large-scale system of linear differential equations that allows statistical calibration of individual-based random models to real data on scabies in residential care homes. In particular, we review and benchmark different numerical methods for the integration of the differential equation system, and then select the most appropriate of these methods to perform inference using Markov chain Monte Carlo. We test the goodness-of-fit of this model using posterior predictive intervals and propagate forward the resulting parameter uncertainty in a Bayesian framework to consider the economic cost of delayed interventions against scabies, quantifying the benefits of prompt action in the event of detection. We also revisit the previous methodology used to assess the safety of treatments in small population sub-units-in this context ivermectin-and demonstrate that even a very slight relaxation of the implicit assumption of homogeneous death rates significantly increases the plausibility of the hypothesis that ivermectin does not cause excess mortality based upon the data of Barkwell and Shields.'),
(88967, 2018, 'plos', 'From correlation to causation: Estimating effective connectivity from zero-lag covariances of brain signals', 'Schiefer, Jonathan|Niederbühl, Alexander|Pernice, Volker|Lennartz, Carolin|Hennig, Jürgen|LeVan, Pierre|Rotter, Stefan', 'Bernstein Center Freiburg, Freiburg, Germany.|Bernstein Center Freiburg, Freiburg, Germany.|Bernstein Center Freiburg, Freiburg, Germany.|Department of Radiology, Medical Physics, Medical Center - University of Freiburg, Freiburg, Germany.|Department of Radiology, Medical Physics, Medical Center - University of Freiburg, Freiburg, Germany.|Department of Radiology, Medical Physics, Medical Center - University of Freiburg, Freiburg, Germany.|Bernstein Center Freiburg, Freiburg, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany', 0, 'Brain|Brain Mapping|Computer Simulation|Connectome|Databases, Factual|Humans|Linear Models|Magnetic Resonance Imaging|Models, Neurological|Nerve Net|Neural Networks (Computer)|Neural Pathways|Neurons', 'Journal Article', '10.1371/journal.pcbi.1006056', '29579045', 'Knowing brain connectivity is of great importance both in basic research and for clinical applications. We are proposing a method to infer directed connectivity from zero-lag covariances of neuronal activity recorded at multiple sites. This allows us to identify causal relations that are reflected in neuronal population activity. To derive our strategy, we assume a generic linear model of interacting continuous variables, the components of which represent the activity of local neuronal populations. The suggested method for inferring connectivity from recorded signals exploits the fact that the covariance matrix derived from the observed activity contains information about the existence, the direction and the sign of connections. Assuming a sparsely coupled network, we disambiguate the underlying causal structure via L1-minimization, which is known to prefer sparse solutions. In general, this method is suited to infer effective connectivity from resting state data of various types. We show that our method is applicable over a broad range of structural parameters regarding network size and connection probability of the network. We also explored parameters affecting its activity dynamics, like the eigenvalue spectrum. Also, based on the simulation of suitable Ornstein-Uhlenbeck processes to model BOLD dynamics, we show that with our method it is possible to estimate directed connectivity from zero-lag covariances derived from such signals. In this study, we consider measurement noise and unobserved nodes as additional confounding factors. Furthermore, we investigate the amount of data required for a reliable estimate. Additionally, we apply the proposed method on full-brain resting-state fast fMRI datasets. The resulting network exhibits a tendency for close-by areas being connected as well as inter-hemispheric connections between corresponding areas. In addition, we found that a surprisingly large fraction of more than one third of all identified connections were of inhibitory nature.'),
(88968, 2018, 'plos', 'Correction: MAGPIE: Simplifying access and execution of computational models in the life sciences', 'PLOS Computational Biology Staff', 'Bernstein Center Freiburg, Freiburg, Germany.', 'Germany', 0, '-', 'Journal Article', '10.1371/journal.pcbi.1006083', '29579052', '[This corrects the article DOI: 10.1371/journal.pcbi.1005898.].'),
(88969, 2018, 'plos', 'Dynamic combination of sensory and reward information under time pressure', 'Farashahi, Shiva|Ting, Chih-Chung|Kao, Chang-Hao|Wu, Shih-Wei|Soltani, Alireza', 'Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH, United States of America.|CREED, Amsterdam School of Economics, Universiteit van Amsterdam, Amsterdam, the Netherlands.|Department of Psychology, University of Pennsylvania, Philadelphia, PA, United States of America.|Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.|Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH, United States of America.', 'United States|Netherlands|United States|-|United States', 6, 'Adult|Brain|Choice Behavior|Computer Simulation|Decision Making|Female|Humans|Learning|Male|Models, Neurological|Perception|Photic Stimulation|Psychomotor Performance|Reaction Time|Reward|Time|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1006070', '29584717', 'When making choices, collecting more information is beneficial but comes at the cost of sacrificing time that could be allocated to making other potentially rewarding decisions. To investigate how the brain balances these costs and benefits, we conducted a series of novel experiments in humans and simulated various computational models. Under six levels of time pressure, subjects made decisions either by integrating sensory information over time or by dynamically combining sensory and reward information over time. We found that during sensory integration, time pressure reduced performance as the deadline approached, and choice was more strongly influenced by the most recent sensory evidence. By fitting performance and reaction time with various models we found that our experimental results are more compatible with leaky integration of sensory information with an urgency signal or a decision process based on stochastic transitions between discrete states modulated by an urgency signal. When combining sensory and reward information, subjects spent less time on integration than optimally prescribed when reward decreased slowly over time, and the most recent evidence did not have the maximal influence on choice. The suboptimal pattern of reaction time was partially mitigated in an equivalent control experiment in which sensory integration over time was not required, indicating that the suboptimal response time was influenced by the perception of imperfect sensory integration. Meanwhile, during combination of sensory and reward information, performance did not drop as the deadline approached, and response time was not different between correct and incorrect trials. These results indicate a decision process different from what is involved in the integration of sensory information over time. Together, our results not only reveal limitations in sensory integration over time but also illustrate how these limitations influence dynamic combination of sensory and reward information.'),
(88970, 2018, 'plos', 'Dynamic cues for whisker-based object localization: An analytical solution to vibration during active whisker touch', 'Vaxenburg, Roman|Wyche, Isis|Svoboda, Karel|Efros, Alexander L|Hires, Samuel Andrew', 'Computational Materials Science Center, George Mason University, Fairfax, Virginia, United States of America.|Section of Neurobiology, Department of Biological Sciences, University of South California, Los Angeles, California, United States of America.|Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America.|Center for Computational Material Science, Code 6390, Naval Research Laboratory, Washington, DC, United States of America.|Section of Neurobiology, Department of Biological Sciences, University of South California, Los Angeles, California, United States of America.', 'United States|United States|United States|United States|United States', 5, 'Action Potentials|Animals|Biomechanical Phenomena|Computer Simulation|Mechanoreceptors|Mice|Neurons|Physical Stimulation|Touch|Touch Perception|Vibration|Vibrissae', 'Journal Article', '10.1371/journal.pcbi.1006032', '29584719', 'Vibrations are important cues for tactile perception across species. Whisker-based sensation in mice is a powerful model system for investigating mechanisms of tactile perception. However, the role vibration plays in whisker-based sensation remains unsettled, in part due to difficulties in modeling the vibration of whiskers. Here, we develop an analytical approach to calculate the vibrations of whiskers striking objects. We use this approach to quantify vibration forces during active whisker touch at a range of locations along the whisker. The frequency and amplitude of vibrations evoked by contact are strongly dependent on the position of contact along the whisker. The magnitude of vibrational shear force and bending moment is comparable to quasi-static forces. The fundamental vibration frequencies are in a detectable range for mechanoreceptor properties and below the maximum spike rates of primary sensory afferents. These results suggest two dynamic cues exist that rodents can use for object localization: vibration frequency and comparison of vibrational to quasi-static force magnitude. These complement the use of quasi-static force angle as a distance cue, particularly for touches close to the follicle, where whiskers are stiff and force angles hardly change during touch. Our approach also provides a general solution to calculation of whisker vibrations in other sensing tasks.'),
(88971, 2018, 'plos', 'Astrocytic Kir41 channels and gap junctions account for spontaneous epileptic seizure', 'Du, Mengmeng|Li, Jiajia|Chen, Liang|Yu, Yuguo|Wu, Ying', 'State Key Laboratory for Strength and Vibration of Mechanical Structures, School of Aerospace, Xian Jiaotong University, Xian, China.|State Key Laboratory for Strength and Vibration of Mechanical Structures, School of Aerospace, Xian Jiaotong University, Xian, China.|Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.|State Key Laboratory of Medical Neurobiology, School of Life Science and Human Phenome Institute, Institutes of Brain Science, Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China.|State Key Laboratory for Strength and Vibration of Mechanical Structures, School of Aerospace, Xian Jiaotong University, Xian, China.', 'China|China|China|China|China', 1, 'Animals|Astrocytes|Computational Biology|Computer Simulation|Epilepsy|Gap Junctions|Models, Neurological|Potassium|Potassium Channels, Inwardly Rectifying|Rats|Seizures', 'Journal Article', '10.1371/journal.pcbi.1005877', '29590095', 'Experimental recordings in hippocampal slices indicate that astrocytic dysfunction may cause neuronal hyper-excitation or seizures. Considering that astrocytes play important roles in mediating local uptake and spatial buffering of K+ in the extracellular space of the cortical circuit, we constructed a novel model of an astrocyte-neuron network module consisting of a single compartment neuron and 4 surrounding connected astrocytes and including extracellular potassium dynamics. Next, we developed a new model function for the astrocyte gap junctions, connecting two astrocyte-neuron network modules. The function form and parameters of the gap junction were based on nonlinear regression fitting of a set of experimental data published in previous studies. Moreover, we have created numerical simulations using the above single astrocyte-neuron network module and the coupled astrocyte-neuron network modules. Our model validates previous experimental observations that both Kir4.1 channels and gap junctions play important roles in regulating the concentration of extracellular potassium. In addition, we also observe that changes in Kir4.1 channel conductance and gap junction strength induce spontaneous epileptic activity in the absence of external stimuli.'),
(88972, 2018, 'plos', 'Modeling the dynamics of oligodendrocyte precursor cells and the genesis of gliomas', 'Dufour, Aloys|Gontran, Emilie|Deroulers, Christophe|Varlet, Pascale|Pallud, Johan|Grammaticos, Basile|Badoual, Mathilde', 'IMNC Laboratory, CNRS, Univ Paris Saclay, Univ Paris-Sud, Univ Paris Diderot, France.|IMNC Laboratory, CNRS, Univ Paris Saclay, Univ Paris-Sud, Univ Paris Diderot, France.|IMNC Laboratory, CNRS, Univ Paris Saclay, Univ Paris-Sud, Univ Paris Diderot, France.|Department of Neuropathology, Sainte-Anne Hospital, IMA-Brain, INSERM U894, Univ Paris Descartes, Paris, France.|Department of Neurosurgery, Sainte-Anne Hospital, IMA-Brain, INSERM U894, Univ Paris Descartes, Paris, France.|IMNC Laboratory, CNRS, Univ Paris Saclay, Univ Paris-Sud, Univ Paris Diderot, France.|IMNC Laboratory, CNRS, Univ Paris Saclay, Univ Paris-Sud, Univ Paris Diderot, France.', 'France|France|France|France|France|France|France', 1, 'Animals|Cell Count|Cell Differentiation|Cell Proliferation|Computational Biology|Glioma|Humans|Mice|Models, Biological|Oligodendrocyte Precursor Cells', 'Journal Article', '10.1371/journal.pcbi.1005977', '29590097', 'Oligodendrocyte precursor cells (OPCs) have remarkable properties: they represent the most abundant cycling cell population in the adult normal brain and they manage to achieve a uniform and constant density throughout the adult brain. This equilibrium is obtained by the interplay of four processes: division, differentiation or death, migration and active self-repulsion. They are also strongly suspected to be at the origin of gliomas, when their equilibrium is disrupted. In this article, we present a model of the dynamics of OPCs, first in a normal tissue. This model is based on a cellular automaton and its rules are mimicking the ones that regulate the dynamics of real OPCs. The model is able to reproduce the homeostasis of the cell population, with the maintenance of a constant and uniform cell density and the healing of a lesion. We show that there exists a fair quantitative agreement between the simulated and experimental parameters, such as the cell velocity, the time taken to close a lesion, and the duration of the cell cycle. We present three possible scenarios of disruption of the equilibrium: the appearance of an over-proliferating cell, of a deadless/non-differentiating cell, or of a cell that lost any contact-inhibition. We show that the appearance of an over-proliferating cell is sufficient to trigger the growth of a tumor that has low-grade glioma features: an invasive behaviour, a linear radial growth of the tumor with a corresponding growth velocity of less than 2 mm per year, as well a cell density at the center which exceeds the one in normal tissue by a factor of less than two. The loss of contact inhibition leads to a more high-grade-like glioma. The results of our model contribute to the body of evidence that identify OPCs as possible cells of origin of gliomas.'),
(88973, 2018, 'plos', 'Bamgineer: Introduction of simulated allele-specific copy number variants into exome and targeted sequence data sets', 'Samadian, Soroush|Bruce, Jeff P|Pugh, Trevor J', 'Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.', 'Canada|Canada|Canada', 0, 'Algorithms|Alleles|Computer Simulation|DNA Copy Number Variations|Exome|Gene Frequency|Genomics|Haplotypes|High-Throughput Nucleotide Sequencing|Humans|Neoplasms|Sequence Alignment|Sequence Analysis, DNA|Software|Whole Exome Sequencing', 'Journal Article', '10.1371/journal.pcbi.1006080', '29590101', 'Somatic copy number variations (CNVs) play a crucial role in development of many human cancers. The broad availability of next-generation sequencing data has enabled the development of algorithms to computationally infer CNV profiles from a variety of data types including exome and targeted sequence data, currently the most prevalent types of cancer genomics data. However, systemic evaluation and comparison of these tools remains challenging due to a lack of ground truth reference sets. To address this need, we have developed Bamgineer, a tool written in Python to introduce user-defined haplotype-phased allele-specific copy number events into an existing Binary Alignment Mapping (BAM) file, with a focus on targeted and exome sequencing experiments. As input, this tool requires a read alignment file (BAM format), lists of non-overlapping genome coordinates for introduction of gains and losses (bed file), and an optional file defining known haplotypes (vcf format). To improve runtime performance, Bamgineer introduces the desired CNVs in parallel using queuing and parallel processing on a local machine or on a high-performance computing cluster. As proof-of-principle, we applied Bamgineer to a single high-coverage (mean: 220X) exome sequence file from a blood sample to simulate copy number profiles of 3 exemplar tumors from each of 10 tumor types at 5 tumor cellularity levels (20-100%, 150 BAM files in total). To demonstrate feasibility beyond exome data, we introduced read alignments to a targeted 5-gene cell-free DNA sequencing library to simulate EGFR amplifications at frequencies consistent with circulating tumor DNA (10, 1, 0.1 and 0.01%) while retaining the multimodal insert size distribution of the original data. We expect Bamgineer to be of use for development and systematic benchmarking of CNV calling algorithms by users using locally-generated data for a variety of applications. The source code is freely available at http://github.com/pughlab/bamgineer.'),
(88974, 2018, 'plos', 'Eleven quick tips for architecting biomedical informatics workflows with cloud computing', 'Cole, Brian S|Moore, Jason H', 'Institute for Biomedical Informatics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Institute for Biomedical Informatics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.', 'United States|United States', 0, 'Cloud Computing|Computational Biology|Computer Security|Humans|Workflow', 'Journal Article', '10.1371/journal.pcbi.1005994', '29596416', 'Cloud computing has revolutionized the development and operations of hardware and software across diverse technological arenas, yet academic biomedical research has lagged behind despite the numerous and weighty advantages that cloud computing offers. Biomedical researchers who embrace cloud computing can reap rewards in cost reduction, decreased development and maintenance workload, increased reproducibility, ease of sharing data and software, enhanced security, horizontal and vertical scalability, high availability, a thriving technology partner ecosystem, and much more. Despite these advantages that cloud-based workflows offer, the majority of scientific software developed in academia does not utilize cloud computing and must be migrated to the cloud by the user. In this article, we present 11 quick tips for architecting biomedical informatics workflows on compute clouds, distilling knowledge gained from experience developing, operating, maintaining, and distributing software and virtualized appliances on the worlds largest cloud. Researchers who follow these tips stand to benefit immediately by migrating their workflows to cloud computing and embracing the paradigm of abstraction.'),
(88975, 2018, 'plos', 'Eleven quick tips for running an interdisciplinary short course for new graduate students', 'Saunders, Timothy E|He, Cynthia Y|Koehl, Patrice|Ong, L L Sharon|So, Peter T C', 'Department of Biological Sciences, National University of Singapore, Singapore.|Department of Biological Sciences, National University of Singapore, Singapore.|Department of Computer Science and Genome Center, University of California Davis, Davis, California, United States of America.|Singapore MIT Alliance for Research and Technology Centre, Singapore.|Singapore MIT Alliance for Research and Technology Centre, Singapore.', 'Singapore|Singapore|United States|Singapore|Singapore', 0, 'Biological Science Disciplines|Biology|Computational Biology|Curriculum|Education, Graduate|Engineering|Humans|Interdisciplinary Studies|Students', 'Journal Article', '10.1371/journal.pcbi.1006039', '29596417', 'Quantitative reasoning and techniques are increasingly ubiquitous across the life sciences. However, new graduate researchers with a biology background are often not equipped with the skills that are required to utilize such techniques correctly and efficiently. In parallel, there are increasing numbers of engineers, mathematicians, and physical scientists interested in studying problems in biology with only basic knowledge of this field. Students from such varied backgrounds can struggle to engage proactively together to tackle problems in biology. There is therefore a need to establish bridges between those disciplines. It is our proposal that the beginning of graduate school is the appropriate time to initiate those bridges through an interdisciplinary short course. We have instigated an intensive 10-day course that brought together new graduate students in the life sciences from across departments within the National University of Singapore. The course aimed at introducing biological problems as well as some of the quantitative approaches commonly used when tackling those problems. We have run the course for three years with over 100 students attending. Building on this experience, we share 11 quick tips on how to run such an effective, interdisciplinary short course for new graduate students in the biosciences.'),
(88976, 2018, 'plos', 'SARNAclust: Semi-automatic detection of RNA protein binding motifs from immunoprecipitation data', 'Dotu, Ivan|Adamson, Scott I|Coleman, Benjamin|Fournier, Cyril|Ricart-Altimiras, Emma|Eyras, Eduardo|Chuang, Jeffrey H', 'The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States of America.|The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States of America.|The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States of America.|The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States of America.|The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States of America.|Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM)-Pompeu Fabra University (UPF), Barcelona, Spain.|The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States of America.', 'United States|United States|United States|United States|United States|Spain|United States', 2, 'Algorithms|Binding Sites|Cluster Analysis|High-Throughput Nucleotide Sequencing|Immunoprecipitation|Nucleic Acid Conformation|Nucleotide Motifs|Protein Binding|RNA|RNA Recognition Motif Proteins|RNA-Binding Proteins|Sequence Analysis, RNA', 'Journal Article', '10.1371/journal.pcbi.1006078', '29596423', 'RNA-protein binding is critical to gene regulation, controlling fundamental processes including splicing, translation, localization and stability, and aberrant RNA-protein interactions are known to play a role in a wide variety of diseases. However, molecular understanding of RNA-protein interactions remains limited, in particular, identification of RNA motifs that bind proteins has long been challenging, especially when such motifs depend on both sequence and structure. Moreover, although RNA binding proteins (RBPs) often contain more than one binding domain, algorithms capable of identifying more than one binding motif simultaneously have not been developed. In this paper we present a novel pipeline to determine binding peaks in crosslinking immunoprecipitation (CLIP) data, to discover multiple possible RNA sequence/structure motifs among them, and to experimentally validate such motifs. At the core is a new semi-automatic algorithm SARNAclust, the first unsupervised method to identify and deconvolve multiple sequence/structure motifs simultaneously. SARNAclust computes similarity between sequence/structure objects using a graph kernel, providing the ability to isolate the impact of specific features through the bulge graph formalism. Application of SARNAclust to synthetic data shows its capability of clustering 5 motifs at once with a V-measure value of over 0.95, while GraphClust achieves only a V-measure of 0.083 and RNAcontext cannot detect any of the motifs. When applied to existing eCLIP sets, SARNAclust finds known motifs for SLBP and HNRNPC and novel motifs for several other RBPs such as AGGF1, AKAP8L and ILF3. We demonstrate an experimental validation protocol, a targeted Bind-n-Seq-like high-throughput sequencing approach that relies on RNA inverse folding for oligo pool design, that can validate the components within the SLBP motif. Finally, we use this protocol to experimentally interrogate the SARNAclust motif predictions for protein ILF3. Our results support a newly identified partially double-stranded UUUUUGAGA motif similar to that known for the splicing factor HNRNPC.'),
(88977, 2018, 'plos', 'An open source tool for automatic spatiotemporal assessment of calcium transients and local signal-close-to-noise activity in calcium imaging data', 'Prada, Juan|Sasi, Manju|Martin, Corinna|Jablonka, Sibylle|Dandekar, Thomas|Blum, Robert', 'Department of Bioinformatics, University of Würzburg, Würzburg, Germany.|Institute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany.|Institute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany.|Institute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany.|Department of Bioinformatics, University of Würzburg, Würzburg, Germany.|Institute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany', 0, 'Algorithms|Animals|Axons|Calcium|Calcium Signaling|Cells, Cultured|Computational Biology|Mice|Molecular Imaging|Neurons|Software|Spatio-Temporal Analysis', 'Journal Article', '10.1371/journal.pcbi.1006054', '29601577', 'Local and spontaneous calcium signals play important roles in neurons and neuronal networks. Spontaneous or cell-autonomous calcium signals may be difficult to assess because they appear in an unpredictable spatiotemporal pattern and in very small neuronal loci of axons or dendrites. We developed an open source bioinformatics tool for an unbiased assessment of calcium signals in x,y-t imaging series. The tool bases its algorithm on a continuous wavelet transform-guided peak detection to identify calcium signal candidates. The highly sensitive calcium event definition is based on identification of peaks in 1D data through analysis of a 2D wavelet transform surface. For spatial analysis, the tool uses a grid to separate the x,y-image field in independently analyzed grid windows. A document containing a graphical summary of the data is automatically created and displays the loci of activity for a wide range of signal intensities. Furthermore, the number of activity events is summed up to create an estimated total activity value, which can be used to compare different experimental situations, such as calcium activity before or after an experimental treatment. All traces and data of active loci become documented. The tool can also compute the signal variance in a sliding window to visualize activity-dependent signal fluctuations. We applied the calcium signal detector to monitor activity states of cultured mouse neurons. Our data show that both the total activity value and the variance area created by a sliding window can distinguish experimental manipulations of neuronal activity states. Notably, the tool is powerful enough to compute local calcium events and signal-close-to-noise activity in small loci of distal neurites of neurons, which remain during pharmacological blockade of neuronal activity with inhibitors such as tetrodotoxin, to block action potential firing, or inhibitors of ionotropic glutamate receptors. The tool can also offer information about local homeostatic calcium activity events in neurites.'),
(88978, 2018, 'plos', 'Spatial regularity control of phyllotaxis pattern generated by the mutual interaction between auxin and PIN1', 'Fujita, Hironori|Kawaguchi, Masayoshi', 'National Institute for Basic Biology, Okazaki, Aichi, Japan.|National Institute for Basic Biology, Okazaki, Aichi, Japan.', 'Japan|Japan', 4, 'Biological Transport|Body Patterning|Computational Biology|Computer Simulation|Indoleacetic Acids|Membrane Transport Proteins|Models, Biological|Plant Growth Regulators|Plant Leaves|Plant Proteins|Plant Stems|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1006065', '29614066', 'Phyllotaxis, the arrangement of leaves on a plant stem, is well known because of its beautiful geometric configuration, which is derived from the constant spacing between leaf primordia. This phyllotaxis is established by mutual interaction between a diffusible plant hormone auxin and its efflux carrier PIN1, which cooperatively generate a regular pattern of auxin maxima, small regions with high auxin concentrations, leading to leaf primordia. However, the molecular mechanism of the regular pattern of auxin maxima is still largely unknown. To better understand how the phyllotaxis pattern is controlled, we investigated mathematical models based on the auxin-PIN1 interaction through linear stability analysis and numerical simulations, focusing on the spatial regularity control of auxin maxima. As in previous reports, we first confirmed that this spatial regularity can be reproduced by a highly simplified and abstract model. However, this model lacks the extracellular region and is not appropriate for considering the molecular mechanism. Thus, we investigated how auxin maxima patterns are affected under more realistic conditions. We found that the spatial regularity is eliminated by introducing the extracellular region, even in the presence of direct diffusion between cells or between extracellular spaces, and this strongly suggests the existence of an unknown molecular mechanism. To unravel this mechanism, we assumed a diffusible molecule to verify various feedback interactions with auxin-PIN1 dynamics. We revealed that regular patterns can be restored by a diffusible molecule that mediates the signaling from auxin to PIN1 polarization. Furthermore, as in the one-dimensional case, similar results are observed in the two-dimensional space. These results provide a great insight into the theoretical and molecular basis for understanding the phyllotaxis pattern. Our theoretical analysis strongly predicts a diffusible molecule that is pivotal for the phyllotaxis pattern but is yet to be determined experimentally.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(88979, 2018, 'plos', 'Effect of Ca2+ on the promiscuous target-protein binding of calmodulin', 'Westerlund, Annie M|Delemotte, Lucie', 'Science for Life Laboratory, Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden.|Science for Life Laboratory, Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden.', 'Sweden|Sweden', 0, 'Animals|Apoproteins|Binding Sites|Calcium|Calcium Signaling|Calmodulin|Computational Biology|Humans|Hydrophobic and Hydrophilic Interactions|Molecular Dynamics Simulation|Protein Binding|Protein Conformation|Static Electricity', 'Journal Article', '10.1371/journal.pcbi.1006072', '29614072', 'Calmodulin (CaM) is a calcium sensing protein that regulates the function of a large number of proteins, thus playing a crucial part in many cell signaling pathways. CaM has the ability to bind more than 300 different target peptides in a Ca2+-dependent manner, mainly through the exposure of hydrophobic residues. How CaM can bind a large number of targets while retaining some selectivity is a fascinating open question. Here, we explore the mechanism of CaM selective promiscuity for selected target proteins. Analyzing enhanced sampling molecular dynamics simulations of Ca2+-bound and Ca2+-free CaM via spectral clustering has allowed us to identify distinct conformational states, characterized by interhelical angles, secondary structure determinants and the solvent exposure of specific residues. We searched for indicators of conformational selection by mapping solvent exposure of residues in these conformational states to contacts in structures of CaM/target peptide complexes. We thereby identified CaM states involved in various binding classes arranged along a depth binding gradient. Binding Ca2+ modifies the accessible hydrophobic surface of the two lobes and allows for deeper binding. Apo CaM indeed shows shallow binding involving predominantly polar and charged residues. Furthermore, binding to the C-terminal lobe of CaM appears selective and involves specific conformational states that can facilitate deep binding to target proteins, while binding to the N-terminal lobe appears to happen through a more flexible mechanism. Thus the long-ranged electrostatic interactions of the charged residues of the N-terminal lobe of CaM may initiate binding, while the short-ranged interactions of hydrophobic residues in the C-terminal lobe of CaM may account for selectivity. This work furthers our understanding of the mechanism of CaM binding and selectivity to different target proteins and paves the way towards a comprehensive model of CaM selectivity.'),
(88980, 2018, 'plos', 'A probabilistic, distributed, recursive mechanism for decision-making in the brain', 'Caballero, Javier A|Humphries, Mark D|Gurney, Kevin N', 'Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.|Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.|Deptartment of Psychology, The University of Sheffield, Sheffield, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 2, 'Algorithms|Animals|Bayes Theorem|Brain|Brain Mapping|Computational Biology|Computer Simulation|Corpus Striatum|Decision Making|Electrophysiological Phenomena|Haplorhini|Models, Neurological|Models, Psychological|Models, Statistical|Reaction Time|Sensorimotor Cortex', 'Journal Article', '10.1371/journal.pcbi.1006033', '29614077', 'Decision formation recruits many brain regions, but the procedure they jointly execute is unknown. Here we characterize its essential composition, using as a framework a novel recursive Bayesian algorithm that makes decisions based on spike-trains with the statistics of those in sensory cortex (MT). Using it to simulate the random-dot-motion task, we demonstrate it quantitatively replicates the choice behaviour of monkeys, whilst predicting losses of otherwise usable information from MT. Its architecture maps to the recurrent cortico-basal-ganglia-thalamo-cortical loops, whose components are all implicated in decision-making. We show that the dynamics of its mapped computations match those of neural activity in the sensorimotor cortex and striatum during decisions, and forecast those of basal ganglia output and thalamus. This also predicts which aspects of neural dynamics are and are not part of inference. Our single-equation algorithm is probabilistic, distributed, recursive, and parallel. Its success at capturing anatomy, behaviour, and electrophysiology suggests that the mechanism implemented by the brain has these same characteristics.'),
(88981, 2018, 'plos', 'Computational analysis of the oscillatory behavior at the translation level induced by mRNA levels oscillations due to finite intracellular resources', 'Zarai, Yoram|Tuller, Tamir', 'Department of Biomedical Engineering, Tel-Aviv University, Tel-Aviv, Israel.|Department of Biomedical Engineering and the Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel.', 'Israel|Israel', 0, 'Amino Acid Substitution|Codon|Computational Biology|Computer Simulation|Evolution, Molecular|Gene Expression|Genes, Synthetic|Genome, Fungal|Green Fluorescent Proteins|Kinetics|Models, Genetic|Monte Carlo Method|Protein Biosynthesis|RNA, Fungal|RNA, Messenger|Recombinant Proteins|Ribosomes|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1006055', '29614119', 'Recent studies have demonstrated how the competition for the finite pool of available gene expression factors has important effect on fundamental gene expression aspects. In this study, based on a whole-cell model simulation of translation in S. cerevisiae, we evaluate for the first time the expected effect of mRNA levels fluctuations on translation due to the finite pool of ribosomes. We show that fluctuations of a single gene or a group of genes mRNA levels induce periodic behavior in all S. cerevisiae translation factors and aspects: the ribosomal densities and the translation rates of all S. cerevisiae mRNAs oscillate. We numerically measure the oscillation amplitudes demonstrating that fluctuations of endogenous and heterologous genes can cause a significant fluctuation of up to 50% in the steady-state translation rates of the rest of the genes. Furthermore, we demonstrate by synonymous mutations that oscillating the levels of mRNAs that experience high ribosomal occupancy (e.g. ribosomal traffic jam) induces the largest impact on the translation of the S. cerevisiae genome. The results reported here should provide novel insights and principles related to the design of synthetic gene expression circuits and related to the evolutionary constraints shaping gene expression of endogenous genes.'),
(88982, 2018, 'plos', 'Ten quick tips for teaching programming', 'Brown, Neil C C|Wilson, Greg', 'Department of Informatics, Kings College London, London, United Kingdom.|DataCamp, Toronto, Ontario, Canada.', 'United Kingdom|Canada', 14, 'Computational Biology|Humans|Programming Languages|Software', 'Journal Article', '10.1371/journal.pcbi.1006023', '29621229', '-'),
(88983, 2018, 'plos', 'Automated plant species identification-Trends and future directions', 'Wäldchen, Jana|Rzanny, Michael|Seeland, Marco|Mäder, Patrick', 'Department of Biogeochemical Integration, Max Planck Institute for Biogeochemistry, Jena, Thuringia, Germany.|Department of Biogeochemical Integration, Max Planck Institute for Biogeochemistry, Jena, Thuringia, Germany.|Software Engineering for Safety-Critical Systems Group, Technische Universität Ilmenau, Ilmenau, Thuringia, Germany.|Software Engineering for Safety-Critical Systems Group, Technische Universität Ilmenau, Ilmenau, Thuringia, Germany.', 'Germany|Germany|Germany|Germany', 0, 'Artificial Intelligence|Biodiversity|Computational Biology|Conservation of Natural Resources|Flowers|Image Processing, Computer-Assisted|Pattern Recognition, Automated|Pigmentation|Plant Leaves|Plants|Supervised Machine Learning', 'Journal Article', '10.1371/journal.pcbi.1005993', '29621236', 'Current rates of species loss triggered numerous attempts to protect and conserve biodiversity. Species conservation, however, requires species identification skills, a competence obtained through intensive training and experience. Field researchers, land managers, educators, civil servants, and the interested public would greatly benefit from accessible, up-to-date tools automating the process of species identification. Currently, relevant technologies, such as digital cameras, mobile devices, and remote access to databases, are ubiquitously available, accompanied by significant advances in image processing and pattern recognition. The idea of automated species identification is approaching reality. We review the technical status quo on computer vision approaches for plant species identification, highlight the main research challenges to overcome in providing applicable tools, and conclude with a discussion of open and future research thrusts.'),
(88984, 2018, 'plos', 'New computational approaches to understanding molecular protein function', 'Fetrow, Jacquelyn S|Babbitt, Patricia C', 'Office of the President, Albright College, Reading, Pennsylvania, United States of America.|Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.', 'United States|United States', 1, 'Amino Acid Sequence|Catalytic Domain|Cluster Analysis|Computational Biology|Databases, Protein|Enzymes|Gene Ontology|Models, Molecular|Proteins|Sequence Alignment', 'Editorial', '10.1371/journal.pcbi.1005756', '29621256', '-'),
(88985, 2018, 'plos', 'Need for speed: An optimized gridding approach for spatially explicit disease simulations', 'Sellman, Stefan|Tsao, Kimberly|Tildesley, Michael J|Brommesson, Peter|Webb, Colleen T|Wennergren, Uno|Keeling, Matt J|Lindström, Tom', 'Department of Physics, Chemistry and Biology, Division of Theoretical Biology, Linköping University, Linköping, Sweden.|Department of Biology, Colorado State University, Fort Collins, CO, United States of America.|Zeeman Institute (SBIDER), School of Life Sciences and Mathematics Institute, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK.|Department of Physics, Chemistry and Biology, Division of Theoretical Biology, Linköping University, Linköping, Sweden.|Department of Biology, Colorado State University, Fort Collins, CO, United States of America.|Department of Physics, Chemistry and Biology, Division of Theoretical Biology, Linköping University, Linköping, Sweden.|Zeeman Institute (SBIDER), School of Life Sciences and Mathematics Institute, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK.|Department of Physics, Chemistry and Biology, Division of Theoretical Biology, Linköping University, Linköping, Sweden.', 'Sweden|United States|United Kingdom|Sweden|United States|Sweden|United Kingdom|Sweden', 0, 'Algorithms|Animals|Cluster Analysis|Computational Biology|Computer Simulation|Disease Outbreaks|Farms|Foot-and-Mouth Disease|Livestock|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1006086', '29624574', 'Numerical models for simulating outbreaks of infectious diseases are powerful tools for informing surveillance and control strategy decisions. However, large-scale spatially explicit models can be limited by the amount of computational resources they require, which poses a problem when multiple scenarios need to be explored to provide policy recommendations. We introduce an easily implemented method that can reduce computation time in a standard Susceptible-Exposed-Infectious-Removed (SEIR) model without introducing any further approximations or truncations. It is based on a hierarchical infection process that operates on entire groups of spatially related nodes (cells in a grid) in order to efficiently filter out large volumes of susceptible nodes that would otherwise have required expensive calculations. After the filtering of the cells, only a subset of the nodes that were originally at risk are then evaluated for actual infection. The increase in efficiency is sensitive to the exact configuration of the grid, and we describe a simple method to find an estimate of the optimal configuration of a given landscape as well as a method to partition the landscape into a grid configuration. To investigate its efficiency, we compare the introduced methods to other algorithms and evaluate computation time, focusing on simulated outbreaks of foot-and-mouth disease (FMD) on the farm population of the USA, the UK and Sweden, as well as on three randomly generated populations with varying degree of clustering. The introduced method provided up to 500 times faster calculations than pairwise computation, and consistently performed as well or better than other available methods. This enables large scale, spatially explicit simulations such as for the entire continental USA without sacrificing realism or predictive power.'),
(88986, 2018, 'plos', 'Toward a theory of coactivation patterns in excitable neural networks', 'Messé, Arnaud|Hütt, Marc-Thorsten|Hilgetag, Claus C', 'Institute of Computational Neuroscience, University Medical Center Eppendorf, Hamburg University, Hamburg, Germany.|Department of Life Sciences and Chemistry, Jacobs University, Bremen, Germany.|Institute of Computational Neuroscience, University Medical Center Eppendorf, Hamburg University, Hamburg, Germany.', 'Germany|Germany|Germany', 6, 'Activity Cycles|Brain|Computational Biology|Computer Simulation|Humans|Models, Neurological|Nerve Net|Neural Networks (Computer)', 'Journal Article', '10.1371/journal.pcbi.1006084', '29630592', 'The relationship between the structural connectivity (SC) and functional connectivity (FC) of neural systems is of central importance in brain network science. It is an open question, however, how the SC-FC relationship depends on specific topological features of brain networks or the models used for describing neural dynamics. Using a basic but general model of discrete excitable units that follow a susceptible-excited-refractory activity cycle (SER model), we here analyze how the network activity patterns underlying functional connectivity are shaped by the characteristic topological features of the network. We develop an analytical framework for describing the contribution of essential topological elements, such as common inputs and pacemakers, to the coactivation of nodes, and demonstrate the validity of the approach by comparison of the analytical predictions with numerical simulations of various exemplar networks. The present analytic framework may serve as an initial step for the mechanistic understanding of the contributions of brain network topology to brain dynamics.'),
(88987, 2018, 'plos', 'A multitask clustering approach for single-cell RNA-seq analysis in Recessive Dystrophic Epidermolysis Bullosa', 'Zhang, Huanan|Lee, Catherine A A|Li, Zhuliu|Garbe, John R|Eide, Cindy R|Petegrosso, Raphael|Kuang, Rui|Tolar, Jakub', 'Department of Computer Science and Engineering, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Genetics, Cell Biology and Development, 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.|Minnesota Supercomputing Institute, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Pediatrics, 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 Pediatrics, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Algorithms|Animals|Case-Control Studies|Cluster Analysis|Collagen Type VII|Computational Biology|Computer Simulation|Embryonic Stem Cells|Epidermolysis Bullosa Dystrophica|Gene Expression Profiling|Genetic Markers|High-Throughput Nucleotide Sequencing|Humans|Leukocytes, Mononuclear|Lung|Machine Learning|Mice|Models, Genetic|RNA|Sequence Analysis, RNA|Single-Cell Analysis', 'Journal Article', '10.1371/journal.pcbi.1006053', '29630593', 'Single-cell RNA sequencing (scRNA-seq) has been widely applied to discover new cell types by detecting sub-populations in a heterogeneous group of cells. Since scRNA-seq experiments have lower read coverage/tag counts and introduce more technical biases compared to bulk RNA-seq experiments, the limited number of sampled cells combined with the experimental biases and other dataset specific variations presents a challenge to cross-dataset analysis and discovery of relevant biological variations across multiple cell populations. In this paper, we introduce a method of variance-driven multitask clustering of single-cell RNA-seq data (scVDMC) that utilizes multiple single-cell populations from biological replicates or different samples. scVDMC clusters single cells in multiple scRNA-seq experiments of similar cell types and markers but varying expression patterns such that the scRNA-seq data are better integrated than typical pooled analyses which only increase the sample size. By controlling the variance among the cell clusters within each dataset and across all the datasets, scVDMC detects cell sub-populations in each individual experiment with shared cell-type markers but varying cluster centers among all the experiments. Applied to two real scRNA-seq datasets with several replicates and one large-scale droplet-based dataset on three patient samples, scVDMC more accurately detected cell populations and known cell markers than pooled clustering and other recently proposed scRNA-seq clustering methods. In the case study applied to in-house Recessive Dystrophic Epidermolysis Bullosa (RDEB) scRNA-seq data, scVDMC revealed several new cell types and unknown markers validated by flow cytometry. MATLAB/Octave code available at https://github.com/kuanglab/scVDMC.'),
(88988, 2018, 'plos', 'Spatial modeling of the membrane-cytosolic interface in protein kinase signal transduction', 'Giese, Wolfgang|Milicic, Gregor|Schröder, Andreas|Klipp, Edda', 'Mathematical Cell Physiology, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Department of Mathematics, University of Salzburg, Salzburg, Austria.|Department of Mathematics, University of Salzburg, Salzburg, Austria.|Theoretische Biophysik, Humboldt-Universität zu Berlin, Berlin, Germany.', 'Germany|Austria|Austria|Germany', 0, 'Biological Transport, Active|Cell Membrane|Cell Nucleus|Cell Shape|Cell Size|Computational Biology|Computer Simulation|Cytosol|Feedback, Physiological|Finite Element Analysis|Kinetics|Models, Biological|Nonlinear Dynamics|Protein Kinases|Receptors, Cell Surface|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1006075', '29630597', 'The spatial architecture of signaling pathways and the interaction with cell size and morphology are complex, but little understood. With the advances of single cell imaging and single cell biology, it becomes crucial to understand intracellular processes in time and space. Activation of cell surface receptors often triggers a signaling cascade including the activation of membrane-attached and cytosolic signaling components, which eventually transmit the signal to the cell nucleus. Signaling proteins can form steep gradients in the cytosol, which cause strong cell size dependence. We show that the kinetics at the membrane-cytosolic interface and the ratio of cell membrane area to the enclosed cytosolic volume change the behavior of signaling cascades significantly. We suggest an estimate of average concentration for arbitrary cell shapes depending on the cell volume and cell surface area. The normalized variance, known from image analysis, is suggested as an alternative measure to quantify the deviation from the average concentration. A mathematical analysis of signal transduction in time and space is presented, providing analytical solutions for different spatial arrangements of linear signaling cascades. Quantification of signaling time scales reveals that signal propagation is faster at the membrane than at the nucleus, while this time difference decreases with the number of signaling components in the cytosol. Our investigations are complemented by numerical simulations of non-linear cascades with feedback and asymmetric cell shapes. We conclude that intracellular signal propagation is highly dependent on cell geometry and, thereby, conveys information on cell size and shape to the nucleus.'),
(88989, 2018, 'plos', 'Interactions of spatial strategies producing generalization gradient and blocking: A computational approach', 'Dollé, Laurent|Chavarriaga, Ricardo|Guillot, Agnès|Khamassi, Mehdi', 'Institute of Intelligent Systems and Robotics, Sorbonne Université, CNRS, F-75005 Paris, France.|Defitech Chair in Brain-Machine Interface, Center for Neuroprosthetics, Institute of Bioengineering and School of Engineering, EPFL, Geneva, Switzerland.|Institute of Intelligent Systems and Robotics, Sorbonne Université, CNRS, F-75005 Paris, France.|Institute of Intelligent Systems and Robotics, Sorbonne Université, CNRS, F-75005 Paris, France.', 'France|Switzerland|France|France', 3, 'Animals|Behavior, Animal|Cognition|Computational Biology|Computer Simulation|Cues|Mammals|Maze Learning|Memory|Models, Psychological|Reinforcement (Psychology)|Spatial Navigation', 'Journal Article', '10.1371/journal.pcbi.1006092', '29630600', 'We present a computational model of spatial navigation comprising different learning mechanisms in mammals, i.e., associative, cognitive mapping and parallel systems. This model is able to reproduce a large number of experimental results in different variants of the Morris water maze task, including standard associative phenomena (spatial generalization gradient and blocking), as well as navigation based on cognitive mapping. Furthermore, we show that competitive and cooperative patterns between different navigation strategies in the model allow to explain previous apparently contradictory results supporting either associative or cognitive mechanisms for spatial learning. The key computational mechanism to reconcile experimental results showing different influences of distal and proximal cues on the behavior, different learning times, and different abilities of individuals to alternatively perform spatial and response strategies, relies in the dynamic coordination of navigation strategies, whose performance is evaluated online with a common currency through a modular approach. We provide a set of concrete experimental predictions to further test the computational model. Overall, this computational work sheds new light on inter-individual differences in navigation learning, and provides a formal and mechanistic approach to test various theories of spatial cognition in mammals.'),
(88990, 2018, 'plos', 'Cox-nnet: An artificial neural network method for prognosis prediction of high-throughput omics data', 'Ching, Travers|Zhu, Xun|Garmire, Lana X', 'Molecular Biosciences and Bioengineering Graduate Program, University of Hawaii at Manoa, Honolulu, HI, United States of America.|Molecular Biosciences and Bioengineering Graduate Program, University of Hawaii at Manoa, Honolulu, HI, United States of America.|Molecular Biosciences and Bioengineering Graduate Program, University of Hawaii at Manoa, Honolulu, HI, United States of America.', 'United States|United States|United States', 0, 'Computational Biology|Databases, Nucleic Acid|Female|Gene Expression Profiling|Gene Regulatory Networks|High-Throughput Nucleotide Sequencing|Humans|Kaplan-Meier Estimate|Male|Metabolic Networks and Pathways|Neoplasms|Neural Networks (Computer)|Prognosis|Proportional Hazards Models|Sequence Analysis, RNA|Survival Analysis', 'Comparative Study', '10.1371/journal.pcbi.1006076', '29634719', 'Artificial neural networks (ANN) are computing architectures with many interconnections of simple neural-inspired computing elements, and have been applied to biomedical fields such as imaging analysis and diagnosis. We have developed a new ANN framework called Cox-nnet to predict patient prognosis from high throughput transcriptomics data. In 10 TCGA RNA-Seq data sets, Cox-nnet achieves the same or better predictive accuracy compared to other methods, including Cox-proportional hazards regression (with LASSO, ridge, and mimimax concave penalty), Random Forests Survival and CoxBoost. Cox-nnet also reveals richer biological information, at both the pathway and gene levels. The outputs from the hidden layer node provide an alternative approach for survival-sensitive dimension reduction. In summary, we have developed a new method for accurate and efficient prognosis prediction on high throughput data, with functional biological insights. The source code is freely available at https://github.com/lanagarmire/cox-nnet.'),
(88991, 2018, 'plos', 'Eleven quick tips for finding research data', 'Gregory, Kathleen|Khalsa, Siri Jodha|Michener, William K|Psomopoulos, Fotis E|de Waard, Anita|Wu, Mingfang', 'Data Archiving and Networked Services, Royal Netherlands Academy of Arts and Sciences, The Hague, Netherlands.|National Snow and Ice Data Centre, Cooperative Institute for Research in Environmental Sciences, University of Colorado, Boulder, Colorado, United States of America.|College of University Libraries & Learning Sciences, The University of New Mexico, Albuquerque, New Mexico, United States of America.|Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece.|Research Data Management Solutions, Elsevier, Jericho, Vermont, United States of America.|Australia National Data Service, Melbourne, Australia.', 'Netherlands|United States|Mexico|Greece|United States|Australia', 4, 'Computational Biology|Data Interpretation, Statistical|Information Storage and Retrieval|Research|Search Engine', 'Journal Article', '10.1371/journal.pcbi.1006038', '29649206', '-'),
(88992, 2018, 'plos', 'Physics-based simulations of aerial attacks by peregrine falcons reveal that stooping at high speed maximizes catch success against agile prey', 'Mills, Robin|Hildenbrandt, Hanno|Taylor, Graham K|Hemelrijk, Charlotte K', 'Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, Groningen, Netherlands.|Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, Groningen, Netherlands.|Department of Zoology, University of Oxford, Oxford, Oxfordshire, United Kingdom.|Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, Groningen, Netherlands.', 'Netherlands|Netherlands|United Kingdom|Netherlands', 4, 'Altitude|Animals|Biophysical Phenomena|Computational Biology|Computer Simulation|Falconiformes|Flight, Animal|Models, Biological|Predatory Behavior|Starlings|Vision, Ocular', 'Journal Article', '10.1371/journal.pcbi.1006044', '29649207', 'The peregrine falcon Falco peregrinus is renowned for attacking its prey from high altitude in a fast controlled dive called a stoop. Many other raptors employ a similar mode of attack, but the functional benefits of stooping remain obscure. Here we investigate whether, when, and why stooping promotes catch success, using a three-dimensional, agent-based modeling approach to simulate attacks of falcons on aerial prey. We simulate avian flapping and gliding flight using an analytical quasi-steady model of the aerodynamic forces and moments, parametrized by empirical measurements of flight morphology. The model-birds flight control inputs are commanded by their guidance system, comprising a phenomenological model of its vision, guidance, and control. To intercept its prey, model-falcons use the same guidance law as missiles (pure proportional navigation), this assumption is corroborated by empirical data on peregrine falcons hunting lures. We parametrically vary the falcons starting position relative to its prey, together with the feedback gain of its guidance loop, under differing assumptions regarding its errors and delay in vision and control, and for three different patterns of prey motion. We find that, when the prey maneuvers erratically, high-altitude stoops increase catch success compared to low-altitude attacks, but only if the falcons guidance law is appropriately tuned, and only given a high degree of precision in vision and control. Remarkably, the optimal tuning of the guidance law in our simulations coincides closely with what has been observed empirically in peregrines. High-altitude stoops are shown to be beneficial because their high airspeed enables production of higher aerodynamic forces for maneuvering, and facilitates higher roll agility as the wings are tucked, each of which is essential to catching maneuvering prey at realistic response delays.'),
(88993, 2018, 'plos', 'Assessing the durability and efficiency of landscape-based strategies to deploy plant resistance to pathogens', 'Rimbaud, Loup|Papaïx, Julien|Rey, Jean-François|Barrett, Luke G|Thrall, Peter H', 'CSIRO Agriculture and Food, Canberra, ACT, Australia.|BioSP, INRA, Avignon, France.|BioSP, INRA, Avignon, France.|CSIRO Agriculture and Food, Canberra, ACT, Australia.|CSIRO Agriculture and Food, Canberra, ACT, Australia.', 'Australia|France|France|Australia|Australia', 0, 'Agriculture|Computational Biology|Computer Simulation|Crops, Agricultural|Disease Resistance|Evolution, Molecular|Genes, Plant|Host-Pathogen Interactions|Models, Genetic|Mutation|Plant Diseases|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1006067', '29649208', 'Genetically-controlled plant resistance can reduce the damage caused by pathogens. However, pathogens have the ability to evolve and overcome such resistance. This often occurs quickly after resistance is deployed, resulting in significant crop losses and a continuing need to develop new resistant cultivars. To tackle this issue, several strategies have been proposed to constrain the evolution of pathogen populations and thus increase genetic resistance durability. These strategies mainly rely on varying different combinations of resistance sources across time (crop rotations) and space. The spatial scale of deployment can vary from multiple resistance sources occurring in a single cultivar (pyramiding), in different cultivars within the same field (cultivar mixtures) or in different fields (mosaics). However, experimental comparison of the efficiency (i.e. ability to reduce disease impact) and durability (i.e. ability to limit pathogen evolution and delay resistance breakdown) of landscape-scale deployment strategies presents major logistical challenges. Therefore, we developed a spatially explicit stochastic model able to assess the epidemiological and evolutionary outcomes of the four major deployment options described above, including both qualitative resistance (i.e. major genes) and quantitative resistance traits against several components of pathogen aggressiveness: infection rate, latent period duration, propagule production rate, and infectious period duration. This model, implemented in the R package landsepi, provides a new and useful tool to assess the performance of a wide range of deployment options, and helps investigate the effect of landscape, epidemiological and evolutionary parameters. This article describes the model and its parameterisation for rust diseases of cereal crops, caused by fungi of the genus Puccinia. To illustrate the model, we use it to assess the epidemiological and evolutionary potential of the combination of a major gene and different traits of quantitative resistance. The comparison of the four major deployment strategies described above will be the objective of future studies.'),
(88994, 2018, 'plos', 'Ten simple rules for responsible referencing', 'Penders, Bart', 'Maastricht University, Care and Public Health Research Institute (CAPHRI), Department of Health, Ethics & Society, Maastricht, the Netherlands.', 'Netherlands', 5, 'Computational Biology|Humans|Interdisciplinary Communication|Periodicals as Topic|Publications|Scholarly Communication', 'Editorial', '10.1371/journal.pcbi.1006036', '29649210', '-'),
(88995, 2018, 'plos', 'Principles that govern competition or co-existence in Rho-GTPase driven polarization', 'Chiou, Jian-Geng|Ramirez, Samuel A|Elston, Timothy C|Witelski, Thomas P|Schaeffer, David G|Lew, Daniel J', 'Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.|Department of Mathematics, Duke University, Durham, North Carolina, United States of America.|Department of Mathematics, Duke University, Durham, North Carolina, United States of America.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.', 'United States|United States|United States|United States|United States|United States', 13, 'Binding, Competitive|Cell Polarity|Computational Biology|Computer Simulation|Cytoplasm|Cytoskeleton|Kinetics|Models, Biological|Protein Aggregates|Saccharomyces cerevisiae Proteins|rho GTP-Binding Proteins', 'Journal Article', '10.1371/journal.pcbi.1006095', '29649212', 'Rho-GTPases are master regulators of polarity establishment and cell morphology. Positive feedback enables concentration of Rho-GTPases into clusters at the cell cortex, from where they regulate the cytoskeleton. Different cell types reproducibly generate either one (e.g. the front of a migrating cell) or several clusters (e.g. the multiple dendrites of a neuron), but the mechanistic basis for unipolar or multipolar outcomes is unclear. The design principles of Rho-GTPase circuits are captured by two-component reaction-diffusion models based on conserved aspects of Rho-GTPase biochemistry. Some such models display rapid winner-takes-all competition between clusters, yielding a unipolar outcome. Other models allow prolonged co-existence of clusters. We investigate the behavior of a simple class of models and show that while the timescale of competition varies enormously depending on model parameters, a single factor explains a large majority of this variation. The dominant factor concerns the degree to which the maximal active GTPase concentration in a cluster approaches a saturation point determined by model parameters. We suggest that both saturation and the effect of saturation on competition reflect fundamental properties of the Rho-GTPase polarity machinery, regardless of the specific feedback mechanism, which predict whether the system will generate unipolar or multipolar outcomes.'),
(88996, 2018, 'plos', 'Biobeam-Multiplexed wave-optical simulations of light-sheet microscopy', 'Weigert, Martin|Subramanian, Kaushikaram|Bundschuh, Sebastian T|Myers, Eugene W|Kreysing, Moritz', 'Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.|Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.|Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.|Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.|Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.', 'Germany|Germany|Germany|Germany|Germany', 0, 'Computational Biology|Computer Simulation|Image Enhancement|Image Processing, Computer-Assisted|Imaging, Three-Dimensional|Light|Microscopy, Fluorescence|Optical Phenomena|Scattering, Radiation|Software', 'Journal Article', '10.1371/journal.pcbi.1006079', '29652879', 'Sample-induced image-degradation remains an intricate wave-optical problem in light-sheet microscopy. Here we present biobeam, an open-source software package that enables simulation of operational light-sheet microscopes by combining data from 105-106 multiplexed and GPU-accelerated point-spread-function calculations. The wave-optical nature of these simulations leads to the faithful reproduction of spatially varying aberrations, diffraction artifacts, geometric image distortions, adaptive optics, and emergent wave-optical phenomena, and renders image-formation in light-sheet microscopy computationally tractable.'),
(88997, 2018, 'plos', 'Origins of scale invariance in vocalization sequences and speech', 'Khatami, Fatemeh|Wöhr, Markus|Read, Heather L|Escabí, Monty A', 'Biomedical Engineering, University of Connecticut, Storrs, Connecticut, United States of America.|Behavioral Neuroscience, Experimental and Biological Psychology, Faculty of Psychology, Philipps-University of Marburg, Marburg, Germany.|Biomedical Engineering, University of Connecticut, Storrs, Connecticut, United States of America.|Biomedical Engineering, University of Connecticut, Storrs, Connecticut, United States of America.', 'United States|Germany|United States|United States', 4, 'Acoustic Stimulation|Animals|Auditory Perception|Birds|Brain|Computational Biology|Cues|Databases, Factual|Haplorhini|Humans|Mice|Mice, Inbred C57BL|Models, Neurological|Rats|Rats, Wistar|Speech|Speech Acoustics|Stochastic Processes|Vocalization, Animal', 'Journal Article', '10.1371/journal.pcbi.1005996', '29659561', 'To communicate effectively animals need to detect temporal vocalization cues that vary over several orders of magnitude in their amplitude and frequency content. This large range of temporal cues is evident in the power-law scale-invariant relationship between the power of temporal fluctuations in sounds and the sound modulation frequency (f). Though various forms of scale invariance have been described for natural sounds, the origins and implications of scale invariant phenomenon remain unknown. Using animal vocalization sequences, including continuous human speech, and a stochastic model of temporal amplitude fluctuations we demonstrate that temporal acoustic edges are the primary acoustic cue accounting for the scale invariant phenomenon. The modulation spectrum of vocalization sequences and the model both exhibit a dual regime lowpass structure with a flat region at low modulation frequencies and scale invariant 1/f2 trend for high modulation frequencies. Moreover, we find a time-frequency tradeoff between the average vocalization duration of each vocalization sequence and the cutoff frequency beyond which scale invariant behavior is observed. These results indicate that temporal edges are universal features responsible for scale invariance in vocalized sounds. This is significant since temporal acoustic edges are salient perceptually and the auditory system could exploit such statistical regularities to minimize redundancies and generate compact neural representations of vocalized sounds.'),
(88998, 2018, 'plos', 'Backbone Brackets and Arginine Tweezers delineate Class I and Class II aminoacyl tRNA synthetases', 'Kaiser, Florian|Bittrich, Sebastian|Salentin, Sebastian|Leberecht, Christoph|Haupt, V Joachim|Krautwurst, Sarah|Schroeder, Michael|Labudde, Dirk', 'University of Applied Sciences Mittweida, Mittweida, Germany.|University of Applied Sciences Mittweida, Mittweida, Germany.|Biotechnology Center (BIOTEC), TU Dresden, Dresden, Germany.|University of Applied Sciences Mittweida, Mittweida, Germany.|Biotechnology Center (BIOTEC), TU Dresden, Dresden, Germany.|University of Applied Sciences Mittweida, Mittweida, Germany.|Biotechnology Center (BIOTEC), TU Dresden, Dresden, Germany.|University of Applied Sciences Mittweida, Mittweida, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany', 7, 'Adenosine Triphosphate|Amino Acid Sequence|Amino Acyl-tRNA Synthetases|Arginine|Base Sequence|Catalytic Domain|Codon|Computational Biology|Evolution, Molecular|Genetic Variation|Humans|Ligands|Models, Molecular|Mutagenesis|Protein Conformation|RNA, Transfer', 'Journal Article', '10.1371/journal.pcbi.1006101', '29659563', 'The origin of the machinery that realizes protein biosynthesis in all organisms is still unclear. One key component of this machinery are aminoacyl tRNA synthetases (aaRS), which ligate tRNAs to amino acids while consuming ATP. Sequence analyses revealed that these enzymes can be divided into two complementary classes. Both classes differ significantly on a sequence and structural level, feature different reaction mechanisms, and occur in diverse oligomerization states. The one unifying aspect of both classes is their function of binding ATP. We identified Backbone Brackets and Arginine Tweezers as most compact ATP binding motifs characteristic for each Class. Geometric analysis shows a structural rearrangement of the Backbone Brackets upon ATP binding, indicating a general mechanism of all Class I structures. Regarding the origin of aaRS, the Rodin-Ohno hypothesis states that the peculiar nature of the two aaRS classes is the result of their primordial forms, called Protozymes, being encoded on opposite strands of the same gene. Backbone Brackets and Arginine Tweezers were traced back to the proposed Protozymes and their more efficient successors, the Urzymes. Both structural motifs can be observed as pairs of residues in contemporary structures and it seems that the time of their addition, indicated by their placement in the ancient aaRS, coincides with the evolutionary trace of Proto- and Urzymes.'),
(88999, 2018, 'plos', 'Multiscale modelization in a small virus: Mechanism of proton channeling and its role in triggering capsid disassembly', 'Viso, Juan Francisco|Belelli, Patricia|Machado, Matías|González, Humberto|Pantano, Sergio|Amundarain, María Julia|Zamarreño, Fernando|Branda, Maria Marta|Guérin, Diego M A|Costabel, Marcelo D', 'Departamento de Física (DF), Universidad Nacional del Sur (UNS), Bahía Blanca, Argentina.|DF-UNS, Grupo de Materiales y Sistemas Catalíticos (GRUMASICA), IFISUR, Bahía Blanca, Argentina.|Grupo de Simulaciones Biomoleculares, Institut Pasteur de Montevideo, Montevideo, Uruguay.|Grupo de Simulaciones Biomoleculares, Institut Pasteur de Montevideo, Montevideo, Uruguay.|Grupo de Simulaciones Biomoleculares, Institut Pasteur de Montevideo, Montevideo, Uruguay.|Departamento de Física (DF), Universidad Nacional del Sur (UNS), Bahía Blanca, Argentina.|Departamento de Física (DF), Universidad Nacional del Sur (UNS), Bahía Blanca, Argentina.|Departamento de Física (DF), Universidad Nacional del Sur (UNS), Bahía Blanca, Argentina.|Instituto Biofisika (UPV/EHU, CSIC), Department of Biochemistry and Molecular Biology, University of the Basque Country (EHU), Barrio Sarriena S/N, Leioa, Vizcaya, Spain.|Departamento de Física (DF), Universidad Nacional del Sur (UNS), Bahía Blanca, Argentina.', 'Argentina|Argentina|Uruguay|Uruguay|Uruguay|Argentina|Argentina|Argentina|Spain|Argentina', 0, 'Animals|Capsid|Computational Biology|Dicistroviridae|Hydrogen-Ion Concentration|Hydrophobic and Hydrophilic Interactions|Ion Channels|Models, Biological|Models, Molecular|Molecular Dynamics Simulation|Protons|Static Electricity|Virus Assembly', 'Journal Article', '10.1371/journal.pcbi.1006082', '29659564', 'In this work, we assess a previously advanced hypothesis that predicts the existence of ion channels in the capsid of small and non-enveloped icosahedral viruses. With this purpose we examine Triatoma Virus (TrV) as a case study. This virus has a stable capsid under highly acidic conditions but disassembles and releases the genome in alkaline environments. Our calculations range from a subtle sub-atomic proton interchange to the dismantling of a large-scale system representing several million of atoms. Our results provide structure-based explanations for the three roles played by the capsid to enable genome release. First, we observe, for the first time, the formation of a hydrophobic gate in the cavity along the five-fold axis of the wild-type virus capsid, which can be disrupted by an ion located in the pore. Second, the channel enables protons to permeate the capsid through a unidirectional Grotthuss-like mechanism, which is the most likely process through which the capsid senses pH. Finally, assuming that the proton leak promotes a charge imbalance in the interior of the capsid, we model an internal pressure that forces shell cracking using coarse-grained simulations. Although qualitatively, this last step could represent the mechanism of capsid opening that allows RNA release. All of our calculations are in agreement with current experimental data obtained using TrV and describe a cascade of events that could explain the destabilization and disassembly of similar icosahedral viruses.'),
(89000, 2018, 'plos', 'Allostery in the dengue virus NS3 helicase: Insights into the NTPase cycle from molecular simulations', 'Davidson, Russell B|Hendrix, Josie|Geiss, Brian J|McCullagh, Martin', 'Department of Chemistry, Colorado State University, Fort Collins, Colorado, United States of America.|Department of Chemistry, Colorado State University, Fort Collins, Colorado, United States of America.|Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.|Department of Chemistry, Colorado State University, Fort Collins, Colorado, United States of America.', 'United States|United States|United States|United States', 10, 'Adenosine Triphosphate|Allosteric Regulation|Allosteric Site|Amino Acid Motifs|Antiviral Agents|Catalytic Domain|Computational Biology|Dengue Virus|Drug Design|Enzyme Inhibitors|Humans|Hydrolysis|Molecular Dynamics Simulation|Nucleoside-Triphosphatase|RNA Helicases|RNA, Viral|Serine Endopeptidases|Static Electricity|Viral Nonstructural Proteins', 'Journal Article', '10.1371/journal.pcbi.1006103', '29659571', 'The C-terminus domain of non-structural 3 (NS3) protein of the Flaviviridae viruses (e.g. HCV, dengue, West Nile, Zika) is a nucleotide triphosphatase (NTPase) -dependent superfamily 2 (SF2) helicase that unwinds double-stranded RNA while translocating along the nucleic polymer. Due to these functions, NS3 is an important target for antiviral development yet the biophysics of this enzyme are poorly understood. Microsecond-long molecular dynamic simulations of the dengue NS3 helicase domain are reported from which allosteric effects of RNA and NTPase substrates are observed. The presence of a bound single-stranded RNA catalytically enhances the phosphate hydrolysis reaction by affecting the dynamics and positioning of waters within the hydrolysis active site. Coupled with results from the simulations, electronic structure calculations of the reaction are used to quantify this enhancement to be a 150-fold increase, in qualitative agreement with the experimental enhancement factor of 10-100. Additionally, protein-RNA interactions exhibit NTPase substrate-induced allostery, where the presence of a nucleotide (e.g. ATP or ADP) structurally perturbs residues in direct contact with the phosphodiester backbone of the RNA. Residue-residue network analyses highlight pathways of short ranged interactions that connect the two active sites. These analyses identify motif V as a highly connected region of protein structure through which energy released from either active site is hypothesized to move, thereby inducing the observed allosteric effects. These results lay the foundation for the design of novel allosteric inhibitors of NS3.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(89001, 2018, 'plos', 'A computational study of astrocytic glutamate influence on post-synaptic neuronal excitability', 'Flanagan, Bronac|McDaid, Liam|Wade, John|Wong-Lin, KongFatt|Harkin, Jim', 'Intelligent Systems Research Centre, University of Ulster, Magee Campus, Derry~Londonderry, Northern Ireland, United Kingdom.|Intelligent Systems Research Centre, University of Ulster, Magee Campus, Derry~Londonderry, Northern Ireland, United Kingdom.|Intelligent Systems Research Centre, University of Ulster, Magee Campus, Derry~Londonderry, Northern Ireland, United Kingdom.|Intelligent Systems Research Centre, University of Ulster, Magee Campus, Derry~Londonderry, Northern Ireland, United Kingdom.|Intelligent Systems Research Centre, University of Ulster, Magee Campus, Derry~Londonderry, Northern Ireland, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 6, 'Animals|Astrocytes|Calcium Signaling|Computational Biology|Computer Simulation|Excitatory Amino Acid Transporter 2|Excitatory Postsynaptic Potentials|Glutamic Acid|Humans|Models, Neurological|Neural Pathways|Neurons|Synapses|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1006040', '29659572', 'The ability of astrocytes to rapidly clear synaptic glutamate and purposefully release the excitatory transmitter is critical in the functioning of synapses and neuronal circuits. Dysfunctions of these homeostatic functions have been implicated in the pathology of brain disorders such as mesial temporal lobe epilepsy. However, the reasons for these dysfunctions are not clear from experimental data and computational models have been developed to provide further understanding of the implications of glutamate clearance from the extracellular space, as a result of EAAT2 downregulation: although they only partially account for the glutamate clearance process. In this work, we develop an explicit model of the astrocytic glutamate transporters, providing a more complete description of the glutamate chemical potential across the astrocytic membrane and its contribution to glutamate transporter driving force based on thermodynamic principles and experimental data. Analysis of our model demonstrates that increased astrocytic glutamate content due to glutamine synthetase downregulation also results in increased postsynaptic quantal size due to gliotransmission. Moreover, the proposed model demonstrates that increased astrocytic glutamate could prolong the time course of glutamate in the synaptic cleft and enhances astrocyte-induced slow inward currents, causing a disruption to the clarity of synaptic signalling and the occurrence of intervals of higher frequency postsynaptic firing. Overall, our work distilled the necessity of a low astrocytic glutamate concentration for reliable synaptic transmission of information and the possible implications of enhanced glutamate levels as in epilepsy.'),
(89002, 2018, 'plos', 'Whole-body iron transport and metabolism: Mechanistic, multi-scale model to improve treatment of anemia in chronic kidney disease', 'Sarkar, Joydeep|Potdar, Alka A|Saidel, Gerald M', 'Pricewaterhouse Coopers LLP, New York, NY, United States of America.|Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United States of America.|Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United States of America.', 'United States|United States|United States', 2, 'Anemia|Biological Transport, Active|Bone Marrow|Cation Transport Proteins|Computational Biology|Epoetin Alfa|Erythrocytes|Erythropoietin|Hepcidins|Humans|Iron|Iron-Dextran Complex|Liver|Models, Biological|Mononuclear Phagocyte System|Renal Insufficiency, Chronic|Transferrin', 'Journal Article', '10.1371/journal.pcbi.1006060', '29659573', 'Iron plays vital roles in the human body including enzymatic processes, oxygen-transport via hemoglobin and immune response. Iron metabolism is characterized by ~95% recycling and minor replenishment through diet. Anemia of chronic kidney disease (CKD) is characterized by a lack of synthesis of erythropoietin leading to reduced red blood cell (RBC) formation and aberrant iron recycling. Treatment of CKD anemia aims to normalize RBC count and serum hemoglobin. Clinically, the various fluxes of iron transport and accumulation are not measured so that changes during disease (e.g., CKD) and treatment are unknown. Unwanted iron accumulation in patients is known to lead to adverse effects. Current whole-body models lack the mechanistic details of iron transport related to RBC maturation, transferrin (Tf and TfR) dynamics and assume passive iron efflux from macrophages. Hence, they are not predictive of whole-body iron dynamics and cannot be used to design individualized patient treatment. For prediction, we developed a mechanistic, multi-scale computational model of whole-body iron metabolism incorporating four compartments containing major pools of iron and RBC generation process. The model accounts for multiple forms of iron in vivo, mechanisms involved in iron uptake and release and their regulation. Furthermore, the model is interfaced with drug pharmacokinetics to allow simulation of treatment dynamics. We calibrated our model with experimental and clinical data from peer-reviewed literature to reliably simulate CKD anemia and the effects of current treatment involving combination of epoietin-alpha and iron dextran. This in silico whole-body model of iron metabolism predicts that a year of treatment can potentially lead to 90% downregulation of ferroportin (FPN) levels, 15-fold increase in iron stores with only a 20% increase in iron flux from the reticulo-endothelial system (RES). Model simulations quantified unmeasured iron fluxes, previously unknown effects of treatment on FPN-level and iron stores in the RES. This mechanistic whole-body model can be the basis for future studies that incorporate iron metabolism together with related clinical experiments. Such an approach could pave the way for development of effective personalized treatment of CKD anemia.'),
(89003, 2018, 'plos', 'Cell adhesion and fluid flow jointly initiate genotype spatial distribution in biofilms', 'Martínez-García, Ricardo|Nadell, Carey D|Hartmann, Raimo|Drescher, Knut|Bonachela, Juan A', 'Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America.|Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire, United States of America.|Max Planck Institute for Terrestrial Microbiology, Marburg, Germany.|Max Planck Institute for Terrestrial Microbiology, Marburg, Germany.|Marine Population Modeling Group, Department of Mathematics and Statistics, University of Strathclyde, Glasgow, Scotland, United Kingdom.', 'Jersey|United States|Germany|Germany|United Kingdom', 8, 'Bacterial Adhesion|Biofilms|Computational Biology|Genetic Engineering|Genotype|Humans|Hydrodynamics|Models, Biological|Surface Properties|Vibrio cholerae', 'Journal Article', '10.1371/journal.pcbi.1006094', '29659578', 'Biofilms are microbial collectives that occupy a diverse array of surfaces. It is well known that the function and evolution of biofilms are strongly influenced by the spatial arrangement of different strains and species within them, but how spatiotemporal distributions of different genotypes in biofilm populations originate is still underexplored. Here, we study the origins of biofilm genetic structure by combining model development, numerical simulations, and microfluidic experiments using the human pathogen Vibrio cholerae. Using spatial correlation functions to quantify the differences between emergent cell lineage segregation patterns, we find that strong adhesion often, but not always, maximizes the size of clonal cell clusters on flat surfaces. Counterintuitively, our model predicts that, under some conditions, investing in adhesion can reduce rather than increase clonal group size. Our results emphasize that a complex interaction between fluid flow and cell adhesiveness can underlie emergent patterns of biofilm genetic structure. This structure, in turn, has an outsize influence on how biofilm-dwelling populations function and evolve.'),
(89004, 2018, 'plos', 'Using pseudoalignment and base quality to accurately quantify microbial community composition', 'Reppell, Mark|Novembre, John', 'Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.|Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.', 'United States|United States', 2, 'Base Composition|Computational Biology|Computer Simulation|DNA|Databases, Genetic|Humans|Microbial Consortia|Microbiota|Quantitative Trait Loci|RNA, Ribosomal, 16S|Sequence Alignment|Software', 'Journal Article', '10.1371/journal.pcbi.1006096', '29659582', 'Pooled DNA from multiple unknown organisms arises in a variety of contexts, for example microbial samples from ecological or human health research. Determining the composition of pooled samples can be difficult, especially at the scale of modern sequencing data and reference databases. Here we propose a novel method for taxonomic profiling in pooled DNA that combines the speed and low-memory requirements of k-mer based pseudoalignment with a likelihood framework that uses base quality information to better resolve multiply mapped reads. We apply the method to the problem of classifying 16S rRNA reads using a reference database of known organisms, a common challenge in microbiome research. Using simulations, we show the method is accurate across a variety of read lengths, with different length reference sequences, at different sample depths, and when samples contain reads originating from organisms absent from the reference. We also assess performance in real 16S data, where we reanalyze previous genetic association data to show our method discovers a larger number of quantitative trait associations than other widely used methods. We implement our method in the software Karp, for k-mer based analysis of read pools, to provide a novel combination of speed and accuracy that is uniquely suited for enhancing discoveries in microbial studies.'),
(89005, 2018, 'plos', 'A modelling approach for exploring muscle dynamics during cyclic contractions', 'Ross, Stephanie A|Nigam, Nilima|Wakeling, James M', 'Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.|Department of Mathematics, Simon Fraser University, Burnaby, British Columbia, Canada.|Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.', 'Canada|Canada|Canada', 6, 'Animals|Biomechanical Phenomena|Computational Biology|Computer Simulation|Humans|Locomotion|Models, Biological|Muscle Contraction|Muscle, Skeletal', 'Journal Article', '10.1371/journal.pcbi.1006123', '29659583', 'Hill-type muscle models are widely used within the field of biomechanics to predict and understand muscle behaviour, and are often essential where muscle forces cannot be directly measured. However, these models have limited accuracy, particularly during cyclic contractions at the submaximal levels of activation that typically occur during locomotion. To address this issue, recent studies have incorporated effects into Hill-type models that are oftentimes neglected, such as size-dependent, history-dependent, and activation-dependent effects. However, the contribution of these effects on muscle performance has yet to be evaluated under common contractile conditions that reflect the range of activations, strains, and strain rates that occur in vivo. The purpose of this study was to develop a modelling framework to evaluate modifications to Hill-type muscle models when they contract in cyclic loops that are typical of locomotor muscle function. Here we present a modelling framework composed of a damped harmonic oscillator in series with a Hill-type muscle actuator that consists of a contractile element and parallel elastic element. The intrinsic force-length and force-velocity properties are described using Bézier curves where we present a system to relate physiological parameters to the control points for these curves. The muscle-oscillator system can be geometrically scaled while preserving dynamic and kinematic similarity to investigate the muscle size effects while controlling for the dynamics of the harmonic oscillator. The model is driven by time-varying muscle activations that cause the muscle to cyclically contract and drive the dynamics of the harmonic oscillator. Thus, this framework provides a platform to test current and future Hill-type model formulations and explore factors affecting muscle performance in muscles of different sizes under a range of cyclic contractile conditions.'),
(89006, 2018, 'plos', 'On the role of extrinsic noise in microRNA-mediated bimodal gene expression', 'Del Giudice, Marco|Bo, Stefano|Grigolon, Silvia|Bosia, Carla', 'Department of Applied Science and Technology, Politecnico di Torino, Torino, Italy.|Nordita, Royal Institute of Technology and Stockholm University, Stockholm, Sweden.|The Francis Crick Institute, London, United Kingdom.|Department of Applied Science and Technology, Politecnico di Torino, Torino, Italy.', 'Italy|Sweden|United Kingdom|Italy', 8, 'Computational Biology|Computer Simulation|Gene Expression Regulation|Gene Regulatory Networks|Humans|MicroRNAs|Models, Genetic|Models, Statistical|Normal Distribution|Phenotype|Protein Biosynthesis|Protein Stability|RNA, Messenger|Stochastic Processes|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1006063', '29664903', 'Several studies highlighted the relevance of extrinsic noise in shaping cell decision making and differentiation in molecular networks. Bimodal distributions of gene expression levels provide experimental evidence of phenotypic differentiation, where the modes of the distribution often correspond to different physiological states of the system. We theoretically address the presence of bimodal phenotypes in the context of microRNA (miRNA)-mediated regulation. MiRNAs are small noncoding RNA molecules that downregulate the expression of their target mRNAs. The nature of this interaction is titrative and induces a threshold effect: below a given target transcription rate almost no mRNAs are free and available for translation. We investigate the effect of extrinsic noise on the system by introducing a fluctuating miRNA-transcription rate. We find that the presence of extrinsic noise favours the presence of bimodal target distributions which can be observed for a wider range of parameters compared to the case with intrinsic noise only and for lower miRNA-target interaction strength. Our results suggest that combining threshold-inducing interactions with extrinsic noise provides a simple and robust mechanism for obtaining bimodal populations without requiring fine tuning. Furthermore, we characterise the protein distributions dependence on protein half-life.'),
(89007, 2018, 'plos', 'A computational model of shared fine-scale structure in the human connectome', 'Guntupalli, J Swaroop|Feilong, Ma|Haxby, James V', 'Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH, United States of America.|Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH, United States of America.|Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH, United States of America.', 'United States|United States|United States', 22, 'Acoustic Stimulation|Adult|Algorithms|Brain|Computational Biology|Computer Simulation|Connectome|Female|Humans|Magnetic Resonance Imaging|Male|Models, Neurological|Motion Pictures|Photic Stimulation|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1006120', '29664910', 'Variation in cortical connectivity profiles is typically modeled as having a coarse spatial scale parcellated into interconnected brain areas. We created a high-dimensional common model of the human connectome to search for fine-scale structure that is shared across brains. Projecting individual connectivity data into this new common model connectome accounts for substantially more variance in the human connectome than do previous models. This newly discovered shared structure is closely related to fine-scale distinctions in representations of information. These results reveal a shared fine-scale structure that is a major component of the human connectome that coexists with coarse-scale, areal structure. This shared fine-scale structure was not captured in previous models and was, therefore, inaccessible to analysis and study.'),
(89008, 2018, 'plos', 'Propagating annotations of molecular networks using in silico fragmentation', 'da Silva, Ricardo R|Wang, Mingxun|Nothias, Louis-Félix|van der Hooft, Justin J J|Caraballo-Rodríguez, Andrés Mauricio|Fox, Evan|Balunas, Marcy J|Klassen, Jonathan L|Lopes, Norberto Peporine|Dorrestein, Pieter C', 'Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States of America.|Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States of America.|Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States of America.|Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States of America.|Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States of America.|Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, United States of America.|Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States of America.|Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, United States of America.|NPPNS, Department of Physic and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.|Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 45, 'Animals|Ants|Cluster Analysis|Computational Biology|Computer Simulation|Databases, Chemical|Fungi|Metabolic Networks and Pathways|Metabolomics|Models, Biological|Models, Chemical|Molecular Structure|Software|Tandem Mass Spectrometry', 'Journal Article', '10.1371/journal.pcbi.1006089', '29668671', 'The annotation of small molecules is one of the most challenging and important steps in untargeted mass spectrometry analysis, as most of our biological interpretations rely on structural annotations. Molecular networking has emerged as a structured way to organize and mine data from untargeted tandem mass spectrometry (MS/MS) experiments and has been widely applied to propagate annotations. However, propagation is done through manual inspection of MS/MS spectra connected in the spectral networks and is only possible when a reference library spectrum is available. One of the alternative approaches used to annotate an unknown fragmentation mass spectrum is through the use of in silico predictions. One of the challenges of in silico annotation is the uncertainty around the correct structure among the predicted candidate lists. Here we show how molecular networking can be used to improve the accuracy of in silico predictions through propagation of structural annotations, even when there is no match to a MS/MS spectrum in spectral libraries. This is accomplished through creating a network consensus of re-ranked structural candidates using the molecular network topology and structural similarity to improve in silico annotations. The Network Annotation Propagation (NAP) tool is accessible through the GNPS web-platform https://gnps.ucsd.edu/ProteoSAFe/static/gnps-theoretical.jsp.'),
(89009, 2018, 'plos', 'Bayesian reconstruction of transmission within outbreaks using genomic variants', 'De Maio, Nicola|Worby, Colin J|Wilson, Daniel J|Stoesser, Nicole', 'Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America.|Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.|Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.', 'United Kingdom|Jersey|United Kingdom|United Kingdom', 13, 'Bayes Theorem|Communicable Diseases|Computational Biology|Computer Simulation|Disease Outbreaks|Evolution, Molecular|Genetic Variation|Hemorrhagic Fever, Ebola|Host-Pathogen Interactions|Humans|Models, Genetic|Sierra Leone|Software', 'Journal Article', '10.1371/journal.pcbi.1006117', '29668677', 'Pathogen genome sequencing can reveal details of transmission histories and is a powerful tool in the fight against infectious disease. In particular, within-host pathogen genomic variants identified through heterozygous nucleotide base calls are a potential source of information to identify linked cases and infer direction and time of transmission. However, using such data effectively to model disease transmission presents a number of challenges, including differentiating genuine variants from those observed due to sequencing error, as well as the specification of a realistic model for within-host pathogen population dynamics. Here we propose a new Bayesian approach to transmission inference, BadTrIP (BAyesian epiDemiological TRansmission Inference from Polymorphisms), that explicitly models evolution of pathogen populations in an outbreak, transmission (including transmission bottlenecks), and sequencing error. BadTrIP enables the inference of host-to-host transmission from pathogen sequencing data and epidemiological data. By assuming that genomic variants are unlinked, our method does not require the computationally intensive and unreliable reconstruction of individual haplotypes. Using simulations we show that BadTrIP is robust in most scenarios and can accurately infer transmission events by efficiently combining information from genetic and epidemiological sources, thanks to its realistic model of pathogen evolution and the inclusion of epidemiological data, BadTrIP is also more accurate than existing approaches. BadTrIP is distributed as an open source package (https://bitbucket.org/nicofmay/badtrip) for the phylogenetic software BEAST2. We apply our method to reconstruct transmission history at the early stages of the 2014 Ebola outbreak, showcasing the power of within-host genomic variants to reconstruct transmission events.'),
(89010, 2018, 'plos', 'Biogeography and environmental conditions shape bacteriophage-bacteria networks across the human microbiome', 'Hannigan, Geoffrey D|Duhaime, Melissa B|Koutra, Danai|Schloss, Patrick D', 'Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Computer Science, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America.', 'United States|United States|United States|United States', 15, 'Bacteria|Bacterial Physiological Phenomena|Bacteriophages|Computational Biology|Diet|Humans|Metagenomics|Microbial Consortia|Microbiota|Models, Biological|Phylogeography|Skin', 'Journal Article', '10.1371/journal.pcbi.1006099', '29668682', 'Viruses and bacteria are critical components of the human microbiome and play important roles in health and disease. Most previous work has relied on studying bacteria and viruses independently, thereby reducing them to two separate communities. Such approaches are unable to capture how these microbial communities interact, such as through processes that maintain community robustness or allow phage-host populations to co-evolve. We implemented a network-based analytical approach to describe phage-bacteria network diversity throughout the human body. We built these community networks using a machine learning algorithm to predict which phages could infect which bacteria in a given microbiome. Our algorithm was applied to paired viral and bacterial metagenomic sequence sets from three previously published human cohorts. We organized the predicted interactions into networks that allowed us to evaluate phage-bacteria connectedness across the human body. We observed evidence that gut and skin network structures were person-specific and not conserved among cohabitating family members. High-fat diets appeared to be associated with less connected networks. Network structure differed between skin sites, with those exposed to the external environment being less connected and likely more susceptible to network degradation by microbial extinction events. This study quantified and contrasted the diversity of virome-microbiome networks across the human body and illustrated how environmental factors may influence phage-bacteria interactive dynamics. This work provides a baseline for future studies to better understand system perturbations, such as disease states, through ecological networks.'),
(89011, 2018, 'plos', 'Decision making improves sperm chemotaxis in the presence of noise', 'Kromer, Justus A|Märcker, Steffen|Lange, Steffen|Baier, Christel|Friedrich, Benjamin M', 'cfaed, TU Dresden, Dresden, Sachsen, Germany.|Faculty of Computer Science, TU Dresden, Dresden, Sachsen, Germany.|cfaed, TU Dresden, Dresden, Sachsen, Germany.|Faculty of Computer Science, TU Dresden, Dresden, Sachsen, Germany.|cfaed, TU Dresden, Dresden, Sachsen, Germany.', 'Germany|Germany|Germany|Germany|Germany', 7, 'Animals|Arbacia|Chemotactic Factors|Chemotaxis|Computational Biology|Decision Making|Male|Markov Chains|Models, Biological|Signal Transduction|Sperm Motility|Spermatozoa|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1006109', '29672515', 'To navigate their surroundings, cells rely on sensory input that is corrupted by noise. In cells performing chemotaxis, such noise arises from the stochastic binding of signalling molecules at low chemoattractant concentrations. We reveal a fundamental relationship between the speed of chemotactic steering and the strength of directional fluctuations that result from the amplification of noise in a chemical input signal. This relation implies a trade-off between steering that is slow and reliable, and steering that is fast but less reliable. We show that dynamic switching between these two modes of steering can substantially increase the probability to find a target, such as an egg to be found by sperm cells. This decision making confers no advantage in the absence of noise, but is beneficial when chemical signals are detectable, yet characterized by low signal-to-noise ratios. The latter applies at intermediate distances from a target, where signalling molecules are diluted, thus defining a noise zone that cells have to cross. Our results explain decision making observed in recent experiments on sea urchin sperm chemotaxis. More generally, our theory demonstrates how decision making enables chemotactic agents to cope with high levels of noise in gradient sensing by dynamically adjusting the persistence length of a biased random walk.'),
(89012, 2018, 'plos', 'Optimal dynamic control approach in a multi-objective therapeutic scenario: Application to drug delivery in the treatment of prostate cancer', 'Irurzun-Arana, Itziar|Janda, Alvaro|Ardanza-Trevijano, Sergio|Trocóniz, Iñaki F', 'Pharmacometrics & Systems Pharmacology group, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Navarra, Spain.|Department of Physics and Applied Mathematics, University of Navarra, Pamplona, Navarra, Spain.|Department of Physics and Applied Mathematics, University of Navarra, Pamplona, Navarra, Spain.|Pharmacometrics & Systems Pharmacology group, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Navarra, Spain.', 'Spain|Spain|Spain|Spain', 3, 'Antineoplastic Agents|Antineoplastic Agents, Hormonal|Computational Biology|Computer Simulation|Drug Delivery Systems|Humans|Male|Models, Biological|Neoplasms, Hormone-Dependent|Nonlinear Dynamics|Orchiectomy|Prostatic Neoplasms|Testosterone|Triptorelin Pamoate', 'Journal Article', '10.1371/journal.pcbi.1006087', '29672523', 'Numerous problems encountered in computational biology can be formulated as optimization problems. In this context, optimization of drug release characteristics or dosing schedules for anticancer agents has become a prominent area not only for the development of new drugs, but also for established drugs. However, in complex systems, optimization of drug exposure is not a trivial task and cannot be efficiently addressed through trial-error simulation exercises. Finding a solution to those problems is a challenging task which requires more advanced strategies like optimal control theory. In this work, we perform an optimal control analysis on a previously developed computational model for the testosterone effects of triptorelin in prostate cancer patients with the goal of finding optimal drug-release characteristics. We demonstrate how numerical control optimization of non-linear models can be used to find better therapeutic approaches in order to improve the final outcome of the patients.'),
(89013, 2018, 'plos', 'EmbryoMiner: A new framework for interactive knowledge discovery in large-scale cell tracking data of developing embryos', 'Schott, Benjamin|Traub, Manuel|Schlagenhauf, Cornelia|Takamiya, Masanari|Antritter, Thomas|Bartschat, Andreas|Löffler, Katharina|Blessing, Denis|Otte, Jens C|Kobitski, Andrei Y|Nienhaus, G Ulrich|Strähle, Uwe|Mikut, Ralf|Stegmaier, Johannes', 'Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology, Karlsruhe, Germany.|Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology, Karlsruhe, Germany.|Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology, Karlsruhe, Germany.|Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany.|Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology, Karlsruhe, Germany.|Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology, Karlsruhe, Germany.|Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology, Karlsruhe, Germany.|Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology, Karlsruhe, Germany.|Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany.|Institute of Applied Physics, Karlsruhe Institute of Technology, Karlsruhe, Germany.|Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany.|Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany.|Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology, Karlsruhe, Germany.|Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology, Karlsruhe, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germ', 7, 'Animals|Animals, Genetically Modified|Cell Movement|Cell Tracking|Computational Biology|Embryonic Development|Embryonic Stem Cells|Gastrulation|Germ Layers|Imaging, Three-Dimensional|Microscopy, Fluorescence|Olfactory Mucosa|Software|Zebrafish', 'Journal Article', '10.1371/journal.pcbi.1006128', '29672531', 'State-of-the-art light-sheet and confocal microscopes allow recording of entire embryos in 3D and over time (3D+t) for many hours. Fluorescently labeled structures can be segmented and tracked automatically in these terabyte-scale 3D+t images, resulting in thousands of cell migration trajectories that provide detailed insights to large-scale tissue reorganization at the cellular level. Here we present EmbryoMiner, a new interactive open-source framework suitable for in-depth analyses and comparisons of entire embryos, including an extensive set of trajectory features. Starting at the whole-embryo level, the framework can be used to iteratively focus on a region of interest within the embryo, to investigate and test specific trajectory-based hypotheses and to extract quantitative features from the isolated trajectories. Thus, the new framework provides a valuable new way to quantitatively compare corresponding anatomical regions in different embryos that were manually selected based on biological prior knowledge. As a proof of concept, we analyzed 3D+t light-sheet microscopy images of zebrafish embryos, showcasing potential user applications that can be performed using the new framework.'),
(89014, 2018, 'plos', 'Compositional clustering in task structure learning', 'Franklin, Nicholas T|Frank, Michael J', 'Department of Psychology, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Cognitive, Linguistic & Psychological Sciences, Brown University, Providence, Rhode Island, United States of America.', 'United States|United States', 10, 'Bayes Theorem|Cluster Analysis|Computational Biology|Computer Simulation|Humans|Information Theory|Learning|Models, Psychological|Reward|Statistics, Nonparametric|Stochastic Processes|Task Performance and Analysis', 'Journal Article', '10.1371/journal.pcbi.1006116', '29672581', 'Humans are remarkably adept at generalizing knowledge between experiences in a way that can be difficult for computers. Often, this entails generalizing constituent pieces of experiences that do not fully overlap, but nonetheless share useful similarities with, previously acquired knowledge. However, it is often unclear how knowledge gained in one context should generalize to another. Previous computational models and data suggest that rather than learning about each individual context, humans build latent abstract structures and learn to link these structures to arbitrary contexts, facilitating generalization. In these models, task structures that are more popular across contexts are more likely to be revisited in new contexts. However, these models can only re-use policies as a whole and are unable to transfer knowledge about the transition structure of the environment even if only the goal has changed (or vice-versa). This contrasts with ecological settings, where some aspects of task structure, such as the transition function, will be shared between context separately from other aspects, such as the reward function. Here, we develop a novel non-parametric Bayesian agent that forms independent latent clusters for transition and reward functions, affording separable transfer of their constituent parts across contexts. We show that the relative performance of this agent compared to an agent that jointly clusters reward and transition functions depends environmental task statistics: the mutual information between transition and reward functions and the stochasticity of the observations. We formalize our analysis through an information theoretic account of the priors, and propose a meta learning agent that dynamically arbitrates between strategies across task domains to optimize a statistical tradeoff.'),
(89015, 2018, 'plos', 'Exploiting glycan topography for computational design of Env glycoprotein antigenicity', 'Yu, Wen-Han|Zhao, Peng|Draghi, Monia|Arevalo, Claudia|Karsten, Christina B|Suscovich, Todd J|Gunn, Bronwyn|Streeck, Hendrik|Brass, Abraham L|Tiemeyer, Michael|Seaman, Michael|Mascola, John R|Wells, Lance|Lauffenburger, Douglas A|Alter, Galit', 'Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States of America.|Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, The University of Georgia, Athens, Georgia, United States of America.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States of America.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States of America.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States of America.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States of America.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States of America.|Institute for HIV Research, University Hospital Essen, University Duisburg-Essen, Essen, Germany.|Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, United States of America.|Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, The University of Georgia, Athens, Georgia, United States of America.|Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.|Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.|Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, The University of Georgia, Athens, Georgia, United States of America.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States of America.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States of America.', 'United States|Georgia|United States|United States|United States|United States|United States|Germany|', 10, 'Algorithms|Amino Acid Sequence|Antibodies, Neutralizing|Bayes Theorem|Binding Sites|Computational Biology|Epitopes|Glycosylation|HIV|HIV Antibodies|HIV Antigens|HIV Envelope Protein gp120|Humans|Machine Learning|Models, Molecular|Polysaccharides|Protein Engineering|Recombinant Proteins|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1006093', '29677181', 'Mounting evidence suggests that glycans, rather than merely serving as a shield, contribute critically to antigenicity of the HIV envelope (Env) glycoprotein, representing critical antigenic determinants for many broadly neutralizing antibodies (bNAbs). While many studies have focused on defining the role of individual glycans or groups of proximal glycans in bNAb binding, little is known about the effects of changes in the overall glycan landscape in modulating antibody access and Env antigenicity. Here we developed a systems glycobiology approach to reverse engineer the complexity of HIV glycan heterogeneity to guide antigenicity-based de novo glycoprotein design. bNAb binding was assessed against a panel of 94 recombinant gp120 monomers exhibiting defined glycan site occupancies. Using a Bayesian machine learning algorithm, bNAb-specific glycan footprints were identified and used to design antigens that selectively alter bNAb antigenicity as a proof-of concept. Our approach provides a new design strategy to predictively modulate antigenicity via the alteration of glycan topography, thereby focusing the humoral immune response on sites of viral vulnerability for HIV.'),
(89016, 2018, 'plos', 'Divergent genome evolution caused by regional variation in DNA gain and loss between human and mouse', 'Buckley, Reuben M|Kortschak, R Daniel|Adelson, David L', 'Department of Genetics and Evolution, The University of Adelaide, North Tce, Adelaide, Australia.|Department of Genetics and Evolution, The University of Adelaide, North Tce, Adelaide, Australia.|Department of Genetics and Evolution, The University of Adelaide, North Tce, Adelaide, Australia.', 'Australia|Australia|Australia', 1, 'Animals|Computational Biology|DNA|DNA Transposable Elements|DNA, Intergenic|Evolution, Molecular|Gene Ontology|Genome Size|Genome, Human|Genomics|Humans|Mice|Sequence Deletion|Software|Species Specificity|Time Factors', 'Comparative Study', '10.1371/journal.pcbi.1006091', '29677183', 'The forces driving the accumulation and removal of non-coding DNA and ultimately the evolution of genome size in complex organisms are intimately linked to genome structure and organisation. Our analysis provides a novel method for capturing the regional variation of lineage-specific DNA gain and loss events in their respective genomic contexts. To further understand this connection we used comparative genomics to identify genome-wide individual DNA gain and loss events in the human and mouse genomes. Focusing on the distribution of DNA gains and losses, relationships to important structural features and potential impact on biological processes, we found that in autosomes, DNA gains and losses both followed separate lineage-specific accumulation patterns. However, in both species chromosome X was particularly enriched for DNA gain, consistent with its high L1 retrotransposon content required for X inactivation. We found that DNA loss was associated with gene-rich open chromatin regions and DNA gain events with gene-poor closed chromatin regions. Additionally, we found that DNA loss events tended to be smaller than DNA gain events suggesting that they were able to accumulate in gene-rich open chromatin regions due to their reduced capacity to interrupt gene regulatory architecture. GO term enrichment showed that mouse loss hotspots were strongly enriched for terms related to developmental processes. However, these genes were also located in regions with a high density of conserved elements, suggesting that despite high levels of DNA loss, gene regulatory architecture remained conserved. This is consistent with a model in which DNA gain and loss results in turnover or churning in regulatory element dense regions of open chromatin, where interruption of regulatory elements is selected against.'),
(89017, 2018, 'plos', 'Identifying robust hysteresis in networks', 'Gedeon, Tomáš|Cummins, Bree|Harker, Shaun|Mischaikow, Konstantin', 'Department of Mathematical Sciences, Montana State University, Bozeman, Montana, United States of America.|Department of Mathematical Sciences, Montana State University, Bozeman, Montana, United States of America.|Department of Mathematics, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.|Department of Mathematics, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.', 'United States|United States|Jersey|Jersey', 2, 'Cell Cycle Checkpoints|Computational Biology|Computer Simulation|Gene Regulatory Networks|Humans|Models, Genetic|Nonlinear Dynamics|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1006121', '29684007', 'We present a new modeling and computational tool that computes rigorous summaries of network dynamics over large sets of parameter values. These summaries, organized in a database, can be searched for observed dynamics, e.g., bistability and hysteresis, to discover parameter regimes over which they are supported. We illustrate our approach on several networks underlying the restriction point of the cell cycle in humans and yeast. We rank networks by how robustly they support hysteresis, which is the observed phenotype. We find that the best 6-node human network and the yeast network share similar topology and robustness of hysteresis, in spite of having no homology between the corresponding nodes of the network. Our approach provides a new tool linking network structure and dynamics.'),
(89018, 2018, 'plos', 'DIVERSITY in binding, regulation, and evolution revealed from high-throughput ChIP', 'Mitra, Sneha|Biswas, Anushua|Narlikar, Leelavati', 'Department of Chemical Engineering, CSIR-National Chemical Laboratory, Pune, India.|Department of Chemical Engineering, CSIR-National Chemical Laboratory, Pune, India.|Department of Chemical Engineering, CSIR-National Chemical Laboratory, Pune, India.', 'India|India|India', 1, 'Algorithms|Animals|Bayes Theorem|Binding Sites|Chromatin|Chromatin Immunoprecipitation|Computational Biology|DNA|DNA-Binding Proteins|Evolution, Molecular|High-Throughput Nucleotide Sequencing|Humans|Neurons|Nucleotide Motifs|Protein Binding|Sequence Analysis, DNA|Software|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1006090', '29684008', 'Genome-wide in vivo protein-DNA interactions are routinely mapped using high-throughput chromatin immunoprecipitation (ChIP). ChIP-reported regions are typically investigated for enriched sequence-motifs, which are likely to model the DNA-binding specificity of the profiled protein and/or of co-occurring proteins. However, simple enrichment analyses can miss insights into the binding-activity of the protein. Note that ChIP reports regions making direct contact with the protein as well as those binding through intermediaries. For example, consider a ChIP experiment targeting protein X, which binds DNA at its cognate sites, but simultaneously interacts with four other proteins. Each of these proteins also binds to its own specific cognate sites along distant parts of the genome, a scenario consistent with the current view of transcriptional hubs and chromatin loops. Since ChIP will pull down all X-associated regions, the final reported data will be a union of five distinct sets of regions, each containing binding sites of one of the five proteins, respectively. Characterizing all five different motifs and the corresponding sets is important to interpret the ChIP experiment and ultimately, the role of X in regulation. We present diversity which attempts exactly this: it partitions the data so that each partition can be characterized with its own de novo motif. Diversity uses a Bayesian approach to identify the optimal number of motifs and the associated partitions, which together explain the entire dataset. This is in contrast to standard motif finders, which report motifs individually enriched in the data, but do not necessarily explain all reported regions. We show that the different motifs and associated regions identified by diversity give insights into the various complexes that may be forming along the chromatin, something that has so far not been attempted from ChIP data. Webserver at http://diversity.ncl.res.in/, standalone (Mac OS X/Linux) from https://github.com/NarlikarLab/DIVERSITY/releases/tag/v1.0.0.'),
(89019, 2018, 'plos', 'Switchable slow cellular conductances determine robustness and tunability of network states', 'Drion, Guillaume|Dethier, Julie|Franci, Alessio|Sepulchre, Rodolphe', 'Department of Electrical Engineering and Computer Science, University of Liege, Liege, Belgium.|Department of Electrical Engineering and Computer Science, University of Liege, Liege, Belgium.|National Autonomous University of Mexico, Science Faculty, Department of Mathematics, Coyoacán, D.F., México.|Department of Engineering, University of Cambridge, Cambridge, United Kingdom.', 'Belgium|Belgium|Mexico|United Kingdom', 3, 'Action Potentials|Animals|Brain|Calcium Channels, T-Type|Computational Biology|Computer Simulation|Electrophysiological Phenomena|Humans|Kinetics|Models, Neurological|Nerve Net|Neural Networks (Computer)|Neuronal Plasticity|Neurons', 'Journal Article', '10.1371/journal.pcbi.1006125', '29684009', 'Neuronal information processing is regulated by fast and localized fluctuations of brain states. Brain states reliably switch between distinct spatiotemporal signatures at a network scale even though they are composed of heterogeneous and variable rhythms at a cellular scale. We investigated the mechanisms of this network control in a conductance-based population model that reliably switches between active and oscillatory mean-fields. Robust control of the mean-field properties relies critically on a switchable negative intrinsic conductance at the cellular level. This conductance endows circuits with a shared cellular positive feedback that can switch population rhythms on and off at a cellular resolution. The switch is largely independent from other intrinsic neuronal properties, network size and synaptic connectivity. It is therefore compatible with the temporal variability and spatial heterogeneity induced by slower regulatory functions such as neuromodulation, synaptic plasticity and homeostasis. Strikingly, the required cellular mechanism is available in all cell types that possess T-type calcium channels but unavailable in computational models that neglect the slow kinetics of their activation.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(89020, 2018, 'plos', 'A machine learning based framework to identify and classify long terminal repeat retrotransposons', 'Schietgat, Leander|Vens, Celine|Cerri, Ricardo|Fischer, Carlos N|Costa, Eduardo|Ramon, Jan|Carareto, Claudia M A|Blockeel, Hendrik', 'Department of Computer Science, KU Leuven, Leuven, Belgium.|Department of Computer Science, KU Leuven, Leuven, Belgium.|Department of Computer Science, UFSCar Federal University of São Carlos, São Carlos, São Paulo, Brazil.|Department of Statistics, Applied Mathematics, and Computer Science, UNESP São Paulo State University, Rio Claro, São Paulo, Brazil.|Department of Computer Science, KU Leuven, Leuven, Belgium.|Department of Computer Science, KU Leuven, Leuven, Belgium.|Department of Biology, UNESP São Paulo State University, São José do Rio Preto, São Paulo, Brazil.|Department of Computer Science, KU Leuven, Leuven, Belgium.', 'Belgium|Belgium|Brazil|Brazil|Belgium|Belgium|Brazil|Belgium', 6, 'Animals|Arabidopsis|Arabidopsis Proteins|Computational Biology|Conserved Sequence|DNA, Plant|Decision Trees|Drosophila Proteins|Drosophila melanogaster|Evolution, Molecular|Genome, Insect|Genome, Plant|Machine Learning|Retroelements|Software|Terminal Repeat Sequences', 'Journal Article', '10.1371/journal.pcbi.1006097', '29684010', 'Transposable elements (TEs) are repetitive nucleotide sequences that make up a large portion of eukaryotic genomes. They can move and duplicate within a genome, increasing genome size and contributing to genetic diversity within and across species. Accurate identification and classification of TEs present in a genome is an important step towards understanding their effects on genes and their role in genome evolution. We introduce TE-Learner, a framework based on machine learning that automatically identifies TEs in a given genome and assigns a classification to them. We present an implementation of our framework towards LTR retrotransposons, a particular type of TEs characterized by having long terminal repeats (LTRs) at their boundaries. We evaluate the predictive performance of our framework on the well-annotated genomes of Drosophila melanogaster and Arabidopsis thaliana and we compare our results for three LTR retrotransposon superfamilies with the results of three widely used methods for TE identification or classification: RepeatMasker, Censor and LtrDigest. In contrast to these methods, TE-Learner is the first to incorporate machine learning techniques, outperforming these methods in terms of predictive performance, while able to learn models and make predictions efficiently. Moreover, we show that our method was able to identify TEs that none of the above method could find, and we investigated TE-Learners predictions which did not correspond to an official annotation. It turns out that many of these predictions are in fact strongly homologous to a known TE.'),
(89021, 2018, 'plos', 'Computational mechanisms underlying cortical responses to the affordance properties of visual scenes', 'Bonner, Michael F|Epstein, Russell A', 'Department of Psychology, University of Pennsylvania, Philadelphia, PA, United States of America.|Department of Psychology, University of Pennsylvania, Philadelphia, PA, United States of America.', 'United States|United States', 23, 'Algorithms|Artificial Intelligence|Brain Mapping|Computational Biology|Humans|Magnetic Resonance Imaging|Models, Neurological|Neural Networks (Computer)|Occipital Lobe|Photic Stimulation|Spatial Navigation|Visual Cortex|Visual Fields|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1006111', '29684011', 'Biologically inspired deep convolutional neural networks (CNNs), trained for computer vision tasks, have been found to predict cortical responses with remarkable accuracy. However, the internal operations of these models remain poorly understood, and the factors that account for their success are unknown. Here we develop a set of techniques for using CNNs to gain insights into the computational mechanisms underlying cortical responses. We focused on responses in the occipital place area (OPA), a scene-selective region of dorsal occipitoparietal cortex. In a previous study, we showed that fMRI activation patterns in the OPA contain information about the navigational affordances of scenes, that is, information about where one can and cannot move within the immediate environment. We hypothesized that this affordance information could be extracted using a set of purely feedforward computations. To test this idea, we examined a deep CNN with a feedforward architecture that had been previously trained for scene classification. We found that responses in the CNN to scene images were highly predictive of fMRI responses in the OPA. Moreover the CNN accounted for the portion of OPA variance relating to the navigational affordances of scenes. The CNN could thus serve as an image-computable candidate model of affordance-related responses in the OPA. We then ran a series of in silico experiments on this model to gain insights into its internal operations. These analyses showed that the computation of affordance-related features relied heavily on visual information at high-spatial frequencies and cardinal orientations, both of which have previously been identified as low-level stimulus preferences of scene-selective visual cortex. These computations also exhibited a strong preference for information in the lower visual field, which is consistent with known retinotopic biases in the OPA. Visualizations of feature selectivity within the CNN suggested that affordance-based responses encoded features that define the layout of the spatial environment, such as boundary-defining junctions and large extended surfaces. Together, these results map the sensory functions of the OPA onto a fully quantitative model that provides insights into its visual computations. More broadly, they advance integrative techniques for understanding visual cortex across multiple level of analysis: from the identification of cortical sensory functions to the modeling of their underlying algorithms.'),
(89022, 2018, 'plos', 'Correcting for batch effects in case-control microbiome studies', 'Gibbons, Sean M|Duvallet, Claire|Alm, Eric J', 'Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States of America.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States of America.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States of America.', 'United States|United States|United States', 20, 'Case-Control Studies|Colorectal Neoplasms|Computational Biology|Computer Simulation|Data Interpretation, Statistical|Databases, Nucleic Acid|High-Throughput Nucleotide Sequencing|Humans|Meta-Analysis as Topic|Microbiota|Oligonucleotide Array Sequence Analysis|Statistics, Nonparametric', 'Comparative Study', '10.1371/journal.pcbi.1006102', '29684016', 'High-throughput data generation platforms, like mass-spectrometry, microarrays, and second-generation sequencing are susceptible to batch effects due to run-to-run variation in reagents, equipment, protocols, or personnel. Currently, batch correction methods are not commonly applied to microbiome sequencing datasets. In this paper, we compare different batch-correction methods applied to microbiome case-control studies. We introduce a model-free normalization procedure where features (i.e. bacterial taxa) in case samples are converted to percentiles of the equivalent features in control samples within a study prior to pooling data across studies. We look at how this percentile-normalization method compares to traditional meta-analysis methods for combining independent p-values and to limma and ComBat, widely used batch-correction models developed for RNA microarray data. Overall, we show that percentile-normalization is a simple, non-parametric approach for correcting batch effects and improving sensitivity in case-control meta-analyses.'),
(89023, 2018, 'plos', 'Black-boxing and cause-effect power', 'Marshall, William|Albantakis, Larissa|Tononi, Giulio', 'Department of Psychiatry, Center for Sleep and Consciousness, University of Wisconsin, Madison, WI, United States of America.|Department of Psychiatry, Center for Sleep and Consciousness, University of Wisconsin, Madison, WI, United States of America.|Department of Psychiatry, Center for Sleep and Consciousness, University of Wisconsin, Madison, WI, United States of America.', 'United States|United States|United States', 9, 'Cell Cycle|Computational Biology|Computer Simulation|Models, Biological|Schizosaccharomyces|Systems Biology|Systems Theory', 'Journal Article', '10.1371/journal.pcbi.1006114', '29684020', 'Reductionism assumes that causation in the physical world occurs at the micro level, excluding the emergence of macro-level causation. We challenge this reductionist assumption by employing a principled, well-defined measure of intrinsic cause-effect power-integrated information (xcexa6), and showing that, according to this measure, it is possible for a macro level to beat the micro level. Simple systems were evaluated for xcexa6 across different spatial and temporal scales by systematically considering all possible black boxes. These are macro elements that consist of one or more micro elements over one or more micro updates. Cause-effect power was evaluated based on the inputs and outputs of the black boxes, ignoring the internal micro elements that support their input-output function. We show how black-box elements can have more common inputs and outputs than the corresponding micro elements, revealing the emergence of high-order mechanisms and joint constraints that are not apparent at the micro level. As a consequence, a macro, black-box system can have higher xcexa6 than its micro constituents by having more mechanisms (higher composition) that are more interconnected (higher integration). We also show that, for a given micro system, one can identify local maxima of xcexa6 across several spatiotemporal scales. The framework is demonstrated on a simple biological system, the Boolean network model of the fission-yeast cell-cycle, for which we identify stable local maxima during the course of its simulated biological function. These local maxima correspond to macro levels of organization at which emergent cause-effect properties of physical systems come into focus, and provide a natural vantage point for scientific inquiries.'),
(89024, 2018, 'plos', 'Rational metareasoning and the plasticity of cognitive control', 'Lieder, Falk|Shenhav, Amitai|Musslick, Sebastian|Griffiths, Thomas L', 'Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California, United States of America.|Brown Institute for Brain Science, Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, Rhode Island, United States of America.|Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey, United States of America.|Institute for Cognitive and Brain Sciences, Department of Psychology, University of California, Berkeley, Berkeley, California, United States of America.', 'United States|United States|Jersey|United States', 0, 'Adaptation, Physiological|Adaptation, Psychological|Association Learning|Attention|Brain|Cognition|Computational Biology|Computer Simulation|Decision Making|Humans|Learning|Models, Neurological|Models, Psychological|Neural Pathways|Neuronal Plasticity|Reward', 'Journal Article', '10.1371/journal.pcbi.1006043', '29694347', 'The human brain has the impressive capacity to adapt how it processes information to high-level goals. While it is known that these cognitive control skills are malleable and can be improved through training, the underlying plasticity mechanisms are not well understood. Here, we develop and evaluate a model of how people learn when to exert cognitive control, which controlled process to use, and how much effort to exert. We derive this model from a general theory according to which the function of cognitive control is to select and configure neural pathways so as to make optimal use of finite time and limited computational resources. The central idea of our Learned Value of Control model is that people use reinforcement learning to predict the value of candidate control signals of different types and intensities based on stimulus features. This model correctly predicts the learning and transfer effects underlying the adaptive control-demanding behavior observed in an experiment on visual attention and four experiments on interference control in Stroop and Flanker paradigms. Moreover, our model explained these findings significantly better than an associative learning model and a Win-Stay Lose-Shift model. Our findings elucidate how learning and experience might shape peoples ability and propensity to adaptively control their minds and behavior. We conclude by predicting under which circumstances these learning mechanisms might lead to self-control failure.'),
(89025, 2018, 'plos', 'Effects of spatiotemporal HSV-2 lesion dynamics and antiviral treatment on the risk of HIV-1 acquisition', 'Byrne, Catherine M|Gantt, Soren|Coombs, Daniel', 'Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.|British Columbia Childrens Hospital, Vancouver, British Columbia, Canada.|Institute of Applied Mathematics, University of British Columbia, Vancouver, British Columbia, Canada.', 'Canada|Canada|Canada', 3, 'Antiviral Agents|CD4-Positive T-Lymphocytes|Computational Biology|Computer Simulation|Female|Genitalia, Female|HIV Infections|HIV-1|Herpes Genitalis|Herpesvirus 2, Human|Humans|Immunity, Mucosal|Models, Biological|Pyridines|Risk Factors|Sexual Behavior|Stochastic Processes|Thiazoles', 'Journal Article', '10.1371/journal.pcbi.1006129', '29698393', 'Patients with Herpes Simplex Virus-2 (HSV-2) infection face a significantly higher risk of contracting HIV-1. This is thought to be due to herpetic lesions serving as entry points for HIV-1 and tissue-resident CD4+ T cell counts increasing during HSV-2 lesional events. We have created a stochastic and spatial mathematical model describing the dynamics of HSV-2 infection and immune response in the genital mucosa. Using our model, we first study the dynamics of a developing HSV-2 lesion. We then use our model to quantify the risk of infection with HIV-1 following sexual exposure in HSV-2 positive women. Untreated, we find that HSV-2 infected women are up to 8.6 times more likely to acquire HIV-1 than healthy patients. However, when including the effects of the HSV-2 antiviral drug, pritelivir, the risk of HIV-1 infection is predicted to decrease by up to 35%, depending on drug dosage. We estimate the relative importance of decreased tissue damage versus decreased CD4+ cell presence in determining the effectiveness of pritelivir in reducing HIV-1 infection. Our results suggest that clinical trials should be performed to evaluate the effectiveness of pritelivir or similar agents in preventing HIV-1 infection in HSV-2 positive women.'),
(89026, 2018, 'plos', 'Organization of the core respiratory network: Insights from optogenetic and modeling studies', 'Ausborn, Jessica|Koizumi, Hidehiko|Barnett, William H|John, Tibin T|Zhang, Ruli|Molkov, Yaroslav I|Smith, Jeffrey C|Rybak, Ilya A', 'Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, United States of America.|Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States of America.|Department of Mathematics and Statistics, Georgia State University, Atlanta, United States of America.|Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States of America.|Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States of America.|Department of Mathematics and Statistics, Georgia State University, Atlanta, United States of America.|Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States of America.|Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, United States of America.', 'United States|United States|Georgia|United States|United States|Georgia|United States|United States', 0, 'Animals|Central Pattern Generators|Computational Biology|Computer Simulation|Connectome|Electrophysiological Phenomena|Mice|Mice, Transgenic|Models, Neurological|Optogenetics|Photic Stimulation|Respiratory Center|Respiratory Physiological Phenomena|Vesicular Inhibitory Amino Acid Transport Proteins', 'Journal Article', '10.1371/journal.pcbi.1006148', '29698394', 'The circuit organization within the mammalian brainstem respiratory network, specifically within and between the pre-Bxc3xb6tzinger (pre-Bxc3xb6tC) and Bxc3xb6tzinger (Bxc3xb6tC) complexes, and the roles of these circuits in respiratory pattern generation are continuously debated. We address these issues with a combination of optogenetic experiments and modeling studies. We used transgenic mice expressing channelrhodopsin-2 under the VGAT-promoter to investigate perturbations of respiratory circuit activity by site-specific photostimulation of inhibitory neurons within the pre-Bxc3xb6tC or Bxc3xb6tC. The stimulation effects were dependent on the intensity and phase of the photostimulation. Specifically: (1) Low intensity (xe2x89xa4 1.0 mW) pulses delivered to the pre-Bxc3xb6tC during inspiration did not terminate activity, whereas stronger stimulations (xe2x89xa5 2.0 mW) terminated inspiration. (2) When the pre-Bxc3xb6tC stimulation ended in or was applied during expiration, rebound activation of inspiration occurred after a fixed latency. (3) Relatively weak sustained stimulation (20 Hz, 0.5-2.0 mW) of pre-Bxc3xb6tC inhibitory neurons increased respiratory frequency, while a further increase of stimulus intensity (> 3.0 mW) reduced frequency and finally (xe2x89xa5 5.0 mW) terminated respiratory oscillations. (4) Single pulses (0.2-5.0 s) applied to the Bxc3xb6tC inhibited rhythmic activity for the duration of the stimulation. (5) Sustained stimulation (20 Hz, 0.5-3.0 mW) of the Bxc3xb6tC reduced respiratory frequency and finally led to apnea. We have revised our computational model of pre-Bxc3xb6tC and Bxc3xb6tC microcircuits by incorporating an additional population of post-inspiratory inhibitory neurons in the pre-Bxc3xb6tC that interacts with other neurons in the network. This model was able to reproduce the above experimental findings as well as previously published results of optogenetic activation of pre-Bxc3xb6tC or Bxc3xb6tC neurons obtained by other laboratories. The proposed organization of pre-Bxc3xb6tC and Bxc3xb6tC circuits leads to testable predictions about their specific roles in respiratory pattern generation and provides important insights into key circuit interactions operating within brainstem respiratory networks.'),
(89027, 2018, 'plos', 'Personalizing physical exercise in a computational model of fuel homeostasis', 'Palumbo, Maria Concetta|Morettini, Micaela|Tieri, Paolo|Diele, Fasma|Sacchetti, Massimo|Castiglione, Filippo', 'Institute for Applied Computing (IAC) Mauro Picone, National Research Council of Italy, Rome, Italy.|Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy.|Institute for Applied Computing (IAC) Mauro Picone, National Research Council of Italy, Rome, Italy.|Institute for Applied Computing (IAC) Mauro Picone, National Research Council of Italy, Rome, Italy.|Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Rome, Italy.|Institute for Applied Computing (IAC) Mauro Picone, National Research Council of Italy, Rome, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy', 4, 'Adult|Blood Glucose|Computational Biology|Computer Simulation|Energy Metabolism|Epinephrine|Exercise|Glucagon|Gluconeogenesis|Glycerol|Glycogenolysis|Homeostasis|Humans|Insulin|Male|Models, Biological|Oxygen Consumption|Precision Medicine|Tissue Distribution|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1006073', '29698395', 'The beneficial effects of physical activity for the prevention and management of several chronic diseases are widely recognized. Mathematical modeling of the effects of physical exercise in body metabolism and in particular its influence on the control of glucose homeostasis is of primary importance in the development of eHealth monitoring devices for a personalized medicine. Nonetheless, to date only a few mathematical models have been aiming at this specific purpose. We have developed a whole-body computational model of the effects on metabolic homeostasis of a bout of physical exercise. Built upon an existing model, it allows to detail better both subjects characteristics and physical exercise, thus determining to a greater extent the dynamics of the hormones and the metabolites considered.'),
(89028, 2018, 'plos', 'RIDDLE: Race and ethnicity Imputation from Disease history with Deep LEarning', 'Kim, Ji-Sung|Gao, Xin|Rzhetsky, Andrey', 'Department of Computer Science, Princeton University, Princeton, New Jersey, United States of America.|King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division, Thuwal, Saudi Arabia.|Institute for Genomics and Systems Biology, Computation Institute, Departments of Medicine and Human Genetics, University of Chicago, Chicago, Illinois, United States of America.', 'Jersey|Saudi Arabia|United States', 3, 'Computational Biology|Continental Population Groups|Electronic Health Records|Epidemiologic Factors|Ethnic Groups|Genetic Predisposition to Disease|Genetic Variation|Genetics, Population|Humans|Neural Networks (Computer)|Supervised Machine Learning', 'Journal Article', '10.1371/journal.pcbi.1006106', '29698408', 'Anonymized electronic medical records are an increasingly popular source of research data. However, these datasets often lack race and ethnicity information. This creates problems for researchers modeling human disease, as race and ethnicity are powerful confounders for many health exposures and treatment outcomes, race and ethnicity are closely linked to population-specific genetic variation. We showed that deep neural networks generate more accurate estimates for missing racial and ethnic information than competing methods (e.g., logistic regression, random forest, support vector machines, and gradient-boosted decision trees). RIDDLE yielded significantly better classification performance across all metrics that were considered: accuracy, cross-entropy loss (error), precision, recall, and area under the curve for receiver operating characteristic plots (all p < 10-9). We made specific efforts to interpret the trained neural network models to identify, quantify, and visualize medical features which are predictive of race and ethnicity. We used these characterizations of informative features to perform a systematic comparison of differential disease patterns by race and ethnicity. The fact that clinical histories are informative for imputing race and ethnicity could reflect (1) a skewed distribution of blue- and white-collar professions across racial and ethnic groups, (2) uneven accessibility and subjective importance of prophylactic health, (3) possible variation in lifestyle, such as dietary habits, and (4) differences in background genetic variation which predispose to diseases.'),
(89029, 2018, 'plos', 'Mechanical unfolding reveals stable 3-helix intermediates in talin and xcexb1-catenin', 'Mykuliak, Vasyl V|Haining, Alexander William M|von Essen, Magdalxc3xa9na|Del Rxc3xado Hernxc3xa1ndez, Armando|Hytxc3xb6nen, Vesa P', 'Faculty of Medicine and Life Sciences and BioMediTech, University of Tampere, Finland and Fimlab Laboratories, Tampere, Finland.|Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, United Kingdom.|Faculty of Medicine and Life Sciences and BioMediTech, University of Tampere, Finland and Fimlab Laboratories, Tampere, Finland.|Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, United Kingdom.|Faculty of Medicine and Life Sciences and BioMediTech, University of Tampere, Finland and Fimlab Laboratories, Tampere, Finland.', 'Finland|United Kingdom|Finland|United Kingdom|Finland', 0, 'Amino Acid Substitution|Animals|Biomechanical Phenomena|Computational Biology|Humans|Microscopy, Atomic Force|Molecular Dynamics Simulation|Mutagenesis, Site-Directed|Protein Conformation, alpha-Helical|Protein Engineering|Protein Folding|Protein Stability|Talin|Unfolded Protein Response|alpha Catenin', 'Journal Article', '10.1371/journal.pcbi.1006126', '29698481', 'Mechanical stability is a key feature in the regulation of structural scaffolding proteins and their functions. Despite the abundance of xcexb1-helical structures among the human proteome and their undisputed importance in health and disease, the fundamental principles of their behavior under mechanical load are poorly understood. Talin and xcexb1-catenin are two key molecules in focal adhesions and adherens junctions, respectively. In this study, we used a combination of atomistic steered molecular dynamics (SMD) simulations, polyprotein engineering, and single-molecule atomic force microscopy (smAFM) to investigate unfolding of these proteins. SMD simulations revealed that talin rod xcexb1-helix bundles as well as xcexb1-catenin xcexb1-helix domains unfold through stable 3-helix intermediates. While the 5-helix bundles were found to be mechanically stable, a second stable conformation corresponding to the 3-helix state was revealed. Mechanically weaker 4-helix bundles easily unfolded into a stable 3-helix conformation. The results of smAFM experiments were in agreement with the findings of the computational simulations. The disulfide clamp mutants, designed to protect the stable state, support the 3-helix intermediate model in both experimental and computational setups. As a result, multiple discrete unfolding intermediate states in the talin and xcexb1-catenin unfolding pathway were discovered. Better understanding of the mechanical unfolding mechanism of xcexb1-helix proteins is a key step towards comprehensive models describing the mechanoregulation of proteins.'),
(89030, 2018, 'plos', 'RosettaAntibodyDesign (RAbD): A general framework for computational antibody design', 'Adolf-Bryfogle, Jared|Kalyuzhniy, Oleks|Kubitz, Michael|Weitzner, Brian D|Hu, Xiaozhen|Adachi, Yumiko|Schief, William R|Dunbrack, Roland L', 'Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, United States of America.|The Scripps Research Institute, La Jolla, CA, United States of America.|The Scripps Research Institute, La Jolla, CA, United States of America.|Department of Biochemistry, University of Washington, Seattle, WA, United States of America.|The Scripps Research Institute, La Jolla, CA, United States of America.|IAVI Neutralizing Antibody Center at TSRI, La Jolla, CA, United States of America.|The Scripps Research Institute, La Jolla, CA, United States of America.|Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 19, 'Amino Acid Sequence|Animals|Antibodies|Antigen-Antibody Complex|Complementarity Determining Regions|Computational Biology|Computer Simulation|Directed Molecular Evolution|Drug Design|Humans|Models, Molecular|Monte Carlo Method|Protein Conformation|Protein Engineering|Software', 'Journal Article', '10.1371/journal.pcbi.1006112', '29702641', 'A structural-bioinformatics-based computational methodology and framework have been developed for the design of antibodies to targets of interest. RosettaAntibodyDesign (RAbD) samples the diverse sequence, structure, and binding space of an antibody to an antigen in highly customizable protocols for the design of antibodies in a broad range of applications. The program samples antibody sequences and structures by grafting structures from a widely accepted set of the canonical clusters of CDRs (North et al., J. Mol. Biol., 406:228-256, 2011). It then performs sequence design according to amino acid sequence profiles of each cluster, and samples CDR backbones using a flexible-backbone design protocol incorporating cluster-based CDR constraints. Starting from an existing experimental or computationally modeled antigen-antibody structure, RAbD can be used to redesign a single CDR or multiple CDRs with loops of different length, conformation, and sequence. We rigorously benchmarked RAbD on a set of 60 diverse antibody-antigen complexes, using two design strategies-optimizing total Rosetta energy and optimizing interface energy alone. We utilized two novel metrics for measuring success in computational protein design. The design risk ratio (DRR) is equal to the frequency of recovery of native CDR lengths and clusters divided by the frequency of sampling of those features during the Monte Carlo design procedure. Ratios greater than 1.0 indicate that the design process is picking out the native more frequently than expected from their sampled rate. We achieved DRRs for the non-H3 CDRs of between 2.4 and 4.0. The antigen risk ratio (ARR) is the ratio of frequencies of the native amino acid types, CDR lengths, and clusters in the output decoys for simulations performed in the presence and absence of the antigen. For CDRs, we achieved cluster ARRs as high as 2.5 for L1 and 1.5 for H2. For sequence design simulations without CDR grafting, the overall recovery for the native amino acid types for residues that contact the antigen in the native structures was 72% in simulations performed in the presence of the antigen and 48% in simulations performed without the antigen, for an ARR of 1.5. For the non-contacting residues, the ARR was 1.08. This shows that the sequence profiles are able to maintain the amino acid types of these conserved, buried sites, while recovery of the exposed, contacting residues requires the presence of the antigen-antibody interface. We tested RAbD experimentally on both a lambda and kappa antibody-antigen complex, successfully improving their affinities 10 to 50 fold by replacing individual CDRs of the native antibody with new CDR lengths and clusters.'),
(89031, 2018, 'plos', 'Material and shape perception based on two types of intensity gradient information', 'Sawayama, Masataka|Nishida, Shinya', 'Human Information Science Laboratory, NTT Communication Science Laboratories, Nippon Telegraph and Telephone Corporation, Atsugi, Kanagawa, Japan.|Human Information Science Laboratory, NTT Communication Science Laboratories, Nippon Telegraph and Telephone Corporation, Atsugi, Kanagawa, Japan.', 'Japan|Japan', 8, 'Computational Biology|Computer Simulation|Form Perception|Humans|Image Processing, Computer-Assisted|Models, Neurological|Models, Psychological|Photic Stimulation|Psychophysics|Surface Properties|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1006061', '29702644', 'Visual estimation of the material and shape of an object from a single image includes a hard ill-posed computational problem. However, in our daily life we feel we can estimate both reasonably well. The neural computation underlying this ability remains poorly understood. Here we propose that the human visual system uses different aspects of object images to separately estimate the contributions of the material and shape. Specifically, material perception relies mainly on the intensity gradient magnitude information, while shape perception relies mainly on the intensity gradient order information. A clue to this hypothesis was provided by the observation that luminance-histogram manipulation, which changes luminance gradient magnitudes but not the luminance-order map, effectively alters the material appearance but not the shape of an object. In agreement with this observation, we found that the simulated physical material changes do not significantly affect the intensity order information. A series of psychophysical experiments further indicate that human surface shape perception is robust against intensity manipulations provided they do not disturb the intensity order information. In addition, we show that the two types of gradient information can be utilized for the discrimination of albedo changes from highlights. These findings suggest that the visual system relies on these diagnostic image features to estimate physical properties in a distal world.'),
(89032, 2018, 'plos', 'Effects of growth rate, cell size, motion, and elemental stoichiometry on nutrient transport kinetics', 'Flynn, Kevin J|Skibinski, David O F|Lindemann, Christian', 'Biosciences, Swansea University, Swansea, United Kingdom.|Swansea University Medical School, Swansea University, Swansea, United Kingdom.|Department of Biological Sciences, University of Bergen, Bergen, Norway.', 'United Kingdom|United Kingdom|Norway', 7, 'Biological Transport, Active|Carbon|Computational Biology|Food|Kinetics|Microbial Consortia|Microbiological Phenomena|Models, Biological|Movement|Phytoplankton', 'Journal Article', '10.1371/journal.pcbi.1006118', '29702650', 'Nutrient acquisition is a critical determinant for the competitive advantage for auto- and osmohetero- trophs alike. Nutrient limited growth is commonly described on a whole cell basis through reference to a maximum growth rate (Gmax) and a half-saturation constant (KG). This empirical application of a Michaelis-Menten like description ignores the multiple underlying feedbacks between physiology contributing to growth, cell size, elemental stoichiometry and cell motion. Here we explore these relationships with reference to the kinetics of the nutrient transporter protein, the transporter rate density at the cell surface (TRD, potential transport rate per unit plasma-membrane area), and diffusion gradients. While the half saturation value for the limiting nutrient increases rapidly with cell size, significant mitigation is afforded by cell motion (swimming or sedimentation), and by decreasing the cellular carbon density. There is thus potential for high vacuolation and high sedimentation rates in diatoms to significantly decrease KG and increase species competitive advantage. Our results also suggest that Gmax for larger non-diatom protists may be constrained by rates of nutrient transport. For a given carbon density, cell size and TRD, the value of Gmax/KG remains constant. This implies that species or strains with a lower Gmax might coincidentally have a competitive advantage under nutrient limited conditions as they also express lower values of KG. The ability of cells to modulate the TRD according to their nutritional status, and hence change the instantaneous maximum transport rate, has a very marked effect upon transport and growth kinetics. Analyses and dynamic models that do not consider such modulation will inevitably fail to properly reflect competitive advantage in nutrient acquisition. This has important implications for the accurate representation and predictive capabilities of model applications, in particular in a changing environment.'),
(89033, 2018, 'plos', 'Automated evaluation of quaternary structures from protein crystals', 'Bliven, Spencer|Lafita, Aleix|Parker, Althea|Capitani, Guido|Duarte, Jose M', 'Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.|Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.|Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.|Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.|Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 0, 'Algorithms|Computational Biology|Crystallography, X-Ray|Databases, Protein|Models, Molecular|Protein Interaction Domains and Motifs|Protein Structure, Quaternary|Proteins|Software', 'Journal Article', '10.1371/journal.pcbi.1006104', '29708963', 'A correct assessment of the quaternary structure of proteins is a fundamental prerequisite to understanding their function, physico-chemical properties and mode of interaction with other proteins. Currently about 90% of structures in the Protein Data Bank are crystal structures, in which the correct quaternary structure is embedded in the crystal lattice among a number of crystal contacts. Computational methods are required to 1) classify all protein-protein contacts in crystal lattices as biologically relevant or crystal contacts and 2) provide an assessment of how the biologically relevant interfaces combine into a biological assembly. In our previous work we addressed the first problem with our EPPIC (Evolutionary Protein Protein Interface Classifier) method. Here, we present our solution to the second problem with a new method that combines the interface classification results with symmetry and topology considerations. The new algorithm enumerates all possible valid assemblies within the crystal using a graph representation of the lattice and predicts the most probable biological unit based on the pairwise interface scoring. Our method achieves 85% precision (ranging from 76% to 90% for different oligomeric types) on a new dataset of 1,481 biological assemblies with consensus of PDB annotations. Although almost the same precision is achieved by PISA, currently the most popular quaternary structure assignment method, we show that, due to the fundamentally different approach to the problem, the two methods are complementary and could be combined to improve biological assembly assignments. The software for the automatic assessment of protein assemblies (EPPIC version 3) has been made available through a web server at http://www.eppic-web.org.'),
(89034, 2018, 'plos', 'Topological and statistical analyses of gene regulatory networks reveal unifying yet quantitatively different emergent properties', 'Ouma, Wilberforce Zachary|Pogacar, Katja|Grotewold, Erich', 'Molecular and Cellular Imaging Center (MCIC), Ohio Agricultural and Research Development Center (OARDC), Ohio State University, Wooster, OH, United States of America.|Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, United States of America.|Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, United States of America.', 'United States|United States|United States', 7, 'Animals|Arabidopsis|Caenorhabditis elegans|Computational Biology|Computer Simulation|Drosophila melanogaster|Gene Regulatory Networks|Models, Genetic|Phenotype|Saccharomyces cerevisiae|Species Specificity|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1006098', '29708965', 'Understanding complexity in physical, biological, social and information systems is predicated on describing interactions amongst different components. Advances in genomics are facilitating the high-throughput identification of molecular interactions, and graphs are emerging as indispensable tools in explaining how the connections in the network drive organismal phenotypic plasticity. Here, we describe the architectural organization and associated emergent topological properties of gene regulatory networks (GRNs) that describe protein-DNA interactions (PDIs) in several model eukaryotes. By analyzing GRN connectivity, our results show that the anticipated scale-free network architectures are characterized by organism-specific power law scaling exponents. These exponents are independent of the fraction of the GRN experimentally sampled, enabling prediction of properties of the complete GRN for an organism. We further demonstrate that the exponents describe inequalities in transcription factor (TF)-target gene recognition across GRNs. These observations have the important biological implication that they predict the existence of an intrinsic organism-specific trans and/or cis regulatory landscape that constrains GRN topologies. Consequently, architectural GRN organization drives not only phenotypic plasticity within a species, but is also likely implicated in species-specific phenotype.'),
(89035, 2018, 'plos', 'Estimation of the dispersal distances of an aphid-borne virus in a patchy landscape', 'Pleydell, David R J|Soubeyrand, Samuel|Dallot, Sylvie|Labonne, Gérard|Chadœuf, Joël|Jacquot, Emmanuel|Thébaud, Gaël', 'BGPI, INRA, Montpellier SupAgro, Univ. Montpellier, Cirad, TA A-54/K, Campus de Baillarguet, 34398, Montpellier cedex 5, France.|BioSP, INRA, 84914, Avignon, France.|BGPI, INRA, Montpellier SupAgro, Univ. Montpellier, Cirad, TA A-54/K, Campus de Baillarguet, 34398, Montpellier cedex 5, France.|BGPI, INRA, Montpellier SupAgro, Univ. Montpellier, Cirad, TA A-54/K, Campus de Baillarguet, 34398, Montpellier cedex 5, France.|BioSP, INRA, 84914, Avignon, France.|BGPI, INRA, Montpellier SupAgro, Univ. Montpellier, Cirad, TA A-54/K, Campus de Baillarguet, 34398, Montpellier cedex 5, France.|BGPI, INRA, Montpellier SupAgro, Univ. Montpellier, Cirad, TA A-54/K, Campus de Baillarguet, 34398, Montpellier cedex 5, France.', 'France|France|France|France|France|France|France', 0, 'Agriculture|Algorithms|Animals|Aphids|Bayes Theorem|Computational Biology|Computer Simulation|Insect Vectors|Models, Biological|Plant Diseases|Plum Pox Virus|Prunus', 'Journal Article', '10.1371/journal.pcbi.1006085', '29708968', 'Characterising the spatio-temporal dynamics of pathogens in natura is key to ensuring their efficient prevention and control. However, it is notoriously difficult to estimate dispersal parameters at scales that are relevant to real epidemics. Epidemiological surveys can provide informative data, but parameter estimation can be hampered when the timing of the epidemiological events is uncertain, and in the presence of interactions between disease spread, surveillance, and control. Further complications arise from imperfect detection of disease and from the huge number of data on individual hosts arising from landscape-level surveys. Here, we present a Bayesian framework that overcomes these barriers by integrating over associated uncertainties in a model explicitly combining the processes of disease dispersal, surveillance and control. Using a novel computationally efficient approach to account for patch geometry, we demonstrate that disease dispersal distances can be estimated accurately in a patchy (i.e. fragmented) landscape when disease control is ongoing. Applying this model to data for an aphid-borne virus (Plum pox virus) surveyed for 15 years in 605 orchards, we obtain the first estimate of the distribution of flight distances of infectious aphids at the landscape scale. About 50% of aphid flights terminate beyond 90 m, which implies that most infectious aphids leaving a tree land outside the bounds of a 1-ha orchard. Moreover, long-distance flights are not rare-10% of flights exceed 1 km. By their impact on our quantitative understanding of winged aphid dispersal, these results can inform the design of management strategies for plant viruses, which are mainly aphid-borne.'),
(89036, 2018, 'plos', 'Quantitative analysis reveals crosstalk mechanisms of heat shock-induced attenuation of NF-xcexbaB signaling at the single cell level', 'Kardyxc5x84ska, Maxc5x82gorzata|Paszek, Anna|xc5x9amieja, Jarosxc5x82aw|Spiller, David|Widxc5x82ak, Wiesxc5x82awa|White, Michael R H|Paszek, Pawel|Kimmel, Marek', 'Systems Engineering Group, Silesian University of Technology, Gliwice, Poland.|Systems Engineering Group, Silesian University of Technology, Gliwice, Poland.|Systems Engineering Group, Silesian University of Technology, Gliwice, Poland.|System Microscopy Centre, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.|Maria Skxc5x82odowska-Curie Institute-Oncology Center, Gliwice Branch, Gliwice, Poland.|System Microscopy Centre, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.|System Microscopy Centre, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.|Systems Engineering Group, Silesian University of Technology, Gliwice, Poland.', 'Poland|Poland|Poland|United Kingdom|Poland|United Kingdom|United Kingdom|Poland', 0, 'Cell Line|Computational Biology|Computer Simulation|Green Fluorescent Proteins|Heat-Shock Response|Humans|I-kappa B Kinase|Models, Biological|NF-kappa B|Recombinant Fusion Proteins|Signal Transduction|Single-Cell Analysis|Transcription Factor RelA|Tumor Necrosis Factor-alpha', 'Journal Article', '10.1371/journal.pcbi.1006130', '29708974', 'Elevated temperature induces the heat shock (HS) response, which modulates cell proliferation, apoptosis, the immune and inflammatory responses. However, specific mechanisms linking the HS response pathways to major cellular signaling systems are not fully understood. Here we used integrated computational and experimental approaches to quantitatively analyze the crosstalk mechanisms between the HS-response and a master regulator of inflammation, cell proliferation, and apoptosis the Nuclear Factor xcexbaB (NF-xcexbaB) system. We found that populations of human osteosarcoma cells, exposed to a clinically relevant 43xc2xb0C HS had an attenuated NF-xcexbaB p65 response to Tumor Necrosis Factor xcexb1 (TNFxcexb1) treatment. The degree of inhibition of the NF-xcexbaB response depended on the HS exposure time. Mathematical modeling of single cells indicated that individual crosstalk mechanisms differentially encode HS-mediated NF-xcexbaB responses while being consistent with the observed population-level responses. In particular all-or-nothing encoding mechanisms were involved in the HS-dependent regulation of the IKK activity and IxcexbaBxcexb1 phosphorylation, while others involving transport were analogue. In order to discriminate between these mechanisms, we used live-cell imaging of nuclear translocations of the NF-xcexbaB p65 subunit. The single cell responses exhibited all-or-nothing encoding. While most cells did not respond to TNFxcexb1 stimulation after a 60 min HS, 27% showed responses similar to those not receiving HS. We further demonstrated experimentally and theoretically that the predicted inhibition of IKK activity was consistent with the observed HS-dependent depletion of the IKKxcexb1 and IKKxcexb2 subunits in whole cell lysates. However, a combination of all-or-nothing crosstalk mechanisms was required to completely recapitulate the single cell data. We postulate therefore that the heterogeneity of the single cell responses might be explained by the cell-intrinsic variability of HS-modulated IKK signaling. In summary, we show that high temperature modulates NF-xcexbaB responses in single cells in a complex and unintuitive manner, which needs to be considered in hyperthermia-based treatment strategies.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(89037, 2018, 'plos', 'Identification of animal behavioral strategies by inverse reinforcement learning', 'Yamaguchi, Shoichiro|Naoki, Honda|Ikeda, Muneki|Tsukada, Yuki|Nakano, Shunji|Mori, Ikue|Ishii, Shin', 'Integrated Systems Biology Laboratory, Graduate School of Informatics, Kyoto University, Sakyo, Kyoto, Japan.|Laboratory of Theoretical Biology, Graduate School of Biostudies, Kyoto University, Yoshidakonoecho, Sakyo, Kyoto, Japan.|Group of Molecular Neurobiology, Graduate School of Science, Nagoya University, Furoucho, Chikusa, Nagoya, Aichi, Japan.|Group of Molecular Neurobiology, Graduate School of Science, Nagoya University, Furoucho, Chikusa, Nagoya, Aichi, Japan.|Group of Molecular Neurobiology, Graduate School of Science, Nagoya University, Furoucho, Chikusa, Nagoya, Aichi, Japan.|Group of Molecular Neurobiology, Graduate School of Science, Nagoya University, Furoucho, Chikusa, Nagoya, Aichi, Japan.|Integrated Systems Biology Laboratory, Graduate School of Informatics, Kyoto University, Sakyo, Kyoto, Japan.', 'Japan|Japan|Japan|Japan|Japan|Japan|Japan', 0, 'Animals|Behavior, Animal|Caenorhabditis elegans|Computational Biology|Decision Making|Learning|Reinforcement (Psychology)|Taxis Response', 'Journal Article', '10.1371/journal.pcbi.1006122', '29718905', 'Animals are able to reach a desired state in an environment by controlling various behavioral patterns. Identification of the behavioral strategy used for this control is important for understanding animals decision-making and is fundamental to dissect information processing done by the nervous system. However, methods for quantifying such behavioral strategies have not been fully established. In this study, we developed an inverse reinforcement-learning (IRL) framework to identify an animals behavioral strategy from behavioral time-series data. We applied this framework to C. elegans thermotactic behavior, after cultivation at a constant temperature with or without food, fed worms prefer, while starved worms avoid the cultivation temperature on a thermal gradient. Our IRL approach revealed that the fed worms used both the absolute temperature and its temporal derivative and that their behavior involved two strategies: directed migration (DM) and isothermal migration (IM). With DM, worms efficiently reached specific temperatures, which explains their thermotactic behavior when fed. With IM, worms moved along a constant temperature, which reflects isothermal tracking, well-observed in previous studies. In contrast to fed animals, starved worms escaped the cultivation temperature using only the absolute, but not the temporal derivative of temperature. We also investigated the neural basis underlying these strategies, by applying our method to thermosensory neuron-deficient worms. Thus, our IRL-based approach is useful in identifying animal strategies from behavioral time-series data and could be applied to a wide range of behavioral studies, including decision-making, in other organisms.'),
(89038, 2018, 'plos', 'beachmat: A Bioconductor C++ API for accessing high-throughput biological data from a variety of R matrix types', 'Lun, Aaron T L|Pagès, Hervé|Smith, Mike L', 'Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.|Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.', 'United Kingdom|United States|Germany', 0, 'Algorithms|Computational Biology|Databases, Genetic|High-Throughput Nucleotide Sequencing|Humans|Sequence Analysis, RNA|Software', 'Journal Article', '10.1371/journal.pcbi.1006135', '29723188', 'Biological experiments involving genomics or other high-throughput assays typically yield a data matrix that can be explored and analyzed using the R programming language with packages from the Bioconductor project. Improvements in the throughput of these assays have resulted in an explosion of data even from routine experiments, which poses a challenge to the existing computational infrastructure for statistical data analysis. For example, single-cell RNA sequencing (scRNA-seq) experiments frequently generate large matrices containing expression values for each gene in each cell, requiring sparse or file-backed representations for memory-efficient manipulation in R. These alternative representations are not easily compatible with high-performance C++ code used for computationally intensive tasks in existing R/Bioconductor packages. Here, we describe a C++ interface named beachmat, which enables agnostic data access from various matrix representations. This allows package developers to write efficient C++ code that is interoperable with dense, sparse and file-backed matrices, amongst others. We evaluated the performance of beachmat for accessing data from each matrix representation using both simulated and real scRNA-seq data, and defined a clear memory/speed trade-off to motivate the choice of an appropriate representation. We also demonstrate how beachmat can be incorporated into the code of other packages to drive analyses of a very large scRNA-seq data set.'),
(89039, 2018, 'plos', 'Predictive modelling of a novel anti-adhesion therapy to combat bacterial colonisation of burn wounds', 'Roberts, Paul A|Huebinger, Ryan M|Keen, Emma|Krachler, Anne-Marie|Jabbari, Sara', 'School of Mathematics, University of Birmingham, Edgbaston, Birmingham, United Kingdom.|Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.|Department of Microbiology and Molecular Genetics, University of Texas McGovern Medical School at Houston, Houston, Texas, United States of America.|School of Mathematics, University of Birmingham, Edgbaston, Birmingham, United Kingdom.', 'United Kingdom|United States|United Kingdom|United States|United Kingdom', 4, 'Animals|Anti-Bacterial Agents|Bacterial Adhesion|Bacterial Infections|Burns|Computational Biology|Disease Models, Animal|Models, Statistical|Rats|Rats, Sprague-Dawley|Wound Infection', 'Journal Article', '10.1371/journal.pcbi.1006071', '29723210', 'As the development of new classes of antibiotics slows, bacterial resistance to existing antibiotics is becoming an increasing problem. A potential solution is to develop treatment strategies with an alternative mode of action. We consider one such strategy: anti-adhesion therapy. Whereas antibiotics act directly upon bacteria, either killing them or inhibiting their growth, anti-adhesion therapy impedes the binding of bacteria to host cells. This prevents bacteria from deploying their arsenal of virulence mechanisms, while simultaneously rendering them more susceptible to natural and artificial clearance. In this paper, we consider a particular form of anti-adhesion therapy, involving biomimetic multivalent adhesion molecule 7 coupled polystyrene microbeads, which competitively inhibit the binding of bacteria to host cells. We develop a mathematical model, formulated as a system of ordinary differential equations, to describe inhibitor treatment of a Pseudomonas aeruginosa burn wound infection in the rat. Benchmarking our model against in vivo data from an ongoing experimental programme, we use the model to explain bacteria population dynamics and to predict the efficacy of a range of treatment strategies, with the aim of improving treatment outcome. The model consists of two physical compartments: the host cells and the exudate. It is found that, when effective in reducing the bacterial burden, inhibitor treatment operates both by preventing bacteria from binding to the host cells and by reducing the flux of daughter cells from the host cells into the exudate. Our model predicts that inhibitor treatment cannot eliminate the bacterial burden when used in isolation, however, when combined with regular or continuous debridement of the exudate, elimination is theoretically possible. Lastly, we present ways to improve therapeutic efficacy, as predicted by our mathematical model.'),
(89040, 2018, 'plos', 'Functional triplet motifs underlie accurate predictions of single-trial responses in populations of tuned and untuned V1 neurons', 'Dechery, Joseph B|MacLean, Jason N', 'Committee on Computational Neuroscience, University of Chicago, Chicago, Illinois, United States of America.|Committee on Computational Neuroscience, University of Chicago, Chicago, Illinois, United States of America.', 'United States|United States', 0, 'Animals|Calcium|Computational Biology|Mice|Models, Neurological|Neurons|Photic Stimulation|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1006153', '29727448', 'Visual stimuli evoke activity in visual cortical neuronal populations. Neuronal activity can be selectively modulated by particular visual stimulus parameters, such as the direction of a moving bar of light, resulting in well-defined trial averaged tuning properties. However, given any single stimulus parameter, a large number of neurons in visual cortex remain unmodulated, and the role of this untuned population is not well understood. Here, we use two-photon calcium imaging to record, in an unbiased manner, from large populations of layer 2/3 excitatory neurons in mouse primary visual cortex to describe co-varying activity on single trials in neuronal populations consisting of both tuned and untuned neurons. Specifically, we summarize pairwise covariability with an asymmetric partial correlation coefficient, allowing us to analyze the resultant population correlation structure, or functional network, with graph theory. Using the graph neighbors of a neuron, we find that the local population, including both tuned and untuned neurons, are able to predict individual neuron activity on a moment to moment basis, while also recapitulating tuning properties of tuned neurons. Variance explained in total population activity scales with the number of neurons imaged, demonstrating larger sample sizes are required to fully capture local network interactions. We also find that a specific functional triplet motif in the graph results in the best predictions, suggesting a signature of informative correlations in these populations. In summary, we show that unbiased sampling of the local population can explain single trial response variability as well as trial-averaged tuning properties in V1, and the ability to predict responses is tied to the occurrence of a functional triplet motif.'),
(89041, 2018, 'plos', 'Differential polarization of cortical pyramidal neuron dendrites through weak extracellular fields', 'Aspart, Florian|Remme, Michiel W H|Obermayer, Klaus', 'Department of Software Engineering and Theoretical Computer Science, Technische Universität Berlin, Berlin, Germany.|Institute for Theoretical Biology, Humboldt-Universität zu Berlin, Berlin, Germany.|Department of Software Engineering and Theoretical Computer Science, Technische Universität Berlin, Berlin, Germany.', 'Germany|Germany|Germany', 12, 'Action Potentials|Animals|Cerebral Cortex|Computational Biology|Dendrites|Models, Neurological|Pyramidal Cells|Rats|Transcranial Direct Current Stimulation', 'Journal Article', '10.1371/journal.pcbi.1006124', '29727454', 'The rise of transcranial current stimulation (tCS) techniques have sparked an increasing interest in the effects of weak extracellular electric fields on neural activity. These fields modulate ongoing neural activity through polarization of the neuronal membrane. While the somatic polarization has been investigated experimentally, the frequency-dependent polarization of the dendritic trees in the presence of alternating (AC) fields has received little attention yet. Using a biophysically detailed model with experimentally constrained active conductances, we analyze the subthreshold response of cortical pyramidal cells to weak AC fields, as induced during tCS. We observe a strong frequency resonance around 10-20 Hz in the apical dendrites sensitivity to polarize in response to electric fields but not in the basal dendrites nor the soma. To disentangle the relative roles of the cell morphology and active and passive membrane properties in this resonance, we perform a thorough analysis using simplified models, e.g. a passive pyramidal neuron model, simple passive cables and reconstructed cell model with simplified ion channels. We attribute the origin of the resonance in the apical dendrites to (i) a locally increased sensitivity due to the morphology and to (ii) the high density of h-type channels. Our systematic study provides an improved understanding of the subthreshold response of cortical cells to weak electric fields and, importantly, allows for an improved design of tCS stimuli.'),
(89042, 2018, 'plos', 'Assessing the public health impact of tolerance-based therapies with mathematical models', 'Hozé, Nathanaël|Bonhoeffer, Sebastian|Regoes, Roland', 'Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland.|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland.|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland.', 'Switzerland|Switzerland|Switzerland', 0, 'Communicable Disease Control|Communicable Diseases|Computational Biology|Host-Pathogen Interactions|Humans|Models, Theoretical|Public Health', 'Journal Article', '10.1371/journal.pcbi.1006119', '29727455', 'Disease tolerance is a defense strategy against infections that aims at maintaining host health even at high pathogen replication or load. Tolerance mechanisms are currently intensively studied with the long-term goal of exploiting them therapeutically. Because tolerance-based treatment imposes less selective pressure on the pathogen it has been hypothesised to be evolution-proof. However, the primary public health goal is to reduce the incidence and mortality associated with a disease. From this perspective, tolerance-based treatment bears the risk of increasing the prevalence of the disease, which may lead to increased mortality. We assessed the promise of tolerance-based treatment strategies using mathematical models. Conventional treatment was implemented as an increased recovery rate, while tolerance-based treatment was assumed to reduce the disease-related mortality of infected hosts without affecting recovery. We investigated the endemic phase of two types of infections: acute and chronic. Additionally, we considered the effect of pathogen resistance against conventional treatment. We show that, for low coverage of tolerance-based treatment, chronic infections can cause even more deaths than without treatment. Overall, we found that conventional treatment always outperforms tolerance-based treatment, even when we allow the emergence of pathogen resistance. Our results cast doubt on the potential benefit of tolerance-based over conventional treatment. Any clinical application of tolerance-based treatment of infectious diseases has to consider the associated detrimental epidemiological feedback.'),
(89043, 2018, 'plos', 'Art in Science Competition invites artworks to the annual exhibition on ISMB 2018 in Chicago', 'Frenkel-Morgenstern, Milana|Welch, Lonnie|Gaeta, Bruno|Kovats, Diane E', 'The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.|School of EECS, Ohio University, Athens, Ohio, United States of America.|School of Computer Science and Engineering, University of New South Wales, Australia.|International Society for Computational Biology (ISCB), Bethesda, Maryland, United States of America.', 'Israel|United States|Australia|United States', 0, 'Art|Chicago|Computational Biology|Humans', 'Journal Article', '10.1371/journal.pcbi.1006139', '29734340', '-'),
(89044, 2018, 'plos', 'Network inference reveals novel connections in pathways regulating growth and defense in the yeast salt response', 'MacGilvray, Matthew E|Shishkova, Evgenia|Chasman, Deborah|Place, Michael|Gitter, Anthony|Coon, Joshua J|Gasch, Audrey P', 'Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI, United States of America.|Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI, United States of America.|Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, United States of America.|Great Lakes Bioenergy Research Center, University of Wisconsin-Madison, Madison, WI, United States of America.|Department of Biostatistics and Medical Informatics, University of Wisconsin -Madison, Madison, WI, United States of America.|Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI, United States of America.|Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 0, 'Cell Cycle|Computational Biology|Computer Simulation|Cyclic AMP-Dependent Protein Kinases|Immunoprecipitation|Mass Spectrometry|Models, Biological|Osmotic Pressure|Phosphorylation|Protein Interaction Mapping|Protein-Serine-Threonine Kinases|Proteome|Proteomics|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Signal Transduction|Sodium Chloride|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1006088', '29738528', 'Cells respond to stressful conditions by coordinating a complex, multi-faceted response that spans many levels of physiology. Much of the response is coordinated by changes in protein phosphorylation. Although the regulators of transcriptome changes during stress are well characterized in Saccharomyces cerevisiae, the upstream regulatory network controlling protein phosphorylation is less well dissected. Here, we developed a computational approach to infer the signaling network that regulates phosphorylation changes in response to salt stress. We developed an approach to link predicted regulators to groups of likely co-regulated phospho-peptides responding to stress, thereby creating new edges in a background protein interaction network. We then use integer linear programming (ILP) to integrate wild type and mutant phospho-proteomic data and predict the network controlling stress-activated phospho-proteomic changes. The network we inferred predicted new regulatory connections between stress-activated and growth-regulating pathways and suggested mechanisms coordinating metabolism, cell-cycle progression, and growth during stress. We confirmed several network predictions with co-immunoprecipitations coupled with mass-spectrometry protein identification and mutant phospho-proteomic analysis. Results show that the cAMP-phosphodiesterase Pde2 physically interacts with many stress-regulated transcription factors targeted by PKA, and that reduced phosphorylation of those factors during stress requires the Rck2 kinase that we show physically interacts with Pde2. Together, our work shows how a high-quality computational network model can facilitate discovery of new pathway interactions during osmotic stress.'),
(89045, 2018, 'plos', 'The AmP project: Comparing species on the basis of dynamic energy budget parameters', 'Marques, Gonçalo M|Augustine, Starrlight|Lika, Konstadia|Pecquerie, Laure|Domingos, Tiago|Kooijman, Sebastiaan A L M', 'MARETEC - Marine, Environment & Technology Center, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.|Akvaplan-niva, Fram High North Research Centre for Climate and the Environment, Tromsø, Norway.|Department of Biology, University of Crete, Heraklion, Greece.|LEMAR, IRD, CNRS, UBO, Ifremer, Plouzané, France.|MARETEC - Marine, Environment & Technology Center, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.|Department of Theoretical Biology, VU University Amsterdam, Amsterdam, The Netherlands.', 'Portugal|Norway|Greece|France|Portugal|Netherlands', 57, 'Animals|Biodiversity|Biological Evolution|Computational Biology|Crustacea|Databases, Factual|Energy Metabolism|Fishes|Life Cycle Stages|Models, Biological|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.1006100', '29742099', 'We developed new methods for parameter estimation-in-context and, with the help of 125 authors, built the AmP (Add-my-Pet) database of Dynamic Energy Budget (DEB) models, parameters and referenced underlying data for animals, where each species constitutes one database entry. The combination of DEB parameters covers all aspects of energetics throughout the full organisms life cycle, from the start of embryo development to death by aging. The species-specific parameter values capture biodiversity and can now, for the first time, be compared between animals species. An important insight brought by the AmP project is the classification of animal energetics according to a family of related DEB models that is structured on the basis of the mode of metabolic acceleration, which links up with the development of larval stages. We discuss the evolution of metabolism in this context, among animals in general, and ray-finned fish, mollusks and crustaceans in particular. New DEBtool code for estimating DEB parameters from data has been written. AmPtool code for analyzing patterns in parameter values has also been created. A new web-interface supports multiple ways to visualize data, parameters, and implied properties from the entire collection as well as on an entry by entry basis. The DEB models proved to fit data well, the median relative error is only 0.07, for the 1035 animal species at 2018/03/12, including some extinct ones, from all large phyla and all chordate orders, spanning a range of body masses of 16 orders of magnitude. This study is a first step to include evolutionary aspects into parameter estimation, allowing to infer properties of species for which very little is known.'),
(89046, 2018, 'plos', 'Bi-stability in cooperative transport by ants in the presence of obstacles', 'Ron, Jonathan E|Pinkoviezky, Itai|Fonio, Ehud|Feinerman, Ofer|Gov, Nir S', 'Department of Chemical and Biological Physics, Weizmann Institute, Rehovot, Israel.|Department of Biology, Emory University, Atlanta, Georgia, USA.|Department of Physics of Complex Systems, Weizmann Institute, Rehovot, Israel.|Department of Physics of Complex Systems, Weizmann Institute, Rehovot, Israel.|Department of Chemical and Biological Physics, Weizmann Institute, Rehovot, Israel.', 'Israel|Georgia|Israel|Israel|Israel', 0, 'Algorithms|Animals|Ants|Behavior, Animal|Computational Biology|Cooperative Behavior|Models, Biological|Problem Solving|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1006068', '29746457', 'To cooperatively carry large food items to the nest, individual ants conform their efforts and coordinate their motion. Throughout this expedition, collective motion is driven both by internal interactions between the carrying ants and a response to newly arrived informed ants that orient the cargo towards the nest. During the transport process, the carrying group must overcome obstacles that block their path to the nest. Here, we investigate the dynamics of cooperative transport, when the motion of the ants is frustrated by a linear obstacle that obstructs the motion of the cargo. The obstacle contains a narrow opening that serves as the only available passage to the nest, and through which single ants can pass but not with the cargo. We provide an analytical model for the ant-cargo system in the constrained environment that predicts a bi-stable dynamic behavior between an oscillatory mode of motion along the obstacle and a convergent mode of motion near the opening. Using both experiments and simulations, we show how for small cargo sizes, the system exhibits spontaneous transitions between these two modes of motion due to fluctuations in the applied force on the cargo. The bi-stability provides two possible problem solving strategies for overcoming the obstacle, either by attempting to pass through the opening, or take large excursions to circumvent the obstacle.'),
(89047, 2018, 'plos', 'How stimulation frequency and intensity impact on the long-lasting effects of coordinated reset stimulation', 'Manos, Thanos|Zeitler, Magteld|Tass, Peter A', 'Institute of Neuroscience and Medicine (INM-7), Research Centre Jülich, Jülich, Germany.|Institute of Neuroscience and Medicine (INM-7), Research Centre Jülich, Jülich, Germany.|Department of Neurosurgery, Stanford University, Stanford, CA, United States of America.', 'Germany|Germany|United States', 6, 'Action Potentials|Animals|Computer Simulation|Electric Stimulation|Models, Neurological|Neuronal Plasticity', 'Journal Article', '10.1371/journal.pcbi.1006113', '29746458', 'Several brain diseases are characterized by abnormally strong neuronal synchrony. Coordinated Reset (CR) stimulation was computationally designed to specifically counteract abnormal neuronal synchronization processes by desynchronization. In the presence of spike-timing-dependent plasticity (STDP) this may lead to a decrease of synaptic excitatory weights and ultimately to an anti-kindling, i.e. unlearning of abnormal synaptic connectivity and abnormal neuronal synchrony. The long-lasting desynchronizing impact of CR stimulation has been verified in pre-clinical and clinical proof of concept studies. However, as yet it is unclear how to optimally choose the CR stimulation frequency, i.e. the repetition rate at which the CR stimuli are delivered. This work presents the first computational study on the dependence of the acute and long-term outcome on the CR stimulation frequency in neuronal networks with STDP. For this purpose, CR stimulation was applied with Rapidly Varying Sequences (RVS) as well as with Slowly Varying Sequences (SVS) in a wide range of stimulation frequencies and intensities. Our findings demonstrate that acute desynchronization, achieved during stimulation, does not necessarily lead to long-term desynchronization after cessation of stimulation. By comparing the long-term effects of the two different CR protocols, the RVS CR stimulation turned out to be more robust against variations of the stimulation frequency. However, SVS CR stimulation can obtain stronger anti-kindling effects. We revealed specific parameter ranges that are favorable for long-term desynchronization. For instance, RVS CR stimulation at weak intensities and with stimulation frequencies in the range of the neuronal firing rates turned out to be effective and robust, in particular, if no closed loop adaptation of stimulation parameters is (technically) available. From a clinical standpoint, this may be relevant in the context of both invasive as well as non-invasive CR stimulation.'),
(89048, 2018, 'plos', 'Porcupine: A visual pipeline tool for neuroimaging analysis', 'van Mourik, Tim|Snoek, Lukas|Knapen, Tomas|Norris, David G', 'Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Kapittelweg, Nijmegen, The Netherlands.|University of Amsterdam, Department of Brain & Cognition, Nieuwe Achtergracht, Amsterdam, The Netherlands.|Cognitive Psychology & Institute for Brain & Behavior, Vd Boechorststraat, Amsterdam, The Netherlands.|Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Kapittelweg, Nijmegen, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands', 2, 'Computational Biology|Connectome|Humans|Image Processing, Computer-Assisted|Neuroimaging|Software|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1006064', '29746461', 'The field of neuroimaging is rapidly adopting a more reproducible approach to data acquisition and analysis. Data structures and formats are being standardised and data analyses are getting more automated. However, as data analysis becomes more complicated, researchers often have to write longer analysis scripts, spanning different tools across multiple programming languages. This makes it more difficult to share or recreate code, reducing the reproducibility of the analysis. We present a tool, Porcupine, that constructs ones analysis visually and automatically produces analysis code. The graphical representation improves understanding of the performed analysis, while retaining the flexibility of modifying the produced code manually to custom needs. Not only does Porcupine produce the analysis code, it also creates a shareable environment for running the code in the form of a Docker image. Together, this forms a reproducible way of constructing, visualising and sharing ones analysis. Currently, Porcupine links to Nipype functionalities, which in turn accesses most standard neuroimaging analysis tools. Our goal is to release researchers from the constraints of specific implementation details, thereby freeing them to think about novel and creative ways to solve a given problem. Porcupine improves the overview researchers have of their processing pipelines, and facilitates both the development and communication of their work. This will reduce the threshold at which less expert users can generate reusable pipelines. With Porcupine, we bridge the gap between a conceptual and an implementational level of analysis and make it easier for researchers to create reproducible and shareable science. We provide a wide range of examples and documentation, as well as installer files for all platforms on our website: https://timvanmourik.github.io/Porcupine. Porcupine is free, open source, and released under the GNU General Public License v3.0.'),
(89049, 2018, 'plos', 'Nonlinear decoding of a complex movie from the mammalian retina', 'Botella-Soler, Vicente|Deny, Stxc3xa9phane|Martius, Georg|Marre, Olivier|Tkaxc4x8dik, Gaxc5xa1per', 'Institute of Science and Technology Austria, Klosterneuburg, Austria.|Sorbonne Universitxc3xa9, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France.|Max Planck Institute for Intelligent Systems, Txc3xbcbingen, Germany.|Sorbonne Universitxc3xa9, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France.|Institute of Science and Technology Austria, Klosterneuburg, Austria.', 'Austria|France|Germany|France|Austria', 0, 'Action Potentials|Animals|Computational Biology|Male|Models, Neurological|Neural Networks (Computer)|Nonlinear Dynamics|Rats|Rats, Long-Evans|Retina', 'Journal Article', '10.1371/journal.pcbi.1006057', '29746463', 'Retina is a paradigmatic system for studying sensory encoding: the transformation of light into spiking activity of ganglion cells. The inverse problem, where stimulus is reconstructed from spikes, has received less attention, especially for complex stimuli that should be reconstructed pixel-by-pixel. We recorded around a hundred neurons from a dense patch in a rat retina and decoded movies of multiple small randomly-moving discs. We constructed nonlinear (kernelized and neural network) decoders that improved significantly over linear results. An important contribution to this was the ability of nonlinear decoders to reliably separate between neural responses driven by locally fluctuating light signals, and responses at locally constant light driven by spontaneous-like activity. This improvement crucially depended on the precise, non-Poisson temporal structure of individual spike trains, which originated in the spike-history dependence of neural responses. We propose a general principle by which downstream circuitry could discriminate between spontaneous and stimulus-driven activity based solely on higher-order statistical structure in the incoming spike trains.'),
(89050, 2018, 'plos', 'Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach', 'Blazquez-Navarro, Arturo|Schachtner, Thomas|Stervbo, Ulrik|Sefrin, Anett|Stein, Maik|Westhoff, Timm H|Reinke, Petra|Klipp, Edda|Babel, Nina|Neumann, Avidan U|Or-Guil, Michal', 'Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin, Berlin, Germany.|Department of Nephrology and Internal Intensive Care, Charité-Universitätsmedizin, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin, Berlin, Germany.|Medical Clinic I, Marien Hospital Herne, Ruhr University Bochum, Herne, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin, Berlin, Germany.|Theoretical Biophysics Group, Department of Biology, Humboldt-Universität zu Berlin, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin, Berlin, Germany.|Systems Immunology Lab, Department of Biology, Humboldt-Universität zu Berlin, Berlin, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany', 5, 'Antigens, Viral|BK Virus|Computational Biology|Enzyme-Linked Immunospot Assay|Host-Pathogen Interactions|Humans|Kidney Diseases|Kidney Transplantation|Kinetics|Models, Biological|Polyomavirus Infections|T-Lymphocytes|Viral Load', 'Journal Article', '10.1371/journal.pcbi.1005998', '29746472', 'BK virus (BKV) associated nephropathy affects 1-10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot) in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.'),
(89051, 2018, 'plos', 'A loop-counting method for covariate-corrected low-rank biclustering of gene-expression and genome-wide association study data', 'Rangan, Aaditya V|McGrouther, Caroline C|Kelsoe, John|Schork, Nicholas|Stahl, Eli|Zhu, Qian|Krishnan, Arjun|Yao, Vicky|Troyanskaya, Olga|Bilaloglu, Seda|Raghavan, Preeti|Bergen, Sarah|Jureus, Anders|Landen, Mikael|Bipolar Disorders Working Group of the Psychiatric Genomics Consortium', 'Mathematics, New York University, New York, New York, United States of America.|Mathematics, New York University, New York, New York, United States of America.|Psychiatry, University of California, San Diego, California, United States of America.|Human Biology, J. Craig Venters Institute, La Jolla, California, United States of America.|Genetics and Genomic Sciences, Mount Sinai Medical School, New York, New York, United States of America.|Computer Science, Princeton University, Princeton, New Jersey, United States of America.|Computational Mathematics Science and Engineering, Michigan State University, East Lansing, Michigan, United States of America.|Computer Science, Princeton University, Princeton, New Jersey, United States of America.|Center for Computational Biology, Flatiron Institute, New York, New York, United States of America.|Department of Rehabilitation Medicine, New York University Medical School, New York, New York, United States of America.|Department of Rehabilitation Medicine, New York University Medical School, New York, New York, United States of America.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.', 'United States|United States|United States|United States|United States|Jersey|United States|Jersey|Un', 1, 'Algorithms|Bipolar Disorder|Breast Neoplasms|Cluster Analysis|Databases, Genetic|Female|Gene Expression Profiling|Genome-Wide Association Study|Humans|Male', 'Journal Article', '10.1371/journal.pcbi.1006105', '29758032', 'A common goal in data-analysis is to sift through a large data-matrix and detect any significant submatrices (i.e., biclusters) that have a low numerical rank. We present a simple algorithm for tackling this biclustering problem. Our algorithm accumulates information about 2-by-2 submatrices (i.e., loops) within the data-matrix, and focuses on rows and columns of the data-matrix that participate in an abundance of low-rank loops. We demonstrate, through analysis and numerical-experiments, that this loop-counting method performs well in a variety of scenarios, outperforming simple spectral methods in many situations of interest. Another important feature of our method is that it can easily be modified to account for aspects of experimental design which commonly arise in practice. For example, our algorithm can be modified to correct for controls, categorical- and continuous-covariates, as well as sparsity within the data. We demonstrate these practical features with two examples, the first drawn from gene-expression analysis and the second drawn from a much larger genome-wide-association-study (GWAS).'),
(89052, 2018, 'plos', 'Near real-time forecasting for cholera decision making in Haiti after Hurricane Matthew', 'Pasetto, Damiano|Finger, Flavio|Camacho, Anton|Grandesso, Francesco|Cohuet, Sandra|Lemaitre, Joseph C|Azman, Andrew S|Luquero, Francisco J|Bertuzzo, Enrico|Rinaldo, Andrea', 'Laboratory of Ecohydrology, School of Architecture, Civil and Environmental Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Laboratory of Ecohydrology, School of Architecture, Civil and Environmental Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Centre for the Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom.|Epicentre, Paris, France.|Epicentre, Paris, France.|Laboratory of Ecohydrology, School of Architecture, Civil and Environmental Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America.|Epicentre, Geneva, Switzerland.|Department of Environmental Sciences, Informatics and Statistics, University Ca Foscari Venezia, Venezia Mestre, Italy.|Laboratory of Ecohydrology, School of Architecture, Civil and Environmental Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.', 'Switzerland|Switzerland|United Kingdom|France|France|Switzerland|United States|Switzerland|Italy|Swi', 2, 'Cholera|Computer Simulation|Cyclonic Storms|Decision Making|Disease Outbreaks|Forecasting|Haiti|Humans|Incidence', 'Journal Article', '10.1371/journal.pcbi.1006127', '29768401', 'Computational models of cholera transmission can provide objective insights into the course of an ongoing epidemic and aid decision making on allocation of health care resources. However, models are typically designed, calibrated and interpreted post-hoc. Here, we report the efforts of a team from academia, field research and humanitarian organizations to model in near real-time the Haitian cholera outbreak after Hurricane Matthew in October 2016, to assess risk and to quantitatively estimate the efficacy of a then ongoing vaccination campaign. A rainfall-driven, spatially-explicit meta-community model of cholera transmission was coupled to a data assimilation scheme for computing short-term projections of the epidemic in near real-time. The model was used to forecast cholera incidence for the months after the passage of the hurricane (October-December 2016) and to predict the impact of a planned oral cholera vaccination campaign. Our first projection, from October 29 to December 31, predicted the highest incidence in the departments of Grande Anse and Sud, accounting for about 45% of the total cases in Haiti. The projection included a second peak in cholera incidence in early December largely driven by heavy rainfall forecasts, confirming the urgency for rapid intervention. A second projection (from November 12 to December 31) used updated rainfall forecasts to estimate that 835 cases would be averted by vaccinations in Grande Anse (90% Prediction Interval [PI] 476-1284) and 995 in Sud (90% PI 508-2043). The experience gained by this modeling effort shows that state-of-the-art computational modeling and data-assimilation methods can produce informative near real-time projections of cholera incidence. Collaboration among modelers and field epidemiologists is indispensable to gain fast access to field data and to translate model results into operational recommendations for emergency management during an outbreak. Future efforts should thus draw together multi-disciplinary teams to ensure model outputs are appropriately based, interpreted and communicated.'),
(89053, 2018, 'plos', '2018 outstanding contributions to ISCB award: Russ Altman', 'Fogg, Christiana N|Kovats, Diane E|Shamir, Ron', 'Freelance Writer, Kensington, Maryland, United States of America.|International Society for Computational Biology.|Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.', 'United States|-|Israel', 0, 'Awards and Prizes|Computational Biology|History, 21st Century|Humans', 'Historical Article', '10.1371/journal.pcbi.1006140', '29771913', '-'),
(89054, 2018, 'plos', '2018 ISCB accomplishments by a senior scientist award', 'Fogg, Christiana N|Kovats, Diane E|Shamir, Ron', 'Freelance Writer, Kensington, Maryland, United States of America.|International Society for Computational Biology.|Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.', 'United States|-|Israel', 1, 'Awards and Prizes|Computational Biology|History, 21st Century|Humans', 'Historical Article', '10.1371/journal.pcbi.1006138', '29771916', '-'),
(89055, 2018, 'plos', 'Firing-rate based network modeling of the dLGN circuit: Effects of cortical feedback on spatiotemporal response properties of relay cells', 'Mobarhan, Milad Hobbi|Halnes, Geir|Martínez-Cañada, Pablo|Hafting, Torkel|Fyhn, Marianne|Einevoll, Gaute T', 'Centre for Integrative Neuroplasticity, University of Oslo, Oslo, Norway.|Centre for Integrative Neuroplasticity, University of Oslo, Oslo, Norway.|Centro de Investigación en Tecnologías de la Información y de las Comunicaciones (CITIC), University of Granada, Granada, Spain.|Centre for Integrative Neuroplasticity, University of Oslo, Oslo, Norway.|Centre for Integrative Neuroplasticity, University of Oslo, Oslo, Norway.|Centre for Integrative Neuroplasticity, University of Oslo, Oslo, Norway.', 'Norway|Norway|Spain|Norway|Norway|Norway', 0, 'Animals|Cats|Computational Biology|Feedback|Geniculate Bodies|Mice|Models, Neurological|Visual Pathways', 'Journal Article', '10.1371/journal.pcbi.1006156', '29771919', 'Visually evoked signals in the retina pass through the dorsal geniculate nucleus (dLGN) on the way to the visual cortex. This is however not a simple feedforward flow of information: there is a significant feedback from cortical cells back to both relay cells and interneurons in the dLGN. Despite four decades of experimental and theoretical studies, the functional role of this feedback is still debated. Here we use a firing-rate model, the extended difference-of-Gaussians (eDOG) model, to explore cortical feedback effects on visual responses of dLGN relay cells. For this model the responses are found by direct evaluation of two- or three-dimensional integrals allowing for fast and comprehensive studies of putative effects of different candidate organizations of the cortical feedback. Our analysis identifies a special mixed configuration of excitatory and inhibitory cortical feedback which seems to best account for available experimental data. This configuration consists of (i) a slow (long-delay) and spatially widespread inhibitory feedback, combined with (ii) a fast (short-delayed) and spatially narrow excitatory feedback, where (iii) the excitatory/inhibitory ON-ON connections are accompanied respectively by inhibitory/excitatory OFF-ON connections, i.e. following a phase-reversed arrangement. The recent development of optogenetic and pharmacogenetic methods has provided new tools for more precise manipulation and investigation of the thalamocortical circuit, in particular for mice. Such data will expectedly allow the eDOG model to be better constrained by data from specific animal model systems than has been possible until now for cat. We have therefore made the Python tool pyLGN which allows for easy adaptation of the eDOG model to new situations.'),
(89056, 2018, 'plos', 'Enzyme sequestration by the substrate: An analysis in the deterministic and stochastic domains', 'Petrides, Andreas|Vinnicombe, Glenn', 'Department of Engineering, University of Cambridge, Cambridge, United Kingdom.|Department of Engineering, University of Cambridge, Cambridge, United Kingdom.', 'United Kingdom|United Kingdom', 0, 'Enzymes|Molecular Docking Simulation|Phosphotransferases|Protein Binding|Protein Domains|Stochastic Processes|Substrate Specificity', 'Journal Article', '10.1371/journal.pcbi.1006107', '29771922', 'This paper is concerned with the potential multistability of protein concentrations in the cell. That is, situations where one, or a family of, proteins may sit at one of two or more different steady state concentrations in otherwise identical cells, and in spite of them being in the same environment. For models of multisite protein phosphorylation for example, in the presence of excess substrate, it has been shown that the achievable number of stable steady states can increase linearly with the number of phosphosites available. In this paper, we analyse the consequences of adding enzyme docking to these and similar models, with the resultant sequestration of phosphatase and kinase by the fully unphosphorylated and by the fully phosphorylated substrates respectively. In the large molecule numbers limit, where deterministic analysis is applicable, we prove that there are always values for these rates of sequestration which, when exceeded, limit the extent of multistability. For the models considered here, these numbers are much smaller than the affinity of the enzymes to the substrate when it is in a modifiable state. As substrate enzyme-sequestration is increased, we further prove that the number of steady states will inevitably be reduced to one. For smaller molecule numbers a stochastic analysis is more appropriate, where multistability in the large molecule numbers limit can manifest itself as multimodality of the probability distribution, the system spending periods of time in the vicinity of one mode before jumping to another. Here, we find that substrate enzyme sequestration can induce bimodality even in systems where only a single steady state can exist at large numbers. To facilitate this analysis, we develop a weakly chained diagonally dominant M-matrix formulation of the Chemical Master Equation, allowing greater insights in the way particular mechanisms, like enzyme sequestration, can shape probability distributions and therefore exhibit different behaviour across different regimes.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(89057, 2018, 'plos', 'Atomic resolution mechanism of ligand binding to a solvent inaccessible cavity in T4 lysozyme', 'Mondal, Jagannath|Ahalawat, Navjeet|Pandit, Subhendu|Kay, Lewis E|Vallurupalli, Pramodh', 'Tata Institute of Fundamental Research, Hyderabad, India.|Tata Institute of Fundamental Research, Hyderabad, India.|Tata Institute of Fundamental Research, Hyderabad, India.|Departments of Molecular Genetics, Biochemistry and Chemistry, University of Toronto, Toronto, Ontario, Canada.|Tata Institute of Fundamental Research, Hyderabad, India.', 'India|India|India|Canada|India', 0, 'Benzene|Binding Sites|Crystallography, X-Ray|Hydrophobic and Hydrophilic Interactions|Ligands|Molecular Dynamics Simulation|Muramidase|Protein Binding', 'Journal Article', '10.1371/journal.pcbi.1006180', '29775455', 'Ligand binding sites in proteins are often localized to deeply buried cavities, inaccessible to bulk solvent. Yet, in many cases binding of cognate ligands occurs rapidly. An intriguing system is presented by the L99A cavity mutant of T4 Lysozyme (T4L L99A) that rapidly binds benzene (~106 M-1s-1). Although the protein has long served as a model system for protein thermodynamics and crystal structures of both free and benzene-bound T4L L99A are available, the kinetic pathways by which benzene reaches its solvent-inaccessible binding cavity remain elusive. The current work, using extensive molecular dynamics simulation, achieves this by capturing the complete process of spontaneous recognition of benzene by T4L L99A at atomistic resolution. A series of multi-microsecond unbiased molecular dynamics simulation trajectories unequivocally reveal how benzene, starting in bulk solvent, diffuses to the protein and spontaneously reaches the solvent inaccessible cavity of T4L L99A. The simulated and high-resolution X-ray derived bound structures are in excellent agreement. A robust four-state Markov model, developed using cumulative 60 xcexbcs trajectories, identifies and quantifies multiple ligand binding pathways with low activation barriers. Interestingly, none of these identified binding pathways required large conformational changes for ligand access to the buried cavity. Rather, these involve transient but crucial opening of a channel to the cavity via subtle displacements in the positions of key helices (helix4/helix6, helix7/helix9) leading to rapid binding. Free energy simulations further elucidate that these channel-opening events would have been unfavorable in wild type T4L. Taken together and via integrating with results from experiments, these simulations provide unprecedented mechanistic insights into the complete ligand recognition process in a buried cavity. By illustrating the power of subtle helix movements in opening up multiple pathways for ligand access, this work offers an alternate view of ligand recognition in a solvent-inaccessible cavity, contrary to the common perception of a single dominant pathway for ligand binding.'),
(89058, 2018, 'plos', 'Potassium and sodium microdomains in thin astroglial processes: A computational model study', 'Breslin, Kevin|Wade, John Joseph|Wong-Lin, KongFatt|Harkin, Jim|Flanagan, Bronac|Van Zalinge, Harm|Hall, Steve|Walker, Matthew|Verkhratsky, Alexei|McDaid, Liam', 'Computational Neuroscience and Neural Engineering (CNET) Research Team, Intelligent Systems Research Centre, Ulster University, Derry, United Kingdom.|Computational Neuroscience and Neural Engineering (CNET) Research Team, Intelligent Systems Research Centre, Ulster University, Derry, United Kingdom.|Neural Systems and Neurotechnology Research Team, Intelligent Systems Research Centre, Ulster University, Derry, United Kingdom.|Computational Neuroscience and Neural Engineering (CNET) Research Team, Intelligent Systems Research Centre, Ulster University, Derry, United Kingdom.|Computational Neuroscience and Neural Engineering (CNET) Research Team, Intelligent Systems Research Centre, Ulster University, Derry, United Kingdom.|Department of Electrical Engineering and Electronics, University of Liverpool, Liverpool, United Kingdom.|Department of Electrical Engineering and Electronics, University of Liverpool, Liverpool, United Kingdom.|Clinical & Experimental Epilepsy Institute of Neurology, University College London, London, United Kingdom.|Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.|Computational Neuroscience and Neural Engineering (CNET) Research Team, Intelligent Systems Research Centre, Ulster University, Derry, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Animals|Astrocytes|Computational Biology|Computer Simulation|Extracellular Space|Glutamic Acid|Models, Biological|Models, Neurological|Potassium|Sodium', 'Journal Article', '10.1371/journal.pcbi.1006151', '29775457', 'A biophysical model that captures molecular homeostatic control of ions at the perisynaptic cradle (PsC) is of fundamental importance for understanding the interplay between astroglial and neuronal compartments. In this paper, we develop a multi-compartmental mathematical model which proposes a novel mechanism whereby the flow of cations in thin processes is restricted due to negatively charged membrane lipids which result in the formation of deep potential wells near the dipole heads. These wells restrict the flow of cations to hopping between adjacent wells as they transverse the process, and this surface retention of cations will be shown to give rise to the formation of potassium (K+) and sodium (Na+) microdomains at the PsC. We further propose that a K+ microdomain formed at the PsC, provides the driving force for the return of K+ to the extracellular space for uptake by the neurone, thereby preventing K+ undershoot. A slow decay of Na+ was also observed in our simulation after a period of glutamate stimulation which is in strong agreement with experimental observations. The pathological implications of microdomain formation during neuronal excitation are also discussed.'),
(89059, 2018, 'plos', 'On the role of sparseness in the evolution of modularity in gene regulatory networks', 'Espinosa-Soto, Carlos', 'Instituto de Física, Universidad Autónoma de San Luis Potosí, Manuel Nava 6, Zona Universitaria, San Luis Potosí, Mexico.', 'Mexico', 6, 'Computational Biology|Computer Simulation|Evolution, Molecular|Gene Regulatory Networks|Models, Genetic', 'Journal Article', '10.1371/journal.pcbi.1006172', '29775459', 'Modularity is a widespread property in biological systems. It implies that interactions occur mainly within groups of system elements. A modular arrangement facilitates adjustment of one module without perturbing the rest of the system. Therefore, modularity of developmental mechanisms is a major factor for evolvability, the potential to produce beneficial variation from random genetic change. Understanding how modularity evolves in gene regulatory networks, that create the distinct gene activity patterns that characterize different parts of an organism, is key to developmental and evolutionary biology. One hypothesis for the evolution of modules suggests that interactions between some sets of genes become maladaptive when selection favours additional gene activity patterns. The removal of such interactions by selection would result in the formation of modules. A second hypothesis suggests that modularity evolves in response to sparseness, the scarcity of interactions within a system. Here I simulate the evolution of gene regulatory networks and analyse diverse experimentally sustained networks to study the relationship between sparseness and modularity. My results suggest that sparseness alone is neither sufficient nor necessary to explain modularity in gene regulatory networks. However, sparseness amplifies the effects of forms of selection that, like selection for additional gene activity patterns, already produce an increase in modularity. That evolution of new gene activity patterns is frequent across evolution also supports that it is a major factor in the evolution of modularity. That sparseness is widespread across gene regulatory networks indicates that it may have facilitated the evolution of modules in a wide variety of cases.'),
(89060, 2018, 'plos', 'Implications for human odor sensing revealed from the statistics of odorant-receptor interactions', 'Bak, Ji Hyun|Jang, Seogjoo J|Hyeon, Changbong', 'School of Computational Sciences, Korea Institute for Advanced Study, Seoul, Korea.|Department of Chemistry and Biochemistry, Queens College, City University of New York, Queens, New York, United States of America.|School of Computational Sciences, Korea Institute for Advanced Study, Seoul, Korea.', '-|United States|-', 1, 'Animals|Computational Biology|Electrophysiological Phenomena|High-Throughput Screening Assays|Humans|Kinetics|Models, Neurological|Odorants|Olfactory Receptor Neurons|Receptors, Odorant', 'Journal Article', '10.1371/journal.pcbi.1006175', '29782484', 'Binding of odorants to olfactory receptors (ORs) elicits downstream chemical and neural signals, which are further processed to odor perception in the brain. Recently, Mainland and colleagues have measured more than 500 pairs of odorant-OR interaction by a high-throughput screening assay method, opening a new avenue to understanding the principles of human odor coding. Here, using a recently developed minimal model for OR activation kinetics, we characterize the statistics of OR activation by odorants in terms of three empirical parameters: the half-maximum effective concentration EC50, the efficacy, and the basal activity. While the data size of odorants is still limited, the statistics offer meaningful information on the breadth and optimality of the tuning of human ORs to odorants, and allow us to relate the three parameters with the microscopic rate constants and binding affinities that define the OR activation kinetics. Despite the stochastic nature of the response expected at individual OR-odorant level, we assess that the confluence of signals in a neuron released from the multitude of ORs is effectively free of noise and deterministic with respect to changes in odorant concentration. Thus, setting a threshold to the fraction of activated OR copy number for neural spiking binarizes the electrophysiological signal of olfactory sensory neuron, thereby making an information theoretic approach a viable tool in studying the principles of odor perception.'),
(89061, 2018, 'plos', 'Systematic interrogation of diverse Omic data reveals interpretable, robust, and generalizable transcriptomic features of clinically successful therapeutic targets', 'Rouillard, Andrew D|Hurle, Mark R|Agarwal, Pankaj', 'Computational Biology, GSK, Collegeville, PA, United States of America.|Computational Biology, GSK, Collegeville, PA, United States of America.|Computational Biology, GSK, Collegeville, PA, United States of America.', 'United States|United States|United States', 0, 'Animals|Cell Line|Computational Biology|Drug Discovery|Gene Expression Profiling|Humans|Mice|Signal Transduction|Transcriptome', 'Journal Article', '10.1371/journal.pcbi.1006142', '29782487', 'Target selection is the first and pivotal step in drug discovery. An incorrect choice may not manifest itself for many years after hundreds of millions of research dollars have been spent. We collected a set of 332 targets that succeeded or failed in phase III clinical trials, and explored whether Omic features describing the target genes could predict clinical success. We obtained features from the recently published comprehensive resource: Harmonizome. Nineteen features appeared to be significantly correlated with phase III clinical trial outcomes, but only 4 passed validation schemes that used bootstrapping or modified permutation tests to assess feature robustness and generalizability while accounting for target class selection bias. We also used classifiers to perform multivariate feature selection and found that classifiers with a single feature performed as well in cross-validation as classifiers with more features (AUROC = 0.57 and AUPR = 0.81). The two predominantly selected features were mean mRNA expression across tissues and standard deviation of expression across tissues, where successful targets tended to have lower mean expression and higher expression variance than failed targets. This finding supports the conventional wisdom that it is favorable for a target to be present in the tissue(s) affected by a disease and absent from other tissues. Overall, our results suggest that it is feasible to construct a model integrating interpretable target features to inform target selection. We anticipate deeper insights and better models in the future, as researchers can reuse the data we have provided to improve methods for handling sample biases and learn more informative features. Code, documentation, and data for this study have been deposited on GitHub at https://github.com/arouillard/omic-features-successful-targets.'),
(89062, 2018, 'plos', 'Community-based benchmarking improves spike rate inference from two-photon calcium imaging data', 'Berens, Philipp|Freeman, Jeremy|Deneux, Thomas|Chenkov, Nikolay|McColgan, Thomas|Speiser, Artur|Macke, Jakob H|Turaga, Srinivas C|Mineault, Patrick|Rupprecht, Peter|Gerhard, Stephan|Friedrich, Rainer W|Friedrich, Johannes|Paninski, Liam|Pachitariu, Marius|Harris, Kenneth D|Bolte, Ben|Machado, Timothy A|Ringach, Dario|Stone, Jasmine|Rogerson, Luke E|Sofroniew, Nicolas J|Reimer, Jacob|Froudarakis, Emmanouil|Euler, Thomas|Román Rosón, Miroslav|Theis, Lucas|Tolias, Andreas S|Bethge, Matthias', 'Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.|Chan Zuckerberg Initiative, San Francisco, California, United States of America.|Unit of Neuroscience Information and Complexity, Centre National de la Recherche Scientifique, Gif-sur-Yvette, France.|Bernstein Center for Computational Neuroscience and Institute for Theoretical Biology, Humboldt-Universität zu Berlin, Berlin, Germany.|Bernstein Center for Computational Neuroscience and Institute for Theoretical Biology, Humboldt-Universität zu Berlin, Berlin, Germany.|Research Center Caesar, an associate of the Max Planck Society, Bonn, Germany.|Research Center Caesar, an associate of the Max Planck Society, Bonn, Germany.|Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America.|Independent Researcher, San Francisco, California, United States of America.|Friedrich Miescher Institute of Biomedical Research, Basel, Switzerland.|Friedrich Miescher Institute of Biomedical Research, Basel, Switzerland.|Friedrich Miescher Institute of Biomedical Research, Basel, Switzerland.|Departments of Statistics and Neuroscience, Grossman Center for the Statistics of Mind, and Center for Theoretical Neuroscience, Columbia University, New York, New York, United States of America.|Departments of Statistics and Neuroscience, Grossman Center for the Statistics of Mind, and Center for Theoretical Neuroscience, Columbia University, New York, New York, United States of America.|Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America.|Institute of Neurology, University College, London, United Kingdom.|Departments of Mathematics and Computer Science, Emory University, Atlanta, United States of America.|Departments of Statistics and Neuroscience, Grossman Center for the Statistics of Mind, and Center for Theoretical Neuroscience, Columbia University, New York, New York, United States of America.|Neurobiology and Psychology, Jules Stein Eye Institute, Biomedical Engineering Program, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.|Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America.|Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.|Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, 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.|Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.|Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.|Twitter, London, United Kingdom.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.|Center for Integrative Neuroscience, University of Tübingen, Tübingen, Germany.', 'Germany|United States|France|Germany|Germany|Germany|Germany|United States|United States|Switzerland', 25, 'Action Potentials|Algorithms|Animals|Calcium|Computational Biology|Databases, Factual|Mice|Models, Neurological|Molecular Imaging|Optical Imaging|Retina|Retinal Neurons', 'Journal Article', '10.1371/journal.pcbi.1006157', '29782491', 'In recent years, two-photon calcium imaging has become a standard tool to probe the function of neural circuits and to study computations in neuronal populations. However, the acquired signal is only an indirect measurement of neural activity due to the comparatively slow dynamics of fluorescent calcium indicators. Different algorithms for estimating spike rates from noisy calcium measurements have been proposed in the past, but it is an open question how far performance can be improved. Here, we report the results of the spikefinder challenge, launched to catalyze the development of new spike rate inference algorithms through crowd-sourcing. We present ten of the submitted algorithms which show improved performance compared to previously evaluated methods. Interestingly, the top-performing algorithms are based on a wide range of principles from deep neural networks to generative models, yet provide highly correlated estimates of the neural activity. The competition shows that benchmark challenges can drive algorithmic developments in neuroscience.'),
(89063, 2018, 'plos', 'Polymorphic sites preferentially avoid co-evolving residues in MHC class I proteins', 'Dib, Linda|Salamin, Nicolas|Gfeller, David', 'Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, Switzerland.|Swiss Institutes of Bioinformatics, Quartier Sorge, Lausanne, Switzerland.|Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, Switzerland.', 'Switzerland|Switzerland|Switzerland', 4, 'Animals|Binding Sites|Evolution, Molecular|Histocompatibility Antigens Class I|Humans|Models, Molecular|Phylogeny|Polymorphism, Genetic|Protein Stability|Vertebrates', 'Journal Article', '10.1371/journal.pcbi.1006188', '29782520', 'Major histocompatibility complex class I (MHC-I) molecules are critical to adaptive immune defence mechanisms in vertebrate species and are encoded by highly polymorphic genes. Polymorphic sites are located close to the ligand-binding groove and entail MHC-I alleles with distinct binding specificities. Some efforts have been made to investigate the relationship between polymorphism and protein stability. However, less is known about the relationship between polymorphism and MHC-I co-evolutionary constraints. Using Direct Coupling Analysis (DCA) we found that co-evolution analysis accurately pinpoints structural contacts, although the protein family is restricted to vertebrates and comprises less than five hundred species, and that the co-evolutionary signal is mainly driven by inter-species changes, and not intra-species polymorphism. Moreover, we show that polymorphic sites in human preferentially avoid co-evolving residues, as well as residues involved in protein stability. These results suggest that sites displaying high polymorphism may have been selected during vertebrates evolution to avoid co-evolutionary constraints and thereby maximize their mutability.'),
(89064, 2018, 'plos', 'Logistical constraints lead to an intermediate optimum in outbreak response vaccination', 'Tao, Yun|Shea, Katriona|Ferrari, Matthew', 'Department of Biology and The Center for Infectious Disease Dynamics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Department of Biology and The Center for Infectious Disease Dynamics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Department of Biology and The Center for Infectious Disease Dynamics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.', 'United States|United States|United States', 2, 'Computational Biology|Computer Simulation|Disease Outbreaks|Humans|Immunity, Herd|Models, Biological|Time Factors|Vaccination|Vaccines', 'Journal Article', '10.1371/journal.pcbi.1006161', '29791432', 'Dynamic models in disease ecology have historically evaluated vaccination strategies under the assumption that they are implemented homogeneously in space and time. However, this approach fails to formally account for operational and logistical constraints inherent in the distribution of vaccination to the population at risk. Thus, feedback between the dynamic processes of vaccine distribution and transmission might be overlooked. Here, we present a spatially explicit, stochastic Susceptible-Infected-Recovered-Vaccinated model that highlights the density-dependence and spatial constraints of various diffusive strategies of vaccination during an outbreak. The model integrates an agent-based process of disease spread with a partial differential process of vaccination deployment. We characterize the vaccination response in terms of a diffusion rate that describes the distribution of vaccination to the population at risk from a central location. This generates an explicit trade-off between slow diffusion, which concentrates effort near the central location, and fast diffusion, which spreads a fixed vaccination effort thinly over a large area. We use stochastic simulation to identify the optimum vaccination diffusion rate as a function of population density, interaction scale, transmissibility, and vaccine intensity. Our results show that, conditional on a timely response, the optimal strategy for minimizing outbreak size is to distribute vaccination resource at an intermediate rate: fast enough to outpace the epidemic, but slow enough to achieve local herd immunity. If the response is delayed, however, the optimal strategy for minimizing outbreak size changes to a rapidly diffusive distribution of vaccination effort. The latter may also result in significantly larger outbreaks, thus suggesting a benefit of allocating resources to timely outbreak detection and response.'),
(89065, 2018, 'plos', 'Traceability, reproducibility and wiki-exploration for à-la-carte reconstructions of genome-scale metabolic models', 'Aite, Méziane|Chevallier, Marie|Frioux, Clémence|Trottier, Camille|Got, Jeanne|Cortés, María Paz|Mendoza, Sebastián N|Carrier, Grégory|Dameron, Olivier|Guillaudeux, Nicolas|Latorre, Mauricio|Loira, Nicolás|Markov, Gabriel V|Maass, Alejandro|Siegel, Anne', 'IRISA, Univ Rennes, Inria, CNRS, Rennes, France.|IRISA, Univ Rennes, Inria, CNRS, Rennes, France.|IRISA, Univ Rennes, Inria, CNRS, Rennes, France.|IRISA, Univ Rennes, Inria, CNRS, Rennes, France.|IRISA, Univ Rennes, Inria, CNRS, Rennes, France.|Centro de Modelamiento Matemático, Universidad de Chile, Santiago, Chile.|Centro de Modelamiento Matemático, Universidad de Chile, Santiago, Chile.|Laboratoire de Physiologie et de Biotechnologie des Algues, IFREMER, Nantes, France.|IRISA, Univ Rennes, Inria, CNRS, Rennes, France.|IRISA, Univ Rennes, Inria, CNRS, Rennes, France.|Centro de Modelamiento Matemático, Universidad de Chile, Santiago, Chile.|Centro de Modelamiento Matemático, Universidad de Chile, Santiago, Chile.|UMR 8227, Integrative Biology of Marine Models, Station biologique de Roscoff, Sorbonne Université, CNRS, Roscoff, France.|Centro de Modelamiento Matemático, Universidad de Chile, Santiago, Chile.|IRISA, Univ Rennes, Inria, CNRS, Rennes, France.', 'France|France|France|France|France|Chile|Chile|France|France|France|Chile|Chile|France|Chile|France', 12, 'Antioxidants|Databases, Factual|Genomics|Information Storage and Retrieval|Internet|Metabolic Networks and Pathways|Microalgae|Models, Theoretical|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1006146', '29791443', 'Genome-scale metabolic models have become the tool of choice for the global analysis of microorganism metabolism, and their reconstruction has attained high standards of quality and reliability. Improvements in this area have been accompanied by the development of some major platforms and databases, and an explosion of individual bioinformatics methods. Consequently, many recent models result from à la carte pipelines, combining the use of platforms, individual tools and biological expertise to enhance the quality of the reconstruction. Although very useful, introducing heterogeneous tools, that hardly interact with each other, causes loss of traceability and reproducibility in the reconstruction process. This represents a real obstacle, especially when considering less studied species whose metabolic reconstruction can greatly benefit from the comparison to good quality models of related organisms. This work proposes an adaptable workspace, AuReMe, for sustainable reconstructions or improvements of genome-scale metabolic models involving personalized pipelines. At each step, relevant information related to the modifications brought to the model by a method is stored. This ensures that the process is reproducible and documented regardless of the combination of tools used. Additionally, the workspace establishes a way to browse metabolic models and their metadata through the automatic generation of ad-hoc local wikis dedicated to monitoring and facilitating the process of reconstruction. AuReMe supports exploration and semantic query based on RDF databases. We illustrate how this workspace allowed handling, in an integrated way, the metabolic reconstructions of non-model organisms such as an extremophile bacterium or eukaryote algae. Among relevant applications, the latter reconstruction led to putative evolutionary insights of a metabolic pathway.'),
(89066, 2018, 'plos', 'Correction: Solving the influence maximization problem reveals regulatory organization of the yeast cell cycle', 'PLOS Computational Biology Staff', 'IRISA, Univ Rennes, Inria, CNRS, Rennes, France.', 'France', 0, '-', 'Journal Article', '10.1371/journal.pcbi.1006190', '29791444', '[This corrects the article DOI: 10.1371/journal.pcbi.1005591.].'),
(89067, 2018, 'plos', 'Design of optimal nonlinear network controllers for Alzheimers disease', 'Sanchez-Rodriguez, Lazaro M|Iturria-Medina, Yasser|Baines, Erica A|Mallo, Sabela C|Dousty, Mehdy|Sotero, Roberto C|Alzheimer’s Disease Neuroimaging Initiative', 'Biomedical Engineering Graduate Program, University of Calgary, Calgary, Alberta, Canada.|Department of Neurology & Neurosurgery, McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, Quebec, Canada.|Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.|Departament of Developmental Psychology, University of Santiago de Compostela, Santiago de Compostela, Spain.|Biomedical Engineering Graduate Program, University of Calgary, Calgary, Alberta, Canada.|Biomedical Engineering Graduate Program, University of Calgary, Calgary, Alberta, Canada.|Biomedical Engineering Graduate Program, University of Calgary, Calgary, Alberta, Canada.', 'Canada|Canada|Canada|Spain|Canada|Canada|Canada', 0, 'Algorithms|Alzheimer Disease|Brain|Computer Simulation|Diffusion Magnetic Resonance Imaging|Electroencephalography|Humans|Image Processing, Computer-Assisted|Neuroimaging|Nonlinear Dynamics|Signal Processing, Computer-Assisted', 'Journal Article', '10.1371/journal.pcbi.1006136', '29795548', 'Brain stimulation can modulate the activity of neural circuits impaired by Alzheimers disease (AD), having promising clinical benefit. However, all individuals with the same condition currently receive identical brain stimulation, with limited theoretical basis for this generic approach. In this study, we introduce a control theory framework for obtaining exogenous signals that revert pathological electroencephalographic activity in AD at a minimal energetic cost, while reflecting patients biological variability. We used anatomical networks obtained from diffusion magnetic resonance images acquired by the Alzheimers Disease Neuroimaging Initiative (ADNI) as mediators for the interaction between Duffing oscillators. The nonlinear nature of the brain dynamics is preserved, given that we extend the so-called state-dependent Riccati equation control to reflect the stimulation objective in the high-dimensional neural system. By considering nonlinearities in our model, we identified regions for which control inputs fail to correct abnormal activity. There are changes to the way stimulated regions are ranked in terms of the energetic cost of controlling the entire network, from a linear to a nonlinear approach. We also found that limbic system and basal ganglia structures constitute the top target locations for stimulation in AD. Patients with highly integrated anatomical networks-namely, networks having low average shortest path length, high global efficiency-are the most suitable candidates for the propagation of stimuli and consequent success on the control task. Other diseases associated with alterations in brain dynamics and the self-control mechanisms of the brain can be addressed through our framework.'),
(89068, 2018, 'plos', 'Variability in pulmonary vein electrophysiology and fibrosis determines arrhythmia susceptibility and dynamics', 'Roney, Caroline H|Bayer, Jason D|Cochet, Hubert|Meo, Marianna|Dubois, Rémi|Jaïs, Pierre|Vigmond, Edward J', 'IHU Liryc, Electrophysiology and Heart Modeling Institute, foundation Bordeaux Université, F-33600 Pessac- Bordeaux, France.|IHU Liryc, Electrophysiology and Heart Modeling Institute, foundation Bordeaux Université, F-33600 Pessac- Bordeaux, France.|IHU Liryc, Electrophysiology and Heart Modeling Institute, foundation Bordeaux Université, F-33600 Pessac- Bordeaux, France.|IHU Liryc, Electrophysiology and Heart Modeling Institute, foundation Bordeaux Université, F-33600 Pessac- Bordeaux, France.|IHU Liryc, Electrophysiology and Heart Modeling Institute, foundation Bordeaux Université, F-33600 Pessac- Bordeaux, France.|IHU Liryc, Electrophysiology and Heart Modeling Institute, foundation Bordeaux Université, F-33600 Pessac- Bordeaux, France.|IHU Liryc, Electrophysiology and Heart Modeling Institute, foundation Bordeaux Université, F-33600 Pessac- Bordeaux, France.', 'France|France|France|France|France|France|France', 14, 'Action Potentials|Atrial Fibrillation|Cardiac Electrophysiology|Catheter Ablation|Computer Simulation|Fibrosis|Heart Atria|Humans|Models, Cardiovascular|Pulmonary Veins', 'Journal Article', '10.1371/journal.pcbi.1006166', '29795549', 'Success rates for catheter ablation of persistent atrial fibrillation patients are currently low, however, there is a subset of patients for whom electrical isolation of the pulmonary veins alone is a successful treatment strategy. It is difficult to identify these patients because there are a multitude of factors affecting arrhythmia susceptibility and maintenance, and the individual contributions of these factors are difficult to determine clinically. We hypothesised that the combination of pulmonary vein (PV) electrophysiology and atrial body fibrosis determine driver location and effectiveness of pulmonary vein isolation (PVI). We used bilayer biatrial computer models based on patient geometries to investigate the effects of PV properties and atrial fibrosis on arrhythmia inducibility, maintenance mechanisms, and the outcome of PVI. Short PV action potential duration (APD) increased arrhythmia susceptibility, while longer PV APD was found to be protective. Arrhythmia inducibility increased with slower conduction velocity (CV) at the LA/PV junction, but not for cases with homogeneous CV changes or slower CV at the distal PV. Phase singularity (PS) density in the PV region for cases with PV fibrosis was increased. Arrhythmia dynamics depend on both PV properties and fibrosis distribution, varying from meandering rotors to PV reentry (in cases with baseline or long APD), to stable rotors at regions of high fibrosis density. Measurement of fibrosis and PV properties may indicate patient specific susceptibility to AF initiation and maintenance. PV PS density before PVI was higher for cases in which AF terminated or converted to a macroreentry, thus, high PV PS density may indicate likelihood of PVI success.'),
(89069, 2018, 'plos', 'The complex ecosystem in non small cell lung cancer invasion', 'Haney, Seth|Konen, Jessica|Marcus, Adam I|Bazhenov, Maxim', 'Department of Medicine, University of California, San Diego, La Jolla, California, United States of America.|Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.|Department of Medicine, University of California, San Diego, La Jolla, California, United States of America.', 'United States|United States|Georgia|United States', 2, 'Carcinoma, Non-Small-Cell Lung|Cell Line, Tumor|Computational Biology|Ecosystem|Humans|Lung Neoplasms|Microscopy, Fluorescence|Models, Biological|Signal Transduction|Tumor Microenvironment', 'Journal Article', '10.1371/journal.pcbi.1006131', '29795571', 'Many tumors are characterized by genetic instability, producing an assortment of genetic variants of tumor cells called subclones. These tumors and their surrounding environments form complex multi-cellular ecosystems, where subclones compete for resources and cooperate to perform multiple tasks, including cancer invasion. Our recent empirical studies revealed existence of such distinct phenotypes of cancer cells, leaders and followers, in lung cancer. These two cellular subclones exchange a complex array of extracellular signals demonstrating a symbiotic relationship at the cellular level. Here, we develop a computational model of the microenvironment of the lung cancer ecosystem to explore how the interactions between subclones can advance or inhibit invasion. We found that, due to the complexity of the ecosystem, invasion may have very different dynamics characterized by the different levels of aggressiveness. By altering the signaling environment, we could alter the ecological relationship between the cell types and the overall ecosystem development. Competition between leader and follower cell populations (defined by the limited amount of resources), positive feedback within the leader cell population (controlled by the focal adhesion kinase and fibronectin signaling), and impact of the follower cells to the leaders (represented by yet undetermined proliferation signal) all had major effects on the outcome of the collective dynamics. Specifically, our analysis revealed a class of tumors (defined by the strengths of fibronectin signaling and competition) that are particularly sensitive to manipulations of the signaling environment. These tumors can undergo irreversible changes to the tumor ecosystem that outlast the manipulations of feedbacks and have a profound impact on invasive potential. Our study predicts a complex division of labor between cancer cell subclones and suggests new treatment strategies targeting signaling within the tumor ecosystem.'),
(89070, 2018, 'plos', 'Coupled feedback loops maintain synaptic long-term potentiation: A computational model of PKMzeta synthesis and AMPA receptor trafficking', 'Helfer, Peter|Shultz, Thomas R', 'Department of Psychology and Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada.|Department of Psychology and School of Computer Science, McGill University, Montreal, Quebec, Canada.', 'Canada|Canada', 7, 'Animals|Computational Biology|Computer Simulation|Feedback, Physiological|Long-Term Potentiation|Mice|Nerve Tissue Proteins|Protein Kinase C|Protein Synthesis Inhibitors|Rats|Receptors, AMPA', 'Journal Article', '10.1371/journal.pcbi.1006147', '29813048', 'In long-term potentiation (LTP), one of the most studied types of neural plasticity, synaptic strength is persistently increased in response to stimulation. Although a number of different proteins have been implicated in the sub-cellular molecular processes underlying induction and maintenance of LTP, the precise mechanisms remain unknown. A particular challenge is to demonstrate that a proposed molecular mechanism can provide the level of stability needed to maintain memories for months or longer, in spite of the fact that many of the participating molecules have much shorter life spans. Here we present a computational model that combines simulations of several biochemical reactions that have been suggested in the LTP literature and show that the resulting system does exhibit the required stability. At the core of the model are two interlinked feedback loops of molecular reactions, one involving the atypical protein kinase PKMxcexb6 and its messenger RNA, the other involving PKMxcexb6 and GluA2-containing AMPA receptors. We demonstrate that robust bistability-stable equilibria both in the synapses potentiated and unpotentiated states-can arise from a set of simple molecular reactions. The model is able to account for a wide range of empirical results, including induction and maintenance of late-phase LTP, cellular memory reconsolidation and the effects of different pharmaceutical interventions.'),
(89071, 2018, 'plos', 'Detecting change in stochastic sound sequences', 'Skerritt-Davis, Benjamin|Elhilali, Mounya', 'Electrical & Computer Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.|Electrical & Computer Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.', 'United States|United States', 0, 'Adolescent|Adult|Attention|Auditory Perception|Brain|Computational Biology|Electroencephalography|Evoked Potentials, Auditory|Female|Humans|Male|Psychophysics|Sound|Stochastic Processes|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1006162', '29813049', 'Our ability to parse our acoustic environment relies on the brains capacity to extract statistical regularities from surrounding sounds. Previous work in regularity extraction has predominantly focused on the brains sensitivity to predictable patterns in sound sequences. However, natural sound environments are rarely completely predictable, often containing some level of randomness, yet the brain is able to effectively interpret its surroundings by extracting useful information from stochastic sounds. It has been previously shown that the brain is sensitive to the marginal lower-order statistics of sound sequences (i.e., mean and variance). In this work, we investigate the brains sensitivity to higher-order statistics describing temporal dependencies between sound events through a series of change detection experiments, where listeners are asked to detect changes in randomness in the pitch of tone sequences. Behavioral data indicate listeners collect statistical estimates to process incoming sounds, and a perceptual model based on Bayesian inference shows a capacity in the brain to track higher-order statistics. Further analysis of individual subjects behavior indicates an important role of perceptual constraints in listeners ability to track these sensory statistics with high fidelity. In addition, the inference model facilitates analysis of neural electroencephalography (EEG) responses, anchoring the analysis relative to the statistics of each stochastic stimulus. This reveals both a deviance response and a change-related disruption in phase of the stimulus-locked response that follow the higher-order statistics. These results shed light on the brains ability to process stochastic sound sequences.'),
(89072, 2018, 'plos', 'Structural organization and energy storage in crosslinked actin assemblies', 'Ma, Rui|Berro, Julien', 'Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America.', 'United States|United States', 10, 'Actin Cytoskeleton|Cell Membrane|Computational Biology|Endocytosis|Energy Metabolism|Fungal Proteins|Kinetics|Models, Molecular|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1006150', '29813051', 'During clathrin-mediated endocytosis in yeast cells, short actin filaments (< 200nm) and crosslinking protein fimbrin assemble to drive the internalization of the plasma membrane. However, the organization of the actin meshwork during endocytosis remains largely unknown. In addition, only a small fraction of the force necessary to elongate and pinch off vesicles can be accounted for by actin polymerization alone. In this paper, we used mathematical modeling to study the self-organization of rigid actin filaments in the presence of elastic crosslinkers in conditions relevant to endocytosis. We found that actin filaments condense into either a disordered meshwork or an ordered bundle depending on filament length and the mechanical and kinetic properties of the crosslinkers. Our simulations also demonstrated that these nanometer-scale actin structures can store a large amount of elastic energy within the crosslinkers (up to 10kBT per crosslinker). This conversion of binding energy into elastic energy is the consequence of geometric constraints created by the helical pitch of the actin filaments, which results in frustrated configurations of crosslinkers attached to filaments. We propose that this stored elastic energy can be used at a later time in the endocytic process. As a proof of principle, we presented a simple mechanism for sustained torque production by ordered detachment of crosslinkers from a pair of parallel filaments.'),
(89073, 2018, 'plos', 'Can a time varying external drive give rise to apparent criticality in neural systems?', 'Priesemann, Viola|Shriki, Oren', 'Max Planck Institute for Dynamics and Self-Organization, Göttingen, Germany.|Department of Cognitive and Brain Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.', 'Germany|Israel', 3, 'Action Potentials|Animals|Brain|Electroencephalography|Haplorhini|Humans|Macaca|Models, Neurological|Nerve Net|Neurons|Poisson Distribution|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1006081', '29813052', 'The finding of power law scaling in neural recordings lends support to the hypothesis of critical brain dynamics. However, power laws are not unique to critical systems and can arise from alternative mechanisms. Here, we investigate whether a common time-varying external drive to a set of Poisson units can give rise to neuronal avalanches and exhibit apparent criticality. To this end, we analytically derive the avalanche size and duration distributions, as well as additional measures, first for homogeneous Poisson activity, and then for slowly varying inhomogeneous Poisson activity. We show that homogeneous Poisson activity cannot give rise to power law distributions. Inhomogeneous activity can also not generate perfect power laws, but it can exhibit approximate power laws with cutoffs that are comparable to those typically observed in experiments. The mechanism of generating apparent criticality by time-varying external fields, forces or input may generalize to many other systems like dynamics of swarms, diseases or extinction cascades. Here, we illustrate the analytically derived effects for spike recordings in vivo and discuss approaches to distinguish true from apparent criticality. Ultimately, this requires causal interventions, which allow separating internal system properties from externally imposed ones.'),
(89074, 2018, 'plos', 'How epigenome drives chromatin folding and dynamics, insights from efficient coarse-grained models of chromosomes', 'Ghosh, Surya K|Jost, Daniel', 'Univ Grenoble Alpes, CNRS, Grenoble INP, TIMC-IMAG, F-38000 Grenoble, France.|Univ Grenoble Alpes, CNRS, Grenoble INP, TIMC-IMAG, F-38000 Grenoble, France.', 'France|France', 18, 'Animals|Chromatin|Chromatin Assembly and Disassembly|Chromosomes, Insect|Computational Biology|Drosophila|Epigenesis, Genetic|Epigenomics|Models, Genetic|Molecular Dynamics Simulation', 'Journal Article', '10.1371/journal.pcbi.1006159', '29813054', 'The 3D organization of chromosomes is crucial for regulating gene expression and cell function. Many experimental and polymer modeling efforts are dedicated to deciphering the mechanistic principles behind chromosome folding. Chromosomes are long and densely packed-topologically constrained-polymers. The main challenges are therefore to develop adequate models and simulation methods to investigate properly the multi spatio-temporal scales of such macromolecules. Here, we proposed a generic strategy to develop efficient coarse-grained models for self-avoiding polymers on a lattice. Accounting accurately for the polymer entanglement length and the volumic density, we show that our simulation scheme not only captures the steady-state structural and dynamical properties of the system but also tracks the same dynamics at different coarse-graining. This strategy allows a strong power-law gain in numerical efficiency and offers a systematic way to define reliable coarse-grained null models for chromosomes and to go beyond the current limitations by studying long chromosomes during an extended time period with good statistics. We use our formalism to investigate in details the time evolution of the 3D organization of chromosome 3R (20 Mbp) in drosophila during one cell cycle (20 hours). We show that a combination of our coarse-graining strategy with a one-parameter block copolymer model integrating epigenomic-driven interactions quantitatively reproduce experimental data at the chromosome-scale and predict that chromatin motion is very dynamic during the cell cycle.'),
(89075, 2018, 'plos', 'Parameter uncertainty quantification using surrogate models applied to a spatial model of yeast mating polarization', 'Renardy, Marissa|Yi, Tau-Mu|Xiu, Dongbin|Chou, Ching-Shan', 'Department of Mathematics, Ohio State University, Columbus, Ohio, United States of America.|Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, California, United States of America.|Department of Mathematics, Ohio State University, Columbus, Ohio, United States of America.|Department of Mathematics, Ohio State University, Columbus, Ohio, United States of America.', 'United States|United States|United States|United States', 0, 'Cell Culture Techniques|Cell Polarity|Heterotrimeric GTP-Binding Proteins|Models, Biological|Models, Statistical|Peptides|Schizosaccharomyces|Schizosaccharomyces pombe Proteins|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1006181', '29813055', 'A common challenge in systems biology is quantifying the effects of unknown parameters and estimating parameter values from data. For many systems, this task is computationally intractable due to expensive model evaluations and large numbers of parameters. In this work, we investigate a new method for performing sensitivity analysis and parameter estimation of complex biological models using techniques from uncertainty quantification. The primary advance is a significant improvement in computational efficiency from the replacement of model simulation by evaluation of a polynomial surrogate model. We demonstrate the method on two models of mating in budding yeast: a smaller ODE model of the heterotrimeric G-protein cycle, and a larger spatial model of pheromone-induced cell polarization. A small number of model simulations are used to fit the polynomial surrogates, which are then used to calculate global parameter sensitivities. The surrogate models also allow rapid Bayesian inference of the parameters via Markov chain Monte Carlo (MCMC) by eliminating model simulations at each step. Application to the ODE model shows results consistent with published single-point estimates for the model and data, with the added benefit of calculating the correlations between pairs of parameters. On the larger PDE model, the surrogate models allowed convergence for the distribution of 15 parameters, which otherwise would have been computationally prohibitive using simulations at each MCMC step. We inferred parameter distributions that in certain cases peaked at values different from published values, and showed that a wide range of parameters would permit polarization in the model. Strikingly our results suggested different diffusion constants for active versus inactive Cdc42 to achieve good polarization, which is consistent with experimental observations in another yeast species S. pombe.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(89076, 2018, 'plos', 'Quantitative theory of deep brain stimulation of the subthalamic nucleus for the suppression of pathological rhythms in Parkinsons disease', 'Müller, Eli J|Robinson, Peter A', 'School of Physics, The University of Sydney, Sydney, New South Wales, Australia.|School of Physics, The University of Sydney, Sydney, New South Wales, Australia.', 'Australia|Australia', 7, 'Computational Biology|Computer Simulation|Deep Brain Stimulation|Electroencephalography|Humans|Models, Neurological|Parkinson Disease|Subthalamic Nucleus', 'Journal Article', '10.1371/journal.pcbi.1006217', '29813060', 'Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is modeled to explore the mechanisms of this effective, but poorly understood, treatment for motor symptoms of drug-refractory Parkinsons disease and dystonia. First, a neural field model of the corticothalamic-basal ganglia (CTBG) system is developed that reproduces key clinical features of Parkinsons disease, including its characteristic 4-8 Hz and 13-30 Hz electrophysiological signatures. Deep brain stimulation of the STN is then modeled and shown to suppress the pathological 13-30 Hz (beta) activity for physiologically realistic and optimized stimulus parameters. This supports the idea that suppression of abnormally coherent activity in the CTBG system is a major factor in DBS therapy for Parkinsons disease, by permitting normal dynamics to resume. At high stimulus intensities, nonlinear effects in the target population mediate wave-wave interactions between resonant beta activity and the stimulus pulse train, leading to complex spectral structure that shows remarkable similarity to that seen in steady-state evoked potential experiments.'),
(89077, 2018, 'plos', 'Simulations to benchmark time-varying connectivity methods for fMRI', 'Thompson, William Hedley|Richter, Craig Geoffrey|Plavén-Sigray, Pontus|Fransson, Peter', 'Department of Psychology, Stanford University, Palo Alto, California, United States of America.|BCBL, Basque Center on Cognition, Brain and Language, Donostia, Spain.|Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.', 'United States|Spain|Sweden|Sweden', 0, 'Benchmarking|Brain|Computational Biology|Computer Simulation|Connectome|Humans|Image Processing, Computer-Assisted|Magnetic Resonance Imaging', 'Journal Article', '10.1371/journal.pcbi.1006196', '29813064', 'There is a current interest in quantifying time-varying connectivity (TVC) based on neuroimaging data such as fMRI. Many methods have been proposed, and are being applied, revealing new insight into the brains dynamics. However, given that the ground truth for TVC in the brain is unknown, many concerns remain regarding the accuracy of proposed estimates. Since there exist many TVC methods it is difficult to assess differences in time-varying connectivity between studies. In this paper, we present tvc_benchmarker, which is a Python package containing four simulations to test TVC methods. Here, we evaluate five different methods that together represent a wide spectrum of current approaches to estimating TVC (sliding window, tapered sliding window, multiplication of temporal derivatives, spatial distance and jackknife correlation). These simulations were designed to test each methods ability to track changes in covariance over time, which is a key property in TVC analysis. We found that all tested methods correlated positively with each other, but there were large differences in the strength of the correlations between methods. To facilitate comparisons with future TVC methods, we propose that the described simulations can act as benchmark tests for evaluation of methods. Using tvc_benchmarker researchers can easily add, compare and submit their own TVC methods to evaluate its performance.'),
(89078, 2018, 'plos', 'Optimizing the learning rate for adaptive estimation of neural encoding models', 'Hsieh, Han-Lin|Shanechi, Maryam M', 'Ming Hsieh Department of Electrical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, California, United States of America.|Ming Hsieh Department of Electrical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, California, United States of America.', 'United States|United States', 11, 'Action Potentials|Algorithms|Animals|Brain|Computational Biology|Computer Simulation|Humans|Learning|Models, Neurological|Neurons|Primates|Signal Processing, Computer-Assisted', 'Journal Article', '10.1371/journal.pcbi.1006168', '29813069', 'Closed-loop neurotechnologies often need to adaptively learn an encoding model that relates the neural activity to the brain state, and is used for brain state decoding. The speed and accuracy of adaptive learning algorithms are critically affected by the learning rate, which dictates how fast model parameters are updated based on new observations. Despite the importance of the learning rate, currently an analytical approach for its selection is largely lacking and existing signal processing methods vastly tune it empirically or heuristically. Here, we develop a novel analytical calibration algorithm for optimal selection of the learning rate in adaptive Bayesian filters. We formulate the problem through a fundamental trade-off that learning rate introduces between the steady-state error and the convergence time of the estimated model parameters. We derive explicit functions that predict the effect of learning rate on error and convergence time. Using these functions, our calibration algorithm can keep the steady-state parameter error covariance smaller than a desired upper-bound while minimizing the convergence time, or keep the convergence time faster than a desired value while minimizing the error. We derive the algorithm both for discrete-valued spikes modeled as point processes nonlinearly dependent on the brain state, and for continuous-valued neural recordings modeled as Gaussian processes linearly dependent on the brain state. Using extensive closed-loop simulations, we show that the analytical solution of the calibration algorithm accurately predicts the effect of learning rate on parameter error and convergence time. Moreover, the calibration algorithm allows for fast and accurate learning of the encoding model and for fast convergence of decoding to accurate performance. Finally, larger learning rates result in inaccurate encoding models and decoders, and smaller learning rates delay their convergence. The calibration algorithm provides a novel analytical approach to predictably achieve a desired level of error and convergence time in adaptive learning, with application to closed-loop neurotechnologies and other signal processing domains.'),
(89079, 2018, 'plos', 'Submit a Topic Page to PLOS Computational Biology and Wikipedia', 'Mietchen, Daniel|Wodak, Shoshana|Wasik, Szymon|Szostak, Natalia|Dessimoz, Christophe', 'Data Science Institute, University of Virginia, Charlottesville, Virginia, United States of America.|Vlaams Instituut voor Biotechnologie-Vrije Universiteit Brussel Centre for Structural Biology, Brussels, Belgium.|Institute of Computing Science, Poznan University of Technology, Poznan, Poland.|Institute of Computing Science, Poznan University of Technology, Poznan, Poland.|University College London, London, United Kingdom.', 'United States|Belgium|Poland|Poland|United Kingdom', 0, 'Computational Biology|Humans|Internet|Search Engine', 'Editorial', '10.1371/journal.pcbi.1006137', '29851950', '-'),
(89080, 2018, 'plos', 'Minimal model of interictal and ictal discharges Epileptor-2', 'Chizhov, Anton V|Zefirov, Artyom V|Amakhin, Dmitry V|Smirnova, Elena Yu|Zaitsev, Aleksey V', 'Laboratory of Molecular Mechanisms of Neural Interactions, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia.|Laboratory of Molecular Mechanisms of Neural Interactions, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia.|Laboratory of Molecular Mechanisms of Neural Interactions, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia.|Laboratory of Molecular Mechanisms of Neural Interactions, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia.|Laboratory of Molecular Mechanisms of Neural Interactions, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia.', '-|-|-|-|-', 0, 'Animals|Computational Biology|Epilepsy|Humans|Membrane Potentials|Models, Neurological|Potassium|Rats|Seizures|Sodium', 'Journal Article', '10.1371/journal.pcbi.1006186', '29851959', 'Seizures occur in a recurrent manner with intermittent states of interictal and ictal discharges (IIDs and IDs). The transitions to and from IDs are determined by a set of processes, including synaptic interaction and ionic dynamics. Although mathematical models of separate types of epileptic discharges have been developed, modeling the transitions between states remains a challenge. A simple generic mathematical model of seizure dynamics (Epileptor) has recently been proposed by Jirsa et al. (2014), however, it is formulated in terms of abstract variables. In this paper, a minimal population-type model of IIDs and IDs is proposed that is as simple to use as the Epileptor, but the suggested model attributes physical meaning to the variables. The model is expressed in ordinary differential equations for extracellular potassium and intracellular sodium concentrations, membrane potential, and short-term synaptic depression variables. A quadratic integrate-and-fire model driven by the population input current is used to reproduce spike trains in a representative neuron. In simulations, potassium accumulation governs the transition from the silent state to the state of an ID. Each ID is composed of clustered IID-like events. The sodium accumulates during discharge and activates the sodium-potassium pump, which terminates the ID by restoring the potassium gradient and thus polarizing the neuronal membranes. The whole-cell and cell-attached recordings of a 4-AP-based in vitro model of epilepsy confirmed the primary model assumptions and predictions. The mathematical analysis revealed that the IID-like events are large-amplitude stochastic oscillations, which in the case of ID generation are controlled by slow oscillations of ionic concentrations. The IDs originate in the conditions of elevated potassium concentrations in a bath solution via a saddle-node-on-invariant-circle-like bifurcation for a non-smooth dynamical system. By providing a minimal biophysical description of ionic dynamics and network interactions, the model may serve as a hierarchical base from a simple to more complex modeling of seizures.'),
(89081, 2018, 'plos', 'Ten simple rules for writing a cover letter to accompany a job application for an academic position', 'Tomaska, Lubomir|Nosek, Jozef', 'Department of Genetics, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia.|Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia.', 'Slovakia|Slovakia', 1, 'Career Choice|Faculty|Humans|Job Application|Writing', 'Editorial', '10.1371/journal.pcbi.1006132', '29851981', '-'),
(89082, 2018, 'plos', 'Instance-based generalization for human judgments about uncertainty', 'Schustek, Philipp|Moreno-Bote, Rubén', 'Center for Brain and Cognition and Department of Information and Communications Technologies, Pompeu Fabra University, Barcelona, Spain.|Center for Brain and Cognition and Department of Information and Communications Technologies, Pompeu Fabra University, Barcelona, Spain.', 'Spain|Spain', 0, 'Adult|Algorithms|Behavior|Computational Biology|Female|Humans|Judgment|Male|Models, Statistical|Task Performance and Analysis|Uncertainty', 'Journal Article', '10.1371/journal.pcbi.1006205', '29864122', 'While previous studies have shown that human behavior adjusts in response to uncertainty, it is still not well understood how uncertainty is estimated and represented. As probability distributions are high dimensional objects, only constrained families of distributions with a low number of parameters can be specified from finite data. However, it is unknown what the structural assumptions are that the brain uses to estimate them. We introduce a novel paradigm that requires human participants of either sex to explicitly estimate the dispersion of a distribution over future observations. Judgments are based on a very small sample from a centered, normally distributed random variable that was suggested by the framing of the task. This probability density estimation task could optimally be solved by inferring the dispersion parameter of a normal distribution. We find that although behavior closely tracks uncertainty on a trial-by-trial basis and resists an explanation with simple heuristics, it is hardly consistent with parametric inference of a normal distribution. Despite the transparency of the simple generating process, participants estimate a distribution biased towards the observed instances while still strongly generalizing beyond the sample. The inferred internal distributions can be well approximated by a nonparametric mixture of spatially extended basis distributions. Thus, our results suggest that fluctuations have an excessive effect on human uncertainty judgments because of representations that can adapt overly flexibly to the sample. This might be of greater utility in more general conditions in structurally uncertain environments.'),
(89083, 2018, 'plos', 'The role of intracellular signaling in the stripe formation in engineered Escherichia coli populations', 'Xue, Xiaoru|Xue, Chuan|Tang, Min', 'School of Mathematics and Institute of Natural Sciences, Shanghai Jiao Tong University, Shanghai, China.|Department of Mathematics, Ohio State University, Columbus, Ohio, United States of America.|School of Mathematics and Institute of Natural Sciences, Shanghai Jiao Tong University, Shanghai, China.', 'China|United States|China', 6, 'Chemotaxis|Computational Biology|Escherichia coli|Intracellular Space|Models, Biological|Quorum Sensing|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1006178', '29864126', 'Recent experiments showed that engineered Escherichia coli colonies grow and self-organize into periodic stripes with high and low cell densities in semi-solid agar. The stripes develop sequentially behind a radially propagating colony front, similar to the formation of many other periodic patterns in nature. These bacteria were created by genetically coupling the intracellular chemotaxis pathway of wild-type cells with a quorum sensing module through the protein CheZ. In this paper, we develop multiscale models to investigate how this intracellular pathway affects stripe formation. We first develop a detailed hybrid model that treats each cell as an individual particle and incorporates intracellular signaling via an internal ODE system. To overcome the computational cost of the hybrid model caused by the large number of cells involved, we next derive a mean-field PDE model from the hybrid model using asymptotic analysis. We show that this analysis is justified by the tight agreement between the PDE model and the hybrid model in 1D simulations. Numerical simulations of the PDE model in 2D with radial symmetry agree with experimental data semi-quantitatively. Finally, we use the PDE model to make a number of testable predictions on how the stripe patterns depend on cell-level parameters, including cell speed, cell doubling time and the turnover rate of intracellular CheZ.'),
(89084, 2018, 'plos', 'Assessment of ab initio models of protein complexes by molecular dynamics', 'Radom, Filip|Plückthun, Andreas|Paci, Emanuele', 'Department of Biochemistry, University of Zurich, Zurich, Switzerland.|Department of Biochemistry, University of Zurich, Zurich, Switzerland.|Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.', 'Switzerland|Switzerland|United Kingdom', 7, 'Computational Biology|Molecular Dynamics Simulation|Protein Conformation|Protein Folding|Proteins|Software|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1006182', '29864135', 'Determining how proteins interact to form stable complexes is of crucial importance, for example in the development of novel therapeutics. Computational methods to determine the thermodynamically stable conformation of complexes from the structure of the binding partners, such as RosettaDock, might potentially emerge to become a promising alternative to traditional structure determination methods. However, while models virtually identical to the correct experimental structure can in some cases be generated, the main difficulty remains to discriminate correct or approximately correct models from decoys. This is due to the ruggedness of the free-energy landscape, the approximations intrinsic in the scoring functions, and the intrinsic flexibility of proteins. Here we show that molecular dynamics simulations performed starting from a number top-scoring models can not only discriminate decoys and identify the correct structure, but may also provide information on an initial map of the free energy landscape that elucidates the binding mechanism.'),
(89085, 2018, 'plos', 'Bridging structure and function: A model of sequence learning and prediction in primary visual cortex', 'Klos, Christian|Miner, Daniel|Triesch, Jochen', 'Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany.|Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany.|Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany.', 'Germany|Germany|Germany', 0, 'Action Potentials|Animals|Computational Biology|Learning|Models, Neurological|Rats|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1006187', '29870532', 'Recent experiments have demonstrated that visual cortex engages in spatio-temporal sequence learning and prediction. The cellular basis of this learning remains unclear, however. Here we present a spiking neural network model that explains a recent study on sequence learning in the primary visual cortex of rats. The model posits that the sequence learning and prediction abilities of cortical circuits result from the interaction of spike-timing dependent plasticity (STDP) and homeostatic plasticity mechanisms. It also reproduces changes in stimulus-evoked multi-unit activity during learning. Furthermore, it makes precise predictions regarding how training shapes network connectivity to establish its prediction ability. Finally, it predicts that the adapted connectivity gives rise to systematic changes in spontaneous network activity. Taken together, our model establishes a new conceptual bridge between the structure and function of cortical circuits in the context of sequence learning and prediction.'),
(89086, 2018, 'plos', 'Latent environment allocation of microbial community data', 'Higashi, Koichi|Suzuki, Shinya|Kurosawa, Shin|Mori, Hiroshi|Kurokawa, Ken', 'Genome Evolution Laboratory, National Institute of Genetics, Mishima, Japan.|Department of Biological Information, Tokyo Institute of Technology, Ookayama, Meguro-ku, Tokyo, Japan.|Department of Biological Information, Tokyo Institute of Technology, Ookayama, Meguro-ku, Tokyo, Japan.|Genome Evolution Laboratory, National Institute of Genetics, Mishima, Japan.|Genome Evolution Laboratory, National Institute of Genetics, Mishima, Japan.', 'Japan|Japan|Japan|Japan|Japan', 0, 'Computational Biology|Databases, Genetic|Environmental Microbiology|Humans|Metagenomics|Microbiota|Models, Statistical|Rivers', 'Journal Article', '10.1371/journal.pcbi.1006143', '29874232', 'As data for microbial community structures found in various environments has increased, studies have examined the relationship between environmental labels given to retrieved microbial samples and their community structures. However, because environments continuously change over time and space, mixed states of some environments and its effects on community formation should be considered, instead of evaluating effects of discrete environmental categories. Here we applied a hierarchical Bayesian model to paired datasets containing more than 30,000 samples of microbial community structures and sample description documents. From the training results, we extracted latent environmental topics that associate co-occurring microbes with co-occurring word sets among samples. Topics are the core elements of environmental mixtures and the visualization of topic-based samples clarifies the connections of various environments. Based on the model training results, we developed a web application, LEA (Latent Environment Allocation), which provides the way to evaluate typicality and heterogeneity of microbial communities in newly obtained samples without confining environmental categories to be compared. Because topics link words and microbes, LEA also enables to search samples semantically related to the query out of 30,000 microbiome samples.'),
(89087, 2018, 'plos', 'Limits on reliable information flows through stochastic populations', 'Boczkowski, Lucas|Natale, Emanuele|Feinerman, Ofer|Korman, Amos', 'CNRS, IRIF, Université Paris Diderot, Paris, France.|Algorithms and Complexity Department, Max-Planck-Institut für Informatik, Saarbrücken, Germany.|Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.|CNRS, IRIF, Université Paris Diderot, Paris, France.', 'France|Germany|Israel|France', 5, 'Algorithms|Animals|Ants|Communication|Computational Biology|Models, Biological|Noise|Reproducibility of Results|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1006195', '29874234', 'Biological systems can share and collectively process information to yield emergent effects, despite inherent noise in communication. While man-made systems often employ intricate structural solutions to overcome noise, the structure of many biological systems is more amorphous. It is not well understood how communication noise may affect the computational repertoire of such groups. To approach this question we consider the basic collective task of rumor spreading, in which information from few knowledgeable sources must reliably flow into the rest of the population. We study the effect of communication noise on the ability of groups that lack stable structures to efficiently solve this task. We present an impossibility result which strongly restricts reliable rumor spreading in such groups. Namely, we prove that, in the presence of even moderate levels of noise that affect all facets of the communication, no scheme can significantly outperform the trivial one in which agents have to wait until directly interacting with the sources-a process which requires linear time in the population size. Our results imply that in order to achieve efficient rumor spread a system must exhibit either some degree of structural stability or, alternatively, some facet of the communication which is immune to noise. We then corroborate this claim by providing new analyses of experimental data regarding recruitment in Cataglyphis niger desert ants. Finally, in light of our theoretical results, we discuss strategies to overcome noise in other biological systems.'),
(89088, 2018, 'plos', 'Dopamine transporter oligomerization involves the scaffold domain, but spares the bundle domain', 'Jayaraman, Kumaresan|Morley, Alex N|Szxc3xb6llxc5x91si, Daniel|Wassenaar, Tsjerk A|Sitte, Harald H|Stockner, Thomas', 'Medical University of Vienna Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria.|Medical University of Vienna Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria.|Medical University of Vienna Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria.|Groningen Biomolecular Sciences and Biotechnology Institute and Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands.|Medical University of Vienna Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria.|Medical University of Vienna Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria.', 'Austria|Austria|Austria|Netherlands|Austria|Austria', 0, 'Dopamine Plasma Membrane Transport Proteins|Humans|Molecular Dynamics Simulation|Protein Domains|Protein Multimerization', 'Journal Article', '10.1371/journal.pcbi.1006229', '29874235', 'The human dopamine transporter (hDAT) is located on presynaptic neurons, where it plays an essential role in limiting dopaminergic signaling by temporarily curtailing high neurotransmitter concentration through rapid re-uptake. Transport by hDAT is energized by transmembrane ionic gradients. Dysfunction of this transporter leads to disease states, such as Parkinsons disease, bipolar disorder or depression. It has been shown that hDAT and other members of the monoamine transporter family exist in oligomeric forms at the plasma membrane. Several residues are known to be involved in oligomerization, but interaction interfaces, oligomer orientation and the quarternary arrangement in the plasma membrane remain poorly understood. Here we examine oligomeric forms of hDAT using a direct approach, by following dimerization of two randomly-oriented hDAT transporters in 512 independent simulations, each being 2 xcexbcs in length. We employed the DAFT (docking assay for transmembrane components) approach, which is an unbiased molecular dynamics simulation method to identify oligomers, their conformations and populations. The overall ensemble of a total of >1 ms simulation time revealed a limited number of symmetric and asymmetric dimers. The identified dimer interfaces include all residues known to be involved in dimerization. Importantly, we find that the surface of the bundle domain is largely excluded from engaging in dimeric interfaces. Such an interaction would typically lead to inhibition by stabilization of one conformation, while substrate transport relies on a large scale rotation between the inward-facing and the outward-facing state.'),
(89089, 2018, 'plos', '2018 ISCB Innovator Award recognizes M Madan Babu', 'Fogg, Christiana N|Kovats, Diane E|Shamir, Ron', 'Freelance Science Writer, Kensington, Maryland, United States of America.|International Society for Computational Biology, Bethesda, Maryland, United States of America.|Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.', 'United States|United States|Israel', 0, '-', 'Journal Article', '10.1371/journal.pcbi.1006164', '29879101', '-'),
(89090, 2018, 'plos', 'Temporal precision of regulated gene expression', 'Gupta, Shivam|Varennes, Julien|Korswagen, Hendrik C|Mugler, Andrew', 'Department of Physics and Astronomy, Purdue University, West Lafayette, Indiana, United States of America.|Department of Physics and Astronomy, Purdue University, West Lafayette, Indiana, United States of America.|Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, the Netherlands.|Department of Physics and Astronomy, Purdue University, West Lafayette, Indiana, United States of America.', 'India|India|Netherlands|India', 7, 'Animals|Caenorhabditis elegans|Caenorhabditis elegans Proteins|Computational Biology|Frizzled Receptors|Gene Expression Regulation, Developmental|Models, Biological|Neurons|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1006201', '29879102', 'Important cellular processes such as migration, differentiation, and development often rely on precise timing. Yet, the molecular machinery that regulates timing is inherently noisy. How do cells achieve precise timing with noisy components? We investigate this question using a first-passage-time approach, for an event triggered by a molecule that crosses an abundance threshold and that is regulated by either an accumulating activator or a diminishing repressor. We find that either activation or repression outperforms an unregulated strategy. The optimal regulation corresponds to a nonlinear increase in the amount of the target molecule over time, arises from a tradeoff between minimizing the timing noise of the regulator and that of the target molecule itself, and is robust to additional effects such as bursts and cell division. Our results are in quantitative agreement with the nonlinear increase and low noise of mig-1 gene expression in migrating neuroblast cells during Caenorhabditis elegans development. These findings suggest that dynamic regulation may be a simple and powerful strategy for precise cellular timing.'),
(89091, 2018, 'plos', 'Predicting 3D structure and stability of RNA pseudoknots in monovalent and divalent ion solutions', 'Shi, Ya-Zhou|Jin, Lei|Feng, Chen-Jie|Tan, Ya-Lan|Tan, Zhi-Jie', 'Research Center of Nonlinear Science, School of Mathematics and Computer Science, Wuhan Textile University, Wuhan, China.|Department of Physics and Key Laboratory of Artificial Micro- and Nano-structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, China.|Department of Physics and Key Laboratory of Artificial Micro- and Nano-structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, China.|Department of Physics and Key Laboratory of Artificial Micro- and Nano-structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, China.|Department of Physics and Key Laboratory of Artificial Micro- and Nano-structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, China.', 'China|China|China|China|China', 0, 'Magnesium|Molecular Dynamics Simulation|Nucleic Acid Conformation|RNA|RNA Folding|Sodium', 'Journal Article', '10.1371/journal.pcbi.1006222', '29879103', 'RNA pseudoknots are a kind of minimal RNA tertiary structural motifs, and their three-dimensional (3D) structures and stability play essential roles in a variety of biological functions. Therefore, to predict 3D structures and stability of RNA pseudoknots is essential for understanding their functions. In the work, we employed our previously developed coarse-grained model with implicit salt to make extensive predictions and comprehensive analyses on the 3D structures and stability for RNA pseudoknots in monovalent/divalent ion solutions. The comparisons with available experimental data show that our model can successfully predict the 3D structures of RNA pseudoknots from their sequences, and can also make reliable predictions for the stability of RNA pseudoknots with different lengths and sequences over a wide range of monovalent/divalent ion concentrations. Furthermore, we made comprehensive analyses on the unfolding pathway for various RNA pseudoknots in ion solutions. Our analyses for extensive pseudokonts and the wide range of monovalent/divalent ion concentrations verify that the unfolding pathway of RNA pseudoknots is mainly dependent on the relative stability of unfolded intermediate states, and show that the unfolding pathway of RNA pseudoknots can be significantly modulated by their sequences and solution ion conditions.'),
(89092, 2018, 'plos', 'Variation of mutational burden in healthy human tissues suggests non-random strand segregation and allows measuring somatic mutation rates', 'Werner, Benjamin|Sottoriva, Andrea', 'Evolutionary Genomics & Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom.|Evolutionary Genomics & Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom.', 'United Kingdom|United Kingdom', 0, 'Cell Proliferation|Chromosome Segregation|Computational Biology|DNA|DNA Replication|High-Throughput Nucleotide Sequencing|Humans|Intestine, Small|Mutation|Mutation Rate|Organ Specificity|Skin', 'Journal Article', '10.1371/journal.pcbi.1006233', '29879111', 'The immortal strand hypothesis poses that stem cells could produce differentiated progeny while conserving the original template strand, thus avoiding accumulating somatic mutations. However, quantitating the extent of non-random DNA strand segregation in human stem cells remains difficult in vivo. Here we show that the change of the mean and variance of the mutational burden with age in healthy human tissues allows estimating strand segregation probabilities and somatic mutation rates. We analysed deep sequencing data from healthy human colon, small intestine, liver, skin and brain. We found highly effective non-random DNA strand segregation in all adult tissues (mean strand segregation probability: 0.98, standard error bounds (0.97,0.99)). In contrast, non-random strand segregation efficiency is reduced to 0.87 (0.78,0.88) in neural tissue during early development, suggesting stem cell pool expansions due to symmetric self-renewal. Healthy somatic mutation rates differed across tissue types, ranging from 3.5 × 10-9/bp/division in small intestine to 1.6 × 10-7/bp/division in skin.'),
(89093, 2018, 'plos', '2018 ISCB Overton Prize awarded to Cole Trapnell', 'Fogg, Christiana N|Kovats, Diane E|Shamir, Ron', 'Freelance Science Writer, Kensington, Maryland, United States of America.|International Society for Computational Biology, Bethesda, Maryland, United States of America.|Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.', 'United States|United States|Israel', 0, '-', 'Journal Article', '10.1371/journal.pcbi.1006163', '29879112', '-'),
(89094, 2018, 'plos', 'In vivo and in silico dynamics of the development of Metabolic Syndrome', 'Rozendaal, Yvonne J W|Wang, Yanan|Paalvast, Yared|Tambyrajah, Lauren L|Li, Zhuang|Willems van Dijk, Ko|Rensen, Patrick C N|Kuivenhoven, Jan A|Groen, Albert K|Hilbers, Peter A J|van Riel, Natal A W', 'Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.|Department of Pediatrics, Section Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Pediatrics, Section Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Pediatrics, Section Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Pediatrics, Section Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.|Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Neth', 5, 'Animals|Computational Biology|Computer Simulation|Diet, High-Fat|Disease Models, Animal|Humans|Insulin Resistance|Lipid Metabolism|Metabolic Syndrome|Mice|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1006145', '29879115', 'The Metabolic Syndrome (MetS) is a complex, multifactorial disorder that develops slowly over time presenting itself with large differences among MetS patients. We applied a systems biology approach to describe and predict the onset and progressive development of MetS, in a study that combined in vivo and in silico models. A new data-driven, physiological model (MINGLeD: Model INtegrating Glucose and Lipid Dynamics) was developed, describing glucose, lipid and cholesterol metabolism. Since classic kinetic models cannot describe slowly progressing disorders, a simulation method (ADAPT) was used to describe longitudinal dynamics and to predict metabolic concentrations and fluxes. This approach yielded a novel model that can describe long-term MetS development and progression. This model was integrated with longitudinal in vivo data that was obtained from male APOE*3-Leiden.CETP mice fed a high-fat, high-cholesterol diet for three months and that developed MetS as reflected by classical symptoms including obesity and glucose intolerance. Two distinct subgroups were identified: those who developed dyslipidemia, and those who did not. The combination of MINGLeD with ADAPT could correctly predict both phenotypes, without making any prior assumptions about changes in kinetic rates or metabolic regulation. Modeling and flux trajectory analysis revealed that differences in liver fluxes and dietary cholesterol absorption could explain this occurrence of the two different phenotypes. In individual mice with dyslipidemia dietary cholesterol absorption and hepatic turnover of metabolites, including lipid fluxes, were higher compared to those without dyslipidemia. Predicted differences were also observed in gene expression data, and consistent with the emergence of insulin resistance and hepatic steatosis, two well-known MetS co-morbidities. Whereas MINGLeD specifically models the metabolic derangements underlying MetS, the simulation method ADAPT is generic and can be applied to other diseases where dynamic modeling and longitudinal data are available.'),
(89095, 2018, 'plos', 'Anticipating epidemic transitions with imperfect data', 'Brett, Tobias S|ODea, Eamon B|Marty, Éric|Miller, Paige B|Park, Andrew W|Drake, John M|Rohani, Pejman', 'Odum School of Ecology, University of Georgia, Athens, Georgia, United States of America.|Odum School of Ecology, University of Georgia, Athens, Georgia, United States of America.|Odum School of Ecology, University of Georgia, Athens, Georgia, United States of America.|Odum School of Ecology, University of Georgia, Athens, Georgia, United States of America.|Odum School of Ecology, University of Georgia, Athens, Georgia, United States of America.|Odum School of Ecology, University of Georgia, Athens, Georgia, United States of America.|Odum School of Ecology, University of Georgia, Athens, Georgia, United States of America.', 'Georgia|Georgia|Georgia|Georgia|Georgia|Georgia|Georgia', 8, 'Area Under Curve|Cluster Analysis|Computational Biology|Computer Simulation|Databases, Factual|Epidemics|Humans|Models, Statistical', 'Journal Article', '10.1371/journal.pcbi.1006204', '29883444', 'Epidemic transitions are an important feature of infectious disease systems. As the transmissibility of a pathogen increases, the dynamics of disease spread shifts from limited stuttering chains of transmission to potentially large scale outbreaks. One proposed method to anticipate this transition are early-warning signals (EWS), summary statistics which undergo characteristic changes as the transition is approached. Although theoretically predicted, their mathematical basis does not take into account the nature of epidemiological data, which are typically aggregated into periodic case reports and subject to reporting error. The viability of EWS for epidemic transitions therefore remains uncertain. Here we demonstrate that most EWS can predict emergence even when calculated from imperfect data. We quantify performance using the area under the curve (AUC) statistic, a measure of how well an EWS distinguishes between numerical simulations of an emerging disease and one which is stationary. Values of the AUC statistic are compared across a range of different reporting scenarios. We find that different EWS respond to imperfect data differently. The mean, variance and first differenced variance all perform well unless reporting error is highly overdispersed. The autocorrelation, autocovariance and decay time perform well provided that the aggregation period of the data is larger than the serial interval and reporting error is not highly overdispersed. The coefficient of variation, skewness and kurtosis are found to be unreliable indicators of emergence. Overall, we find that seven of ten EWS considered perform well for most realistic reporting scenarios. We conclude that imperfect epidemiological data is not a barrier to using EWS for many potentially emerging diseases.'),
(89096, 2018, 'plos', 'Changes in parasite traits, rather than intensity, affect the dynamics of infection under external perturbation', 'Ghosh, Suma|Ferrari, Matthew J|Pathak, Ashutosh K|Cattadori, Isabella M', 'Department of Mathematics, School of Natural Sciences, Shiv Nadar University, Dadri, Uttar Pradesh, India.|Center for Infectious Disease Dynamics, The Pennsylvania State University, State College, Pennsylvania, United States of America.|Center for Infectious Disease Dynamics, The Pennsylvania State University, State College, Pennsylvania, United States of America.|Center for Infectious Disease Dynamics, The Pennsylvania State University, State College, Pennsylvania, United States of America.', 'India|United States|United States|United States', 2, 'Animals|Anthelmintics|Biological Evolution|Helminths|Host-Parasite Interactions|Models, Biological|Models, Theoretical|Parasites|Rabbits|Trichostrongylus', 'Journal Article', '10.1371/journal.pcbi.1006167', '29889827', 'Understanding the mechanisms that generate complex host-parasite interactions, and how they contribute to variation between and within hosts, is important for predicting risk of infection and transmission, and for developing more effective interventions based on parasite properties. We used the T. retortaeformis (TR)-rabbit system and developed a state-space mathematical framework to capture the variation in intensity of infection and egg shedding in hosts infected weekly, then treated with an anthelminthic and subsequently re-challenged following the same infection regime. Experimental infections indicate that parasite intensity accumulates more slowly in the post-anthelminthic phase but reaches similar maximum numbers. By contrast, parasite EPG (eggs per gram of feces) shed from rabbits in the post-treatment phase is lower and less variable through time. Inference based on EPG alone suggests a decline in parasite intensity over time. Using a state-space model and incorporating all sources of cross-sectional and longitudinal data, we show that while parasite intensity remains relatively constant in both experimental phases, shedding of eggs into the environment is increasingly limited through changes in parasite growth. We suggest that host immunity directly modulates both the accumulation and the growth of the parasite, and indirectly affects transmission by limiting parasite length and thus fecundity. This study provides a better understanding of how within-host trophic interactions influence different components of a helminth population. It also suggests that heterogeneity in parasite traits should be addressed more carefully when examining and managing helminth infections in the absence of some critical data on parasite dynamics.'),
(89097, 2018, 'plos', 'The effect of cell geometry on polarization in budding yeast', 'Trogdon, Michael|Drawert, Brian|Gomez, Carlos|Banavar, Samhita P|Yi, Tau-Mu|Campàs, Otger|Petzold, Linda R', 'Department of Mechanical Engineering, University of California, Santa Barbara, Santa Barbara, California, United States of America.|Department of Computer Science, University of North Carolina, Asheville, Asheville, North Carolina, United States of America.|Department of Molecular, Cell and Developmental Biology, University of California, Santa Barbara, Santa Barbara, California, United States of America.|California NanoSystems Institute, University of California, Santa Barbara, Santa Barbara, California, United States of America.|Department of Molecular, Cell and Developmental Biology, University of California, Santa Barbara, Santa Barbara, California, United States of America.|Department of Mechanical Engineering, University of California, Santa Barbara, Santa Barbara, California, United States of America.|Department of Mechanical Engineering, University of California, Santa Barbara, Santa Barbara, California, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 4, 'Cell Polarity|Cell Shape|Computational Biology|Models, Biological|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1006241', '29889845', 'The localization (or polarization) of proteins on the membrane during the mating of budding yeast (Saccharomyces cerevisiae) is an important model system for understanding simple pattern formation within cells. While there are many existing mathematical models of polarization, for both budding and mating, there are still many aspects of this process that are not well understood. In this paper we set out to elucidate the effect that the geometry of the cell can have on the dynamics of certain models of polarization. Specifically, we look at several spatial stochastic models of Cdc42 polarization that have been adapted from published models, on a variety of tip-shaped geometries, to replicate the shape change that occurs during the growth of the mating projection. We show here that there is a complex interplay between the dynamics of polarization and the shape of the cell. Our results show that while models of polarization can generate a stable polarization cap, its localization at the tip of mating projections is unstable, with the polarization cap drifting away from the tip of the projection in a geometry dependent manner. We also compare predictions from our computational results to experiments that observe cells with projections of varying lengths, and track the stability of the polarization cap. Lastly, we examine one model of actin polarization and show that it is unlikely, at least for the models studied here, that actin dynamics and vesicle traffic are able to overcome this effect of geometry.'),
(89098, 2018, 'plos', 'Mechanical positioning of multiple nuclei in muscle cells', 'Manhart, Angelika|Windner, Stefanie|Baylies, Mary|Mogilner, Alex', 'Courant Institute of Mathematical Sciences, New York University, New York, New York, United States of America.|Program in Developmental Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer, New York, New York, United States of America.|Program in Developmental Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer, New York, New York, United States of America.|Courant Institute of Mathematical Sciences, New York University, New York, New York, United States of America.', 'United States|United States|United States|United States', 9, 'Animals|Biomechanical Phenomena|Cell Nucleus|Drosophila|Larva|Models, Biological|Muscle Fibers, Skeletal', 'Journal Article', '10.1371/journal.pcbi.1006208', '29889846', 'Many types of large cells have multiple nuclei. In skeletal muscle fibers, the nuclei are distributed along the cell to maximize their internuclear distances. This myonuclear positioning is crucial for cell function. Although microtubules, microtubule associated proteins, and motors have been implicated, mechanisms responsible for myonuclear positioning remain unclear. We used a combination of rough interacting particle and detailed agent-based modeling to examine computationally the hypothesis that a force balance generated by microtubules positions the muscle nuclei. Rather than assuming the nature and identity of the forces, we simulated various types of forces between the pairs of nuclei and between the nuclei and cell boundary to position the myonuclei according to the laws of mechanics. We started with a large number of potential interacting particle models and computationally screened these models for their ability to fit biological data on nuclear positions in hundreds of Drosophila larval muscle cells. This reverse engineering approach resulted in a small number of feasible models, the one with the best fit suggests that the nuclei repel each other and the cell boundary with forces that decrease with distance. The model makes nontrivial predictions about the increased nuclear density near the cell poles, the zigzag patterns of the nuclear positions in wider cells, and about correlations between the cell width and elongated nuclear shapes, all of which we confirm by image analysis of the biological data. We support the predictions of the interacting particle model with simulations of an agent-based mechanical model. Taken together, our data suggest that microtubules growing from nuclear envelopes push on the neighboring nuclei and the cell boundaries, which is sufficient to establish the nearly-uniform nuclear spreading observed in muscle fibers.');
