INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84644, 2010, 'plos', 'Enhancement of transport selectivity through nano-channels by non-specific competition', 'Zilman, Anton|Di Talia, Stefano|Jovanovic-Talisman, Tijana|Chait, Brian T|Rout, Michael P|Magnasco, Marcelo O', 'Theoretical Biology and Biophysics Group and Center for Nonlinear Studies, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. zilmana@lanl.gov|Theoretical Biology and Biophysics Group and Center for Nonlinear Studies, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. zilmana@lanl.gov|Theoretical Biology and Biophysics Group and Center for Nonlinear Studies, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. zilmana@lanl.gov|Theoretical Biology and Biophysics Group and Center for Nonlinear Studies, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. zilmana@lanl.gov|Theoretical Biology and Biophysics Group and Center for Nonlinear Studies, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. zilmana@lanl.gov|Theoretical Biology and Biophysics Group and Center for Nonlinear Studies, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. zilmana@lanl.gov', 'Mexico|Mexico|Mexico|Mexico|Mexico|Mexico', 0, 'Biological Transport|Computational Biology|Gold|Kinetics|Models, Biological|Monte Carlo Method|Nanotechnology|Nuclear Pore|Particle Size', 'Journal Article', '10.1371/journal.pcbi.1000804', '20548778', 'The functioning of living cells requires efficient and selective transport of materials into and out of the cell, and between different cellular compartments. Much of this transport occurs through nano-scale channels that do not require large scale molecular re-arrangements (such as transition from a closed to an open state) and do not require a direct input of metabolic energy during transport. Nevertheless, these always open channels are highly selective and pass only their cognate molecules, while efficiently excluding all others, indeed, these channels can efficiently transport specific molecules even in the presence of a vast excess of non-specific molecules. Such biological transporters have inspired the creation of artificial nano-channels. These channels can be used as nano-molecular sorters, and can also serve as testbeds for examining modes of biological transport. In this paper, we propose a simple kinetic mechanism that explains how the selectivity of such always open channels can be based on the exclusion of non-specific molecules by specific ones, due to the competition for limited space inside the channel. The predictions of the theory account for the behavior of the nuclear pore complex and of artificial nanopores that mimic its function. This theory provides the basis for future work aimed at understanding the selectivity of various biological transport phenomena.'),
(84645, 2010, 'plos', 'Rapid transition towards the Division of Labor via evolution of developmental plasticity', 'Gavrilets, Sergey', 'Department of Ecology and Evolutionary Biology, National Institute for Mathematical and Biological Synthesis, University of Tennessee, Knoxville, Tennessee, United States of America. sergey@tiem.utk.edu', 'United States', 49, 'Algorithms|Animals|Cell Differentiation|Cell Survival|Computational Biology|Evolution, Molecular|Fertility|Germ Cells|Insecta|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1000805', '20548941', 'A crucial step in several major evolutionary transitions is the division of labor between components of the emerging higher-level evolutionary unit. Examples include the separation of germ and soma in simple multicellular organisms, appearance of multiple cell types and organs in more complex organisms, and emergence of casts in eusocial insects. How the division of labor was achieved in the face of selfishness of lower-level units is controversial. I present a simple mathematical model describing the evolutionary emergence of the division of labor via developmental plasticity starting with a colony of undifferentiated cells and ending with completely differentiated multicellular organisms. I explore how the plausibility and the dynamics of the division of labor depend on its fitness advantage, mutation rate, costs of developmental plasticity, and the colony size. The model shows that the transition to differentiated multicellularity, which has happened many times in the history of life, can be achieved relatively easily. My approach is expandable in a number of directions including the emergence of multiple cell types, complex organs, or casts of eusocial insects.'),
(84646, 2010, 'plos', 'Functional rotation of the transporter AcrB: insights into drug extrusion from simulations', 'Schulz, Robert|Vargiu, Attilio V|Collu, Francesca|Kleinekathöfer, Ulrich|Ruggerone, Paolo', 'School of Engineering and Science, Jacobs University Bremen, Bremen, Germany.|School of Engineering and Science, Jacobs University Bremen, Bremen, Germany.|School of Engineering and Science, Jacobs University Bremen, Bremen, Germany.|School of Engineering and Science, Jacobs University Bremen, Bremen, Germany.|School of Engineering and Science, Jacobs University Bremen, Bremen, Germany.', 'Germany|Germany|Germany|Germany|Germany', 0, 'Binding Sites|Doxorubicin|Escherichia coli|Escherichia coli Proteins|Molecular Dynamics Simulation|Multidrug Resistance-Associated Proteins|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1000806', '20548943', 'The tripartite complex AcrAB-TolC is the major efflux system in Escherichia coli. It extrudes a wide spectrum of noxious compounds out of the bacterium, including many antibiotics. Its active part, the homotrimeric transporter AcrB, is responsible for the selective binding of substrates and energy transduction. Based on available crystal structures and biochemical data, the transport of substrates by AcrB has been proposed to take place via a functional rotation, in which each monomer assumes a particular conformation. However, there is no molecular-level description of the conformational changes associated with the rotation and their connection to drug extrusion. To obtain insights thereon, we have performed extensive targeted molecular dynamics simulations mimicking the functional rotation of AcrB containing doxorubicin, one of the two substrates that were co-crystallized so far. The simulations, including almost half a million atoms, have been used to test several hypotheses concerning the structure-dynamics-function relationship of this transporter. Our results indicate that, upon induction of conformational changes, the substrate detaches from the binding pocket and approaches the gate to the central funnel. Furthermore, we provide strong evidence for the proposed peristaltic transport involving a zipper-like closure of the binding pocket, responsible for the displacement of the drug. A concerted opening of the channel between the binding pocket and the gate further favors the displacement of the drug. This microscopically well-funded information allows one to identify the role of specific amino acids during the transitions and to shed light on the functioning of AcrB.'),
(84647, 2010, 'plos', 'The organization of local and distant functional connectivity in the human brain', 'Sepulcre, Jorge|Liu, Hesheng|Talukdar, Tanveer|Martincorena, Iñigo|Yeo, B T Thomas|Buckner, Randy L', 'Howard Hughes Medical Institute, Cambridge, Massachusetts, United States of America. sepulcre@nmr.mgh.harvard.edu|Howard Hughes Medical Institute, Cambridge, Massachusetts, United States of America. sepulcre@nmr.mgh.harvard.edu|Howard Hughes Medical Institute, Cambridge, Massachusetts, United States of America. sepulcre@nmr.mgh.harvard.edu|Howard Hughes Medical Institute, Cambridge, Massachusetts, United States of America. sepulcre@nmr.mgh.harvard.edu|Howard Hughes Medical Institute, Cambridge, Massachusetts, United States of America. sepulcre@nmr.mgh.harvard.edu|Howard Hughes Medical Institute, Cambridge, Massachusetts, United States of America. sepulcre@nmr.mgh.harvard.edu', 'United States|United States|United States|United States|United States|United States', 245, 'Adult|Cerebral Cortex|Cluster Analysis|Computational Biology|Female|Humans|Magnetic Resonance Imaging|Male|Models, Neurological|Neocortex', 'Journal Article', '10.1371/journal.pcbi.1000808', '20548945', 'Information processing in the human brain arises from both interactions between adjacent areas and from distant projections that form distributed brain systems. Here we map interactions across different spatial scales by estimating the degree of intrinsic functional connectivity for the local (<or=14 mm) neighborhood directly surrounding brain regions as contrasted with distant (>14 mm) interactions. The balance between local and distant functional interactions measured at rest forms a map that separates sensorimotor cortices from heteromodal association areas and further identifies regions that possess both high local and distant cortical-cortical interactions. Map estimates of network measures demonstrate that high local connectivity is most often associated with a high clustering coefficient, long path length, and low physical cost. Task performance changed the balance between local and distant functional coupling in a subset of regions, particularly, increasing local functional coupling in regions engaged by the task. The observed properties suggest that the brain has evolved a balance that optimizes information-processing efficiency across different classes of specialized areas as well as mechanisms to modulate coupling in support of dynamically changing processing demands. We discuss the implications of these observations and applications of the present method for exploring normal and atypical brain function.'),
(84648, 2010, 'plos', 'Combinatorial gene regulation using auto-regulation', 'Hermsen, Rutger|Ursem, Bas|ten Wolde, Pieter Rein', 'Center for Theoretical Biological Physics, University of California, San Diego, California, United States of America. hermsen@ctbp.ucsd.edu|Center for Theoretical Biological Physics, University of California, San Diego, California, United States of America. hermsen@ctbp.ucsd.edu|Center for Theoretical Biological Physics, University of California, San Diego, California, United States of America. hermsen@ctbp.ucsd.edu', 'United States|United States|United States', 28, 'Algorithms|Binding Sites|Computer Simulation|DNA-Directed RNA Polymerases|Escherichia coli|Escherichia coli Proteins|Evolution, Molecular|Gene Expression Regulation, Bacterial|Models, Genetic|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000813', '20548950', 'As many as 59% of the transcription factors in Escherichia coli regulate the transcription rate of their own genes. This suggests that auto-regulation has one or more important functions. Here, one possible function is studied. Often the transcription rate of an auto-regulator is also controlled by additional transcription factors. In these cases, the way the expression of the auto-regulator responds to changes in the concentrations of the input regulators (the response function) is obviously affected by the auto-regulation. We suggest that, conversely, auto-regulation may be used to optimize this response function. To test this hypothesis, we use an evolutionary algorithm and a chemical-physical model of transcription regulation to design model cis-regulatory constructs with predefined response functions. In these simulations, auto-regulation can evolve if this provides a functional benefit. When selecting for a series of elementary response functions-Boolean logic gates and linear responses-the cis-regulatory regions resulting from the simulations indeed often exploit auto-regulation. Surprisingly, the resulting constructs use auto-activation rather than auto-repression. Several design principles show up repeatedly in the simulation results. They demonstrate how auto-activation can be used to generate sharp, switch-like activation and repression circuits and how linearly decreasing response functions can be obtained. Auto-repression, on the other hand, resulted only when a high response speed or a suppression of intrinsic noise was also selected for. The results suggest that, while auto-repression may primarily be valuable to improve the dynamical properties of regulatory circuits, auto-activation is likely to evolve even when selection acts on the shape of response function only.'),
(84649, 2010, 'plos', 'Polarizable water model for the coarse-grained MARTINI force field', 'Yesylevskyy, Semen O|Schäfer, Lars V|Sengupta, Durba|Marrink, Siewert J', 'Department of Physics of Biological Systems, Institute of Physics, National Academy of Sciences of Ukraine, Kiev, Ukraine.|Department of Physics of Biological Systems, Institute of Physics, National Academy of Sciences of Ukraine, Kiev, Ukraine.|Department of Physics of Biological Systems, Institute of Physics, National Academy of Sciences of Ukraine, Kiev, Ukraine.|Department of Physics of Biological Systems, Institute of Physics, National Academy of Sciences of Ukraine, Kiev, Ukraine.', 'Ukraine|Ukraine|Ukraine|Ukraine', 0, 'Alkanes|Electrochemistry|Ions|Lipid Bilayers|Molecular Dynamics Simulation|Octanes|Sodium Chloride|Temperature|Thermodynamics|Water', 'Journal Article', '10.1371/journal.pcbi.1000810', '20548957', 'Coarse-grained (CG) simulations have become an essential tool to study a large variety of biomolecular processes, exploring temporal and spatial scales inaccessible to traditional models of atomistic resolution. One of the major simplifications of CG models is the representation of the solvent, which is either implicit or modeled explicitly as a van der Waals particle. The effect of polarization, and thus a proper screening of interactions depending on the local environment, is absent. Given the important role of water as a ubiquitous solvent in biological systems, its treatment is crucial to the properties derived from simulation studies. Here, we parameterize a polarizable coarse-grained water model to be used in combination with the CG MARTINI force field. Using a three-bead model to represent four water molecules, we show that the orientational polarizability of real water can be effectively accounted for. This has the consequence that the dielectric screening of bulk water is reproduced. At the same time, we parameterized our new water model such that bulk water density and oil/water partitioning data remain at the same level of accuracy as for the standard MARTINI force field. We apply the new model to two cases for which current CG force fields are inadequate. First, we address the transport of ions across a lipid membrane. The computed potential of mean force shows that the ions now naturally feel the change in dielectric medium when moving from the high dielectric aqueous phase toward the low dielectric membrane interior. In the second application we consider the electroporation process of both an oil slab and a lipid bilayer. The electrostatic field drives the formation of water filled pores in both cases, following a similar mechanism as seen with atomistically detailed models.'),
(84650, 2010, 'plos', 'Does mutational robustness inhibit extinction by lethal mutagenesis in viral populations?', 'ODea, Eamon B|Keller, Thomas E|Wilke, Claus O', 'Section of Integrative Biology, The University of Texas at Austin, Austin, Texas, United States of America.|Section of Integrative Biology, The University of Texas at Austin, Austin, Texas, United States of America.|Section of Integrative Biology, The University of Texas at Austin, Austin, Texas, United States of America.', 'United States|United States|United States', 14, 'Computational Biology|Directed Molecular Evolution|Genetics, Population|Linear Models|Models, Genetic|Mutagenesis|RNA Viruses|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1000811', '20548958', 'Lethal mutagenesis is a promising new antiviral therapy that kills a virus by raising its mutation rate. One potential shortcoming of lethal mutagenesis is that viruses may resist the treatment by evolving genomes with increased robustness to mutations. Here, we investigate to what extent mutational robustness can inhibit extinction by lethal mutagenesis in viruses, using both simple toy models and more biophysically realistic models based on RNA secondary-structure folding. We show that although the evolution of greater robustness may be promoted by increasing the mutation rate of a viral population, such evolution is unlikely to greatly increase the mutation rate required for certain extinction. Using an analytic multi-type branching process model, we investigate whether the evolution of robustness can be relevant on the time scales on which extinction takes place. We find that the evolution of robustness matters only when initial viral population sizes are small and deleterious mutation rates are only slightly above the level at which extinction can occur. The stochastic calculations are in good agreement with simulations of self-replicating RNA sequences that have to fold into a specific secondary structure to reproduce. We conclude that the evolution of mutational robustness is in most cases unlikely to prevent the extinction of viruses by lethal mutagenesis.'),
(84651, 2010, 'plos', 'The carbon assimilation network in Escherichia coli is densely connected and largely sign-determined by directions of metabolic fluxes', 'Baldazzi, Valentina|Ropers, Delphine|Markowicz, Yves|Kahn, Daniel|Geiselmann, Johannes|de Jong, Hidde', 'Institut National de Recherche en Informatique et en Automatique, INRIA Grenoble - Rhône-Alpes, Montbonnot, France.|Institut National de Recherche en Informatique et en Automatique, INRIA Grenoble - Rhône-Alpes, Montbonnot, France.|Institut National de Recherche en Informatique et en Automatique, INRIA Grenoble - Rhône-Alpes, Montbonnot, France.|Institut National de Recherche en Informatique et en Automatique, INRIA Grenoble - Rhône-Alpes, Montbonnot, France.|Institut National de Recherche en Informatique et en Automatique, INRIA Grenoble - Rhône-Alpes, Montbonnot, France.|Institut National de Recherche en Informatique et en Automatique, INRIA Grenoble - Rhône-Alpes, Montbonnot, France.', 'France|France|France|France|France|France', 47, 'Algorithms|Allosteric Regulation|Carbon|Escherichia coli|Gene Regulatory Networks|Gluconeogenesis|Glycolysis|Models, Biological|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000812', '20548959', 'Gene regulatory networks consist of direct interactions but also include indirect interactions mediated by metabolites and signaling molecules. We describe how these indirect interactions can be derived from a model of the underlying biochemical reaction network, using weak time-scale assumptions in combination with sensitivity criteria from metabolic control analysis. We apply this approach to a model of the carbon assimilation network in Escherichia coli. Our results show that the derived gene regulatory network is densely connected, contrary to what is usually assumed. Moreover, the network is largely sign-determined, meaning that the signs of the indirect interactions are fixed by the flux directions of biochemical reactions, independently of specific parameter values and rate laws. An inversion of the fluxes following a change in growth conditions may affect the signs of the indirect interactions though. This leads to a feedback structure that is at the same time robust to changes in the kinetic properties of enzymes and that has the flexibility to accommodate radical changes in the environment.'),
(84652, 2010, 'plos', 'Nonlinearity of mechanochemical motions in motor proteins', 'Togashi, Yuichi|Yanagida, Toshio|Mikhailov, Alexander S', 'Nanobiology Laboratories, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan. togashi@cmc.osaka-u.ac.jp|Nanobiology Laboratories, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan. togashi@cmc.osaka-u.ac.jp|Nanobiology Laboratories, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan. togashi@cmc.osaka-u.ac.jp', 'Japan|Japan|Japan', 0, 'Animals|Chickens|Humans|Kinesin|Molecular Dynamics Simulation|Myosin Type V|Nonlinear Dynamics|Protein Conformation|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000814', '20585540', 'The assumption of linear response of protein molecules to thermal noise or structural perturbations, such as ligand binding or detachment, is broadly used in the studies of protein dynamics. Conformational motions in proteins are traditionally analyzed in terms of normal modes and experimental data on thermal fluctuations in such macromolecules is also usually interpreted in terms of the excitation of normal modes. We have chosen two important protein motors--myosin V and kinesin KIF1A--and performed numerical investigations of their conformational relaxation properties within the coarse-grained elastic network approximation. We have found that the linearity assumption is deficient for ligand-induced conformational motions and can even be violated for characteristic thermal fluctuations. The deficiency is particularly pronounced in KIF1A where the normal mode description fails completely in describing functional mechanochemical motions. These results indicate that important assumptions of the theory of protein dynamics may need to be reconsidered. Neither a single normal mode nor a superposition of such modes yields an approximation of strongly nonlinear dynamics.'),
(84653, 2010, 'plos', 'NeuroML: a language for describing data driven models of neurons and networks with a high degree of biological detail', 'Gleeson, Padraig|Crook, Sharon|Cannon, Robert C|Hines, Michael L|Billings, Guy O|Farinella, Matteo|Morse, Thomas M|Davison, Andrew P|Ray, Subhasis|Bhalla, Upinder S|Barnes, Simon R|Dimitrova, Yoana D|Silver, R Angus', 'Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.|Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.|Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.|Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.|Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.|Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.|Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.|Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.|Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.|Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.|Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.|Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.|Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 158, 'CA1 Region, Hippocampal|Cerebral Cortex|Computational Biology|Computer Simulation|Electrical Synapses|Humans|Models, Neurological|Nerve Net|Neurons|Reproducibility of Results|Software|Thalamus', 'Journal Article', '10.1371/journal.pcbi.1000815', '20585541', 'Biologically detailed single neuron and network models are important for understanding how ion channels, synapses and anatomical connectivity underlie the complex electrical behavior of the brain. While neuronal simulators such as NEURON, GENESIS, MOOSE, NEST, and PSICS facilitate the development of these data-driven neuronal models, the specialized languages they employ are generally not interoperable, limiting model accessibility and preventing reuse of model components and cross-simulator validation. To overcome these problems we have used an Open Source software approach to develop NeuroML, a neuronal model description language based on XML (Extensible Markup Language). This enables these detailed models and their components to be defined in a standalone form, allowing them to be used across multiple simulators and archived in a standardized format. Here we describe the structure of NeuroML and demonstrate its scope by converting into NeuroML models of a number of different voltage- and ligand-gated conductances, models of electrical coupling, synaptic transmission and short-term plasticity, together with morphologically detailed models of individual neurons. We have also used these NeuroML-based components to develop an highly detailed cortical network model. NeuroML-based model descriptions were validated by demonstrating similar model behavior across five independently developed simulators. Although our results confirm that simulations run on different simulators converge, they reveal limits to model interoperability, by showing that for some models convergence only occurs at high levels of spatial and temporal discretisation, when the computational overhead is high. Our development of NeuroML as a common description language for biophysically detailed neuronal and network models enables interoperability across multiple simulation environments, thereby improving model transparency, accessibility and reuse in computational neuroscience.'),
(84654, 2010, 'plos', 'Using entropy maximization to understand the determinants of structural dynamics beyond native contact topology', 'Lezon, Timothy R|Bahar, Ivet', 'Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.', 'United States|United States', 23, 'Algorithms|Computational Biology|Databases, Protein|Entropy|Hydrogen Bonding|Molecular Dynamics Simulation|Normal Distribution|Nuclear Magnetic Resonance, Biomolecular|Protein Conformation|Proteins', 'Journal Article', '10.1371/journal.pcbi.1000816', '20585542', 'Comparison of elastic network model predictions with experimental data has provided important insights on the dominant role of the network of inter-residue contacts in defining the global dynamics of proteins. Most of these studies have focused on interpreting the mean-square fluctuations of residues, or deriving the most collective, or softest, modes of motions that are known to be insensitive to structural and energetic details. However, with increasing structural data, we are in a position to perform a more critical assessment of the structure-dynamics relations in proteins, and gain a deeper understanding of the major determinants of not only the mean-square fluctuations and lowest frequency modes, but the covariance or the cross-correlations between residue fluctuations and the shapes of higher modes. A systematic study of a large set of NMR-determined proteins is analyzed using a novel method based on entropy maximization to demonstrate that the next level of refinement in the elastic network model description of proteins ought to take into consideration properties such as contact order (or sequential separation between contacting residues) and the secondary structure types of the interacting residues, whereas the types of amino acids do not play a critical role. Most importantly, an optimal description of observed cross-correlations requires the inclusion of destabilizing, as opposed to exclusively stabilizing, interactions, stipulating the functional significance of local frustration in imparting native-like dynamics. This study provides us with a deeper understanding of the structural basis of experimentally observed behavior, and opens the way to the development of more accurate models for exploring protein dynamics.'),
(84655, 2010, 'plos', 'Revisiting date and party hubs: novel approaches to role assignment in protein interaction networks', 'Agarwal, Sumeet|Deane, Charlotte M|Porter, Mason A|Jones, Nick S', 'Systems Biology Doctoral Training Centre, University of Oxford, Oxford, United Kingdom.|Systems Biology Doctoral Training Centre, University of Oxford, Oxford, United Kingdom.|Systems Biology Doctoral Training Centre, University of Oxford, Oxford, United Kingdom.|Systems Biology Doctoral Training Centre, University of Oxford, Oxford, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Cell Physiological Phenomena|Computer Simulation|Databases, Protein|Fungal Proteins|Gene Expression Profiling|Humans|Protein Interaction Domains and Motifs|Protein Interaction Mapping|Proteins|Proteomics', 'Journal Article', '10.1371/journal.pcbi.1000817', '20585543', 'The idea of date and party hubs has been influential in the study of protein-protein interaction networks. Date hubs display low co-expression with their partners, whilst party hubs have high co-expression. It was proposed that party hubs are local coordinators whereas date hubs are global connectors. Here, we show that the reported importance of date hubs to network connectivity can in fact be attributed to a tiny subset of them. Crucially, these few, extremely central, hubs do not display particularly low expression correlation, undermining the idea of a link between this quantity and hub function. The date/party distinction was originally motivated by an approximately bimodal distribution of hub co-expression, we show that this feature is not always robust to methodological changes. Additionally, topological properties of hubs do not in general correlate with co-expression. However, we find significant correlations between interaction centrality and the functional similarity of the interacting proteins. We suggest that thinking in terms of a date/party dichotomy for hubs in protein interaction networks is not meaningful, and it might be more useful to conceive of roles for protein-protein interactions rather than for individual proteins.'),
(84656, 2010, 'plos', 'Fast- or slow-inactivated state preference of Na+ channel inhibitors: a simulation and experimental study', 'Karoly, Robert|Lenkey, Nora|Juhasz, Andras O|Vizi, E Sylvester|Mike, Arpad', 'Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.|Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.|Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.|Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.|Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.', 'Hungary|Hungary|Hungary|Hungary|Hungary', 0, 'Animals|Cells, Cultured|Computer Simulation|Electrophysiology|Humans|Models, Biological|Monte Carlo Method|Patch-Clamp Techniques|Sodium Channel Blockers|Sodium Channels|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1000818', '20585544', 'Sodium channels are one of the most intensively studied drug targets. Sodium channel inhibitors (e.g., local anesthetics, anticonvulsants, antiarrhythmics and analgesics) exert their effect by stabilizing an inactivated conformation of the channels. Besides the fast-inactivated conformation, sodium channels have several distinct slow-inactivated conformational states. Stabilization of a slow-inactivated state has been proposed to be advantageous for certain therapeutic applications. Special voltage protocols are used to evoke slow inactivation of sodium channels. It is assumed that efficacy of a drug in these protocols indicates slow-inactivated state preference. We tested this assumption in simulations using four prototypical drug inhibitory mechanisms (fast or slow-inactivated state preference, with either fast or slow binding kinetics) and a kinetic model for sodium channels. Unexpectedly, we found that efficacy in these protocols (e.g., a shift of the steady-state slow inactivation curve), was not a reliable indicator of slow-inactivated state preference. Slowly associating fast-inactivated state-preferring drugs were indistinguishable from slow-inactivated state-preferring drugs. On the other hand, fast- and slow-inactivated state-preferring drugs tended to preferentially affect onset and recovery, respectively. The robustness of these observations was verified: i) by performing a Monte Carlo study on the effects of randomly modifying model parameters, ii) by testing the same drugs in a fundamentally different model and iii) by an analysis of the effect of systematically changing drug-specific parameters. In patch clamp electrophysiology experiments we tested five sodium channel inhibitor drugs on native sodium channels of cultured hippocampal neurons. For lidocaine, phenytoin and carbamazepine our data indicate a preference for the fast-inactivated state, while the results for fluoxetine and desipramine are inconclusive. We suggest that conclusions based on voltage protocols that are used to detect slow-inactivated state preference are unreliable and should be re-evaluated.'),
(84657, 2010, 'plos', 'A cell-based model for quorum sensing in heterogeneous bacterial colonies', 'Melke, Pontus|Sahlin, Patrik|Levchenko, Andre|Jönsson, Henrik', 'Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden.|Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden.|Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden.|Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden.', 'Sweden|Sweden|Sweden|Sweden', 0, 'Acyl-Butyrolactones|Algorithms|Bacteria|Bacterial Physiological Phenomena|Computer Simulation|Models, Biological|Quorum Sensing|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000819', '20585545', 'Although bacteria are unicellular organisms, they have the ability to act in concert by synthesizing and detecting small diffusing autoinducer molecules. The phenomenon, known as quorum sensing, has mainly been proposed to serve as a means for cell-density measurement. Here, we use a cell-based model of growing bacterial microcolonies to investigate a quorum-sensing mechanism at a single cell level. We show that the model indeed predicts a density-dependent behavior, highly dependent on local cell-clustering and the geometry of the space where the colony is evolving. We analyze the molecular network with two positive feedback loops to find the multistability regions and show how the quorum-sensing mechanism depends on different model parameters. Specifically, we show that the switching capability of the network leads to more constraints on parameters in a natural environment where the bacteria themselves produce autoinducer than compared to situations where autoinducer is introduced externally. The cell-based model also allows us to investigate mixed populations, where non-producing cheater cells are shown to have a fitness advantage, but still cannot completely outcompete producer cells. Simulations, therefore, are able to predict the relative fitness of cheater cells from experiments and can also display and account for the paradoxical phenomenon seen in experiments, even though the cheater cells have a fitness advantage in each of the investigated groups, the overall effect is an increase in the fraction of producer cells. The cell-based type of model presented here together with high-resolution experiments will play an integral role in a more explicit and precise comparison of models and experiments, addressing quorum sensing at a cellular resolution.'),
(84658, 2010, 'plos', 'Rule-based cell systems model of aging using feedback loop motifs mediated by stress responses', 'Kriete, Andres|Bosl, William J|Booker, Glenn', 'School of Biomedical Engineering, Science and Health Systems, Drexel University, Bossone Research Center, Philadelphia, Pennsylvania, United States of America. andres.kriete@drexel.edu|School of Biomedical Engineering, Science and Health Systems, Drexel University, Bossone Research Center, Philadelphia, Pennsylvania, United States of America. andres.kriete@drexel.edu|School of Biomedical Engineering, Science and Health Systems, Drexel University, Bossone Research Center, Philadelphia, Pennsylvania, United States of America. andres.kriete@drexel.edu', 'United States|United States|United States', 0, 'Adenosine Triphosphate|Animals|Cellular Senescence|Computer Simulation|Energy Metabolism|Feedback, Physiological|Fuzzy Logic|Humans|Intracellular Signaling Peptides and Proteins|Models, Biological|NF-kappa B|Protein-Serine-Threonine Kinases|Reactive Oxygen Species|Stress, Physiological|Systems Biology|TOR Serine-Threonine Kinases', 'Journal Article', '10.1371/journal.pcbi.1000820', '20585546', 'Investigating the complex systems dynamics of the aging process requires integration of a broad range of cellular processes describing damage and functional decline co-existing with adaptive and protective regulatory mechanisms. We evolve an integrated generic cell network to represent the connectivity of key cellular mechanisms structured into positive and negative feedback loop motifs centrally important for aging. The conceptual network is casted into a fuzzy-logic, hybrid-intelligent framework based on interaction rules assembled from a priori knowledge. Based upon a classical homeostatic representation of cellular energy metabolism, we first demonstrate how positive-feedback loops accelerate damage and decline consistent with a vicious cycle. This model is iteratively extended towards an adaptive response model by incorporating protective negative-feedback loop circuits. Time-lapse simulations of the adaptive response model uncover how transcriptional and translational changes, mediated by stress sensors NF-kappaB and mTOR, counteract accumulating damage and dysfunction by modulating mitochondrial respiration, metabolic fluxes, biosynthesis, and autophagy, crucial for cellular survival. The model allows consideration of lifespan optimization scenarios with respect to fitness criteria using a sensitivity analysis. Our work establishes a novel extendable and scalable computational approach capable to connect tractable molecular mechanisms with cellular network dynamics underlying the emerging aging phenotype.'),
(84659, 2010, 'plos', 'Beauty is in the eye of the beholder: proteins can recognize binding sites of homologous proteins in more than one way', 'Martin, Juliette', 'Université de Lyon, Lyon, France, Université Lyon 1, IFR 128, CNRS, UMR 5086 Institut de Biologie et Chimie des Protéines (IBCP), Lyon, France. juliette.martin@ibcp.fr', 'France', 16, 'Bacterial Proteins|Binding Sites|Cluster Analysis|Databases, Protein|Fungal Proteins|Humans|Models, Molecular|Protein Binding|Protein Interaction Domains and Motifs|Proteins|Sequence Homology, Amino Acid|Software', 'Journal Article', '10.1371/journal.pcbi.1000821', '20585553', 'Understanding the mechanisms of protein-protein interaction is a fundamental problem with many practical applications. The fact that different proteins can bind similar partners suggests that convergently evolved binding interfaces are reused in different complexes. A set of protein complexes composed of non-homologous domains interacting with homologous partners at equivalent binding sites was collected in 2006, offering an opportunity to investigate this point. We considered 433 pairs of protein-protein complexes from the ABAC database (AB and AC binary protein complexes sharing a homologous partner A) and analyzed the extent of physico-chemical similarity at the atomic and residue level at the protein-protein interface. Homologous partners of the complexes were superimposed using Multiprot, and similar atoms at the interface were quantified using a five class grouping scheme and a distance cut-off. We found that the number of interfacial atoms with similar properties is systematically lower in the non-homologous proteins than in the homologous ones. We assessed the significance of the similarity by bootstrapping the atomic properties at the interfaces. We found that the similarity of binding sites is very significant between homologous proteins, as expected, but generally insignificant between the non-homologous proteins that bind to homologous partners. Furthermore, evolutionarily conserved residues are not colocalized within the binding sites of non-homologous proteins. We could only identify a limited number of cases of structural mimicry at the interface, suggesting that this property is less generic than previously thought. Our results support the hypothesis that different proteins can interact with similar partners using alternate strategies, but do not support convergent evolution.'),
(84660, 2010, 'plos', '2010 ISCB Overton Prize Awarded to Steven E Brenner', 'McKay, B J Morrison|Sansom, Clare', 'International Society for Computational Biology, La Jolla, California, United States of America. bj@iscb.org|International Society for Computational Biology, La Jolla, California, United States of America. bj@iscb.org', 'United States|United States', 0, 'Animals|Awards and Prizes|Computational Biology|History, 21st Century|Humans', 'Biography', '10.1371/journal.pcbi.1000831', '20585610', '-'),
(84661, 2010, 'plos', 'Computational prediction and experimental assessment of secreted/surface proteins from Mycobacterium tuberculosis H37Rv', 'Vizcaíno, Carolina|Restrepo-Montoya, Daniel|Rodríguez, Diana|Niño, Luis F|Ocampo, Marisol|Vanegas, Magnolia|Reguero, María T|Martínez, Nora L|Patarroyo, Manuel E|Patarroyo, Manuel A', 'Fundación Instituto de Inmunología de Colombia - FIDIC, Bogotá, Colombia.|Fundación Instituto de Inmunología de Colombia - FIDIC, Bogotá, Colombia.|Fundación Instituto de Inmunología de Colombia - FIDIC, Bogotá, Colombia.|Fundación Instituto de Inmunología de Colombia - FIDIC, Bogotá, Colombia.|Fundación Instituto de Inmunología de Colombia - FIDIC, Bogotá, Colombia.|Fundación Instituto de Inmunología de Colombia - FIDIC, Bogotá, Colombia.|Fundación Instituto de Inmunología de Colombia - FIDIC, Bogotá, Colombia.|Fundación Instituto de Inmunología de Colombia - FIDIC, Bogotá, Colombia.|Fundación Instituto de Inmunología de Colombia - FIDIC, Bogotá, Colombia.|Fundación Instituto de Inmunología de Colombia - FIDIC, Bogotá, Colombia.', 'Colombia|Colombia|Colombia|Colombia|Colombia|Colombia|Colombia|Colombia|Colombia|Colombia', 36, 'Animals|Antibodies, Bacterial|Artificial Intelligence|Bacterial Outer Membrane Proteins|Cell Fractionation|Computational Biology|Electrophoresis, Polyacrylamide Gel|Epitopes, B-Lymphocyte|Escherichia coli|Immunoblotting|Microscopy, Immunoelectron|Models, Statistical|Mycobacterium smegmatis|Mycobacterium tuberculosis|Peptides|Rabbits|Sonication|Subcellular Fractions', 'Journal Article', '10.1371/journal.pcbi.1000824', '20585611', 'The mycobacterial cell envelope has been implicated in the pathogenicity of tuberculosis and therefore has been a prime target for the identification and characterization of surface proteins with potential application in drug and vaccine development. In this study, the genome of Mycobacterium tuberculosis H37Rv was screened using Machine Learning tools that included feature-based predictors, general localizers and transmembrane topology predictors to identify proteins that are potentially secreted to the surface of M. tuberculosis, or to the extracellular milieu through different secretory pathways. The subcellular localization of a set of 8 hypothetically secreted/surface candidate proteins was experimentally assessed by cellular fractionation and immunoelectron microscopy (IEM) to determine the reliability of the computational methodology proposed here, using 4 secreted/surface proteins with experimental confirmation as positive controls and 2 cytoplasmic proteins as negative controls. Subcellular fractionation and IEM studies provided evidence that the candidate proteins Rv0403c, Rv3630, Rv1022, Rv0835, Rv0361 and Rv0178 are secreted either to the mycobacterial surface or to the extracellular milieu. Surface localization was also confirmed for the positive controls, whereas negative controls were located on the cytoplasm. Based on statistical learning methods, we obtained computational subcellular localization predictions that were experimentally assessed and allowed us to construct a computational protocol with experimental support that allowed us to identify a new set of secreted/surface proteins as potential vaccine candidates.'),
(84662, 2010, 'plos', 'Slope-based stochastic resonance: how noise enables phasic neurons to encode slow signals', 'Gai, Yan|Doiron, Brent|Rinzel, John', 'Center for Neural Science, New York University, New York, New York, United States of America. yg30@nyu.edu|Center for Neural Science, New York University, New York, New York, United States of America. yg30@nyu.edu|Center for Neural Science, New York University, New York, New York, United States of America. yg30@nyu.edu', 'United States|United States|United States', 32, 'Action Potentials|Age Factors|Animals|Brain Stem|Gerbillinae|Microscopy, Video|Models, Neurological|Neurons|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1000825', '20585612', 'Fundamental properties of phasic firing neurons are usually characterized in a noise-free condition. In the absence of noise, phasic neurons exhibit Class 3 excitability, which is a lack of repetitive firing to steady current injections. For time-varying inputs, phasic neurons are band-pass filters or slope detectors, because they do not respond to inputs containing exclusively low frequencies or shallow slopes. However, we show that in noisy conditions, response properties of phasic neuron models are distinctly altered. Noise enables a phasic model to encode low-frequency inputs that are outside of the response range of the associated deterministic model. Interestingly, this seemingly stochastic-resonance (SR) like effect differs significantly from the classical SR behavior of spiking systems in both the signal-to-noise ratio and the temporal response pattern. Instead of being most sensitive to the peak of a subthreshold signal, as is typical in a classical SR system, phasic models are most sensitive to the signals rising and falling phases where the slopes are steep. This finding is consistent with the fact that there is not an absolute input threshold in terms of amplitude, rather, a response threshold is more properly defined as a stimulus slope/frequency. We call the encoding of low-frequency signals with noise by phasic models a slope-based SR, because noise can lower or diminish the slope threshold for ramp stimuli. We demonstrate here similar behaviors in three mechanistic models with Class 3 excitability in the presence of slow-varying noise and we suggest that the slope-based SR is a fundamental behavior associated with general phasic properties rather than with a particular biological mechanism.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84663, 2010, 'plos', 'Mammalian sleep dynamics: how diverse features arise from a common physiological framework', 'Phillips, Andrew J K|Robinson, Peter A|Kedziora, David J|Abeysuriya, Romesh G', 'School of Physics, University of Sydney, Sydney, Australia. ajphillips@partners.org|School of Physics, University of Sydney, Sydney, Australia. ajphillips@partners.org|School of Physics, University of Sydney, Sydney, Australia. ajphillips@partners.org|School of Physics, University of Sydney, Sydney, Australia. ajphillips@partners.org', 'Australia|Australia|Australia|Australia', 0, 'Algorithms|Animals|Brain|Cats|Humans|Mammals|Mice|Models, Biological|Organ Size|Rats|Recovery of Function|Sleep|Sleep Deprivation', 'Journal Article', '10.1371/journal.pcbi.1000826', '20585613', 'Mammalian sleep varies widely, ranging from frequent napping in rodents to consolidated blocks in primates and unihemispheric sleep in cetaceans. In humans, rats, mice and cats, sleep patterns are orchestrated by homeostatic and circadian drives to the sleep-wake switch, but it is not known whether this system is ubiquitous among mammals. Here, changes of just two parameters in a recent quantitative model of this switch are shown to reproduce typical sleep patterns for 17 species across 7 orders. Furthermore, the parameter variations are found to be consistent with the assumptions that homeostatic production and clearance scale as brain volume and surface area, respectively. Modeling an additional inhibitory connection between sleep-active neuronal populations on opposite sides of the brain generates unihemispheric sleep, providing a testable hypothetical mechanism for this poorly understood phenomenon. Neuromodulation of this connection alone is shown to account for the ability of fur seals to transition between bihemispheric sleep on land and unihemispheric sleep in water. Determining what aspects of mammalian sleep patterns can be explained within a single framework, and are thus universal, is essential to understanding the evolution and function of mammalian sleep. This is the first demonstration of a single model reproducing sleep patterns for multiple different species. These wide-ranging findings suggest that the core physiological mechanisms controlling sleep are common to many mammalian orders, with slight evolutionary modifications accounting for interspecies differences.'),
(84664, 2010, 'plos', 'Multiscale coarse-graining of the protein energy landscape', 'Hills, Ronald D|Lu, Lanyuan|Voth, Gregory A', 'Department of Chemistry, James Franck Institute and Computation Institute, University of Chicago, Chicago, Illinois, United States of America.|Department of Chemistry, James Franck Institute and Computation Institute, University of Chicago, Chicago, Illinois, United States of America.|Department of Chemistry, James Franck Institute and Computation Institute, University of Chicago, Chicago, Illinois, United States of America.', 'United States|United States|United States', 81, 'Amino Acids|Computational Biology|Computer Simulation|Molecular Dynamics Simulation|Peptides|Proteins|Temperature|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000827', '20585614', 'A variety of coarse-grained (CG) models exists for simulation of proteins. An outstanding problem is the construction of a CG model with physically accurate conformational energetics rivaling all-atom force fields. In the present work, atomistic simulations of peptide folding and aggregation equilibria are force-matched using multiscale coarse-graining to develop and test a CG interaction potential of general utility for the simulation of proteins of arbitrary sequence. The reduced representation relies on multiple interaction sites to maintain the anisotropic packing and polarity of individual sidechains. CG energy landscapes computed from replica exchange simulations of the folding of Trpzip, Trp-cage and adenylate kinase resemble those of other reduced representations, non-native structures are observed with energies similar to those of the native state. The artifactual stabilization of misfolded states implies that non-native interactions play a deciding role in deviations from ideal funnel-like cooperative folding. The role of surface tension, backbone hydrogen bonding and the smooth pairwise CG landscape is discussed. Ab initio folding aside, the improved treatment of sidechain rotamers results in stability of the native state in constant temperature simulations of Trpzip, Trp-cage, and the open to closed conformational transition of adenylate kinase, illustrating the potential value of the CG force field for simulating protein complexes and transitions between well-defined structural states.'),
(84665, 2010, 'plos', 'Platos cave algorithm: inferring functional signaling networks from early gene expression shadows', 'Shimoni, Yishai|Fink, Marc Y|Choi, Soon-gang|Sealfon, Stuart C', 'Department of Neurology and Center for Translational Systems Biology, Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Neurology and Center for Translational Systems Biology, Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Neurology and Center for Translational Systems Biology, Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Neurology and Center for Translational Systems Biology, Mount Sinai School of Medicine, New York, New York, United States of America.', 'United States|United States|United States|United States', 10, 'Algorithms|Animals|Cell Line|Computational Biology|Computer Simulation|Epidermal Growth Factor|Gene Expression|Gene Regulatory Networks|JNK Mitogen-Activated Protein Kinases|Mice|RNA, Messenger|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000828', '20585619', 'Improving the ability to reverse engineer biochemical networks is a major goal of systems biology. Lesions in signaling networks lead to alterations in gene expression, which in principle should allow network reconstruction. However, the information about the activity levels of signaling proteins conveyed in overall gene expression is limited by the complexity of gene expression dynamics and of regulatory network topology. Two observations provide the basis for overcoming this limitation: a. genes induced without de-novo protein synthesis (early genes) show a linear accumulation of product in the first hour after the change in the cells state, b. The signaling components in the network largely function in the linear range of their stimulus-response curves. Therefore, unlike most genes or most time points, expression profiles of early genes at an early time point provide direct biochemical assays that represent the activity levels of upstream signaling components. Such expression data provide the basis for an efficient algorithm (Platos Cave algorithm, PLACA) to reverse engineer functional signaling networks. Unlike conventional reverse engineering algorithms that use steady state values, PLACA uses stimulated early gene expression measurements associated with systematic perturbations of signaling components, without measuring the signaling components themselves. Besides the reverse engineered network, PLACA also identifies the genes detecting the functional interaction, thereby facilitating validation of the predicted functional network. Using simulated datasets, the algorithm is shown to be robust to experimental noise. Using experimental data obtained from gonadotropes, PLACA reverse engineered the interaction network of six perturbed signaling components. The network recapitulated many known interactions and identified novel functional interactions that were validated by further experiment. PLACA uses the results of experiments that are feasible for any signaling network to predict the functional topology of the network and to identify novel relationships.'),
(84666, 2010, 'plos', 'Atomic-resolution simulations predict a transition state for vesicle fusion defined by contact of a few lipid tails', 'Kasson, Peter M|Lindahl, Erik|Pande, Vijay S', 'Department of Chemistry, Stanford University, Stanford, California, United States of America.|Department of Chemistry, Stanford University, Stanford, California, United States of America.|Department of Chemistry, Stanford University, Stanford, California, United States of America.', 'United States|United States|United States', 0, 'Computer Simulation|Hemagglutinins, Viral|Hydrophobic and Hydrophilic Interactions|Membrane Fusion|Models, Molecular|Orthomyxoviridae|Phosphatidylcholines|Phosphatidylethanolamines|Transport Vesicles|Water', 'Journal Article', '10.1371/journal.pcbi.1000829', '20585620', 'Membrane fusion is essential to both cellular vesicle trafficking and infection by enveloped viruses. While the fusion protein assemblies that catalyze fusion are readily identifiable, the specific activities of the proteins involved and nature of the membrane changes they induce remain unknown. Here, we use many atomic-resolution simulations of vesicle fusion to examine the molecular mechanisms for fusion in detail. We employ committor analysis for these million-atom vesicle fusion simulations to identify a transition state for fusion stalk formation. In our simulations, this transition state occurs when the bulk properties of each lipid bilayer remain in a lamellar state but a few hydrophobic tails bulge into the hydrophilic interface layer and make contact to nucleate a stalk. Additional simulations of influenza fusion peptides in lipid bilayers show that the peptides promote similar local protrusion of lipid tails. Comparing these two sets of simulations, we obtain a common set of structural changes between the transition state for stalk formation and the local environment of peptides known to catalyze fusion. Our results thus suggest that the specific molecular properties of individual lipids are highly important to vesicle fusion and yield an explicit structural model that could help explain the mechanism of catalysis by fusion proteins.'),
(84667, 2010, 'plos', 'Protein-protein interactions essentials: key concepts to building and analyzing interactome networks', 'De Las Rivas, Javier|Fontanillo, Celia', 'Bioinformatics & Functional Genomics Research Group, Cancer Research Center (CiC-IBMCC, CSIC/USAL), Salamanca, Spain. jrivas@usal.es|Bioinformatics & Functional Genomics Research Group, Cancer Research Center (CiC-IBMCC, CSIC/USAL), Salamanca, Spain. jrivas@usal.es', 'Spain|Spain', 283, 'Computational Biology|Databases, Protein|Gene Regulatory Networks|Humans|Protein Interaction Domains and Motifs|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000807', '20589078', '-'),
(84668, 2010, 'plos', 'The roots of bioinformatics', 'Searls, David B', 'Bioinformatics & Functional Genomics Research Group, Cancer Research Center (CiC-IBMCC, CSIC/USAL), Salamanca, Spain. jrivas@usal.es', 'Spain', 17, 'Computational Biology|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1000809', '20589079', '-'),
(84669, 2010, 'plos', 'Constraint-based model of Shewanella oneidensis MR-1 metabolism: a tool for data analysis and hypothesis generation', 'Pinchuk, Grigoriy E|Hill, Eric A|Geydebrekht, Oleg V|De Ingeniis, Jessica|Zhang, Xiaolin|Osterman, Andrei|Scott, James H|Reed, Samantha B|Romine, Margaret F|Konopka, Allan E|Beliaev, Alexander S|Fredrickson, Jim K|Reed, Jennifer L', 'Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America. grigoriy.pinchuk@pnl.gov|Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America. grigoriy.pinchuk@pnl.gov|Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America. grigoriy.pinchuk@pnl.gov|Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America. grigoriy.pinchuk@pnl.gov|Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America. grigoriy.pinchuk@pnl.gov|Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America. grigoriy.pinchuk@pnl.gov|Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America. grigoriy.pinchuk@pnl.gov|Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America. grigoriy.pinchuk@pnl.gov|Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America. grigoriy.pinchuk@pnl.gov|Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America. grigoriy.pinchuk@pnl.gov|Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America. grigoriy.pinchuk@pnl.gov|Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America. grigoriy.pinchuk@pnl.gov|Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America. grigoriy.pinchuk@pnl.gov', 'United States|United States|United States|United States|United States|United States|United States|Un', 85, 'Adenosine Triphosphate|Biomass|Computational Biology|Lactic Acid|Linear Models|Metabolic Networks and Pathways|Models, Biological|Oxygen|Phenotype|Reproducibility of Results|Shewanella', 'Journal Article', '10.1371/journal.pcbi.1000822', '20589080', 'Shewanellae are gram-negative facultatively anaerobic metal-reducing bacteria commonly found in chemically (i.e., redox) stratified environments. Occupying such niches requires the ability to rapidly acclimate to changes in electron donor/acceptor type and availability, hence, the ability to compete and thrive in such environments must ultimately be reflected in the organization and utilization of electron transfer networks, as well as central and peripheral carbon metabolism. To understand how Shewanella oneidensis MR-1 utilizes its resources, the metabolic network was reconstructed. The resulting network consists of 774 reactions, 783 genes, and 634 unique metabolites and contains biosynthesis pathways for all cell constituents. Using constraint-based modeling, we investigated aerobic growth of S. oneidensis MR-1 on numerous carbon sources. To achieve this, we (i) used experimental data to formulate a biomass equation and estimate cellular ATP requirements, (ii) developed an approach to identify cycles (such as futile cycles and circulations), (iii) classified how reaction usage affects cellular growth, (iv) predicted cellular biomass yields on different carbon sources and compared model predictions to experimental measurements, and (v) used experimental results to refine metabolic fluxes for growth on lactate. The results revealed that aerobic lactate-grown cells of S. oneidensis MR-1 used less efficient enzymes to couple electron transport to proton motive force generation, and possibly operated at least one futile cycle involving malic enzymes. Several examples are provided whereby model predictions were validated by experimental data, in particular the role of serine hydroxymethyltransferase and glycine cleavage system in the metabolism of one-carbon units, and growth on different sources of carbon and energy. This work illustrates how integration of computational and experimental efforts facilitates the understanding of microbial metabolism at a systems level.'),
(84670, 2010, 'plos', 'TRANSAT-- method for detecting the conserved helices of functional RNA structures, including transient, pseudo-knotted and alternative structures', 'Wiebe, Nicholas J P|Meyer, Irmtraud M', 'Centre for High-Throughput Biology & Department of Computer Science and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.|Centre for High-Throughput Biology & Department of Computer Science and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.', 'Canada|Canada', 23, 'Computational Biology|Databases, Nucleic Acid|Models, Molecular|Models, Statistical|Nucleic Acid Conformation|RNA|Sequence Alignment|Sequence Homology, Nucleic Acid|Software', 'Journal Article', '10.1371/journal.pcbi.1000823', '20589081', 'The prediction of functional RNA structures has attracted increased interest, as it allows us to study the potential functional roles of many genes. RNA structure prediction methods, however, assume that there is a unique functional RNA structure and also do not predict functional features required for in vivo folding. In order to understand how functional RNA structures form in vivo, we require sophisticated experiments or reliable prediction methods. So far, there exist only a few, experimentally validated transient RNA structures. On the computational side, there exist several computer programs which aim to predict the co-transcriptional folding pathway in vivo, but these make a range of simplifying assumptions and do not capture all features known to influence RNA folding in vivo. We want to investigate if evolutionarily related RNA genes fold in a similar way in vivo. To this end, we have developed a new computational method, Transat, which detects conserved helices of high statistical significance. We introduce the method, present a comprehensive performance evaluation and show that Transat is able to predict the structural features of known reference structures including pseudo-knotted ones as well as those of known alternative structural configurations. Transat can also identify unstructured sub-sequences bound by other molecules and provides evidence for new helices which may define folding pathways, supporting the notion that homologous RNA sequence not only assume a similar reference RNA structure, but also fold similarly. Finally, we show that the structural features predicted by Transat differ from those assuming thermodynamic equilibrium. Unlike the existing methods for predicting folding pathways, our method works in a comparative way. This has the disadvantage of not being able to predict features as function of time, but has the considerable advantage of highlighting conserved features and of not requiring a detailed knowledge of the cellular environment.'),
(84671, 2010, 'plos', 'The 20S proteasome splicing activity discovered by SpliceMet', 'Liepe, Juliane|Mishto, Michele|Textoris-Taube, Kathrin|Janek, Katharina|Keller, Christin|Henklein, Petra|Kloetzel, Peter Michael|Zaikin, Alexey', 'Institut für Biochemie, Charité, Universitätsmedizin Berlin, Berlin, Germany.|Institut für Biochemie, Charité, Universitätsmedizin Berlin, Berlin, Germany.|Institut für Biochemie, Charité, Universitätsmedizin Berlin, Berlin, Germany.|Institut für Biochemie, Charité, Universitätsmedizin Berlin, Berlin, Germany.|Institut für Biochemie, Charité, Universitätsmedizin Berlin, Berlin, Germany.|Institut für Biochemie, Charité, Universitätsmedizin Berlin, Berlin, Germany.|Institut für Biochemie, Charité, Universitätsmedizin Berlin, Berlin, Germany.|Institut für Biochemie, Charité, Universitätsmedizin Berlin, Berlin, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany', 45, 'Algorithms|Amino Acid Sequence|Antigens, Nuclear|Autoantigens|CD8-Positive T-Lymphocytes|Computational Biology|Computer Simulation|Databases, Protein|Epitopes, T-Lymphocyte|Fibroblast Growth Factor 5|Humans|Membrane Glycoproteins|Molecular Sequence Data|Peptide Fragments|Proteasome Endopeptidase Complex|Reproducibility of Results|Software|Tandem Mass Spectrometry|gp100 Melanoma Antigen', 'Journal Article', '10.1371/journal.pcbi.1000830', '20613855', 'The identification of proteasome-generated spliced peptides (PSP) revealed a new unpredicted activity of the major cellular protease. However, so far characterization of PSP was entirely dependent on the availability of patient-derived cytotoxic CD8+ T lymphocytes (CTL) thus preventing a systematic investigation of proteasome-catalyzed peptide splicing (PCPS). For an unrestricted PSP identification we here developed SpliceMet, combining the computer-based algorithm ProteaJ with in vitro proteasomal degradation assays and mass spectrometry. By applying SpliceMet for the analysis of proteasomal processing products of four different substrate polypeptides, derived from human tumor as well as viral antigens, we identified fifteen new spliced peptides generated by PCPS either by cis or from two separate substrate molecules, i.e., by trans splicing. Our data suggest that 20S proteasomes represent a molecular machine that, due to its catalytic and structural properties, facilitates the generation of spliced peptides, thereby providing a pool of qualitatively new peptides from which functionally relevant products may be selected.'),
(84672, 2010, 'plos', 'Computer simulation of cellular patterning within the Drosophila pupal eye', 'Larson, David E|Johnson, Ruth I|Swat, Maciej|Cordero, Julia B|Glazier, James A|Cagan, Ross L', 'The Genome Center at Washington University, St. Louis, Missouri, United States of America.|The Genome Center at Washington University, St. Louis, Missouri, United States of America.|The Genome Center at Washington University, St. Louis, Missouri, United States of America.|The Genome Center at Washington University, St. Louis, Missouri, United States of America.|The Genome Center at Washington University, St. Louis, Missouri, United States of America.|The Genome Center at Washington University, St. Louis, Missouri, United States of America.', 'United States|United States|United States|United States|United States|United States', 19, 'Animals|Apoptosis|Cell Adhesion|Cell Movement|Cell Proliferation|Compound Eye, Arthropod|Computer Simulation|Drosophila|Microscopy, Electron, Transmission|Models, Biological|Morphogenesis|Mutation|Pupa|Surface Properties', 'Journal Article', '10.1371/journal.pcbi.1000841', '20617161', 'We present a computer simulation and associated experimental validation of assembly of glial-like support cells into the interweaving hexagonal lattice that spans the Drosophila pupal eye. This process of cell movements organizes the ommatidial array into a functional pattern. Unlike earlier simulations that focused on the arrangements of cells within individual ommatidia, here we examine the local movements that lead to large-scale organization of the emerging eye field. Simulations based on our experimental observations of cell adhesion, cell death, and cell movement successfully patterned a tracing of an emerging wild-type pupal eye. Surprisingly, altering cell adhesion had only a mild effect on patterning, contradicting our previous hypothesis that the patterning was primarily the result of preferential adhesion between IRM-class surface proteins. Instead, our simulations highlighted the importance of programmed cell death (PCD) as well as a previously unappreciated variable: the expansion of cells apical surface areas, which promoted rearrangement of neighboring cells. We tested this prediction experimentally by preventing expansion in the apical area of individual cells: patterning was disrupted in a manner predicted by our simulations. Our work demonstrates the value of combining computer simulation with in vivo experiments to uncover novel mechanisms that are perpetuated throughout the eye field. It also demonstrates the utility of the Glazier-Graner-Hogeweg model (GGH) for modeling the links between local cellular interactions and emergent properties of developing epithelia as well as predicting unanticipated results in vivo.'),
(84673, 2010, 'plos', 'Intergenic and repeat transcription in human, chimpanzee and macaque brains measured by RNA-Seq', 'Xu, Augix Guohua|He, Liu|Li, Zhongshan|Xu, Ying|Li, Mingfeng|Fu, Xing|Yan, Zheng|Yuan, Yuan|Menzel, Corinna|Li, Na|Somel, Mehmet|Hu, Hao|Chen, Wei|Pääbo, Svante|Khaitovich, Philipp', 'Partner Institute for Computational Biology, Shanghai, China.|Partner Institute for Computational Biology, Shanghai, China.|Partner Institute for Computational Biology, Shanghai, China.|Partner Institute for Computational Biology, Shanghai, China.|Partner Institute for Computational Biology, Shanghai, China.|Partner Institute for Computational Biology, Shanghai, China.|Partner Institute for Computational Biology, Shanghai, China.|Partner Institute for Computational Biology, Shanghai, China.|Partner Institute for Computational Biology, Shanghai, China.|Partner Institute for Computational Biology, Shanghai, China.|Partner Institute for Computational Biology, Shanghai, China.|Partner Institute for Computational Biology, Shanghai, China.|Partner Institute for Computational Biology, Shanghai, China.|Partner Institute for Computational Biology, Shanghai, China.|Partner Institute for Computational Biology, Shanghai, China.', 'China|China|China|China|China|China|China|China|China|China|China|China|China|China|China', 47, 'Animals|Cerebellum|Chromosome Mapping|Cluster Analysis|DNA, Intergenic|Gene Expression Profiling|Humans|Macaca|Male|Mice|Models, Genetic|Pan troglodytes|Phenotype|Repetitive Sequences, Nucleic Acid|Sequence Alignment|Sequence Analysis, RNA|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.1000843', '20617162', 'Transcription is the first step connecting genetic information with an organisms phenotype. While expression of annotated genes in the human brain has been characterized extensively, our knowledge about the scope and the conservation of transcripts located outside of the known genes boundaries is limited. Here, we use high-throughput transcriptome sequencing (RNA-Seq) to characterize the total non-ribosomal transcriptome of human, chimpanzee, and rhesus macaque brain. In all species, only 20-28% of non-ribosomal transcripts correspond to annotated exons and 20-23% to introns. By contrast, transcripts originating within intronic and intergenic repetitive sequences constitute 40-48% of the total brain transcriptome. Notably, some repeat families show elevated transcription. In non-repetitive intergenic regions, we identify and characterize 1,093 distinct regions highly expressed in the human brain. These regions are conserved at the RNA expression level across primates studied and at the DNA sequence level across mammals. A large proportion of these transcripts (20%) represents 3UTR extensions of known genes and may play roles in alternative microRNA-directed regulation. Finally, we show that while transcriptome divergence between species increases with evolutionary time, intergenic transcripts show more expression differences among species and exons show less. Our results show that many yet uncharacterized evolutionary conserved transcripts exist in the human brain. Some of these transcripts may play roles in transcriptional regulation and contribute to evolution of human-specific phenotypic traits.'),
(84674, 2010, 'plos', 'Effects of macromolecular crowding on protein conformational changes', 'Dong, Hao|Qin, Sanbo|Zhou, Huan-Xiang', 'Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, United States of America.|Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, United States of America.|Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, United States of America.', 'United States|United States|United States', 64, 'Apoproteins|Molecular Dynamics Simulation|Multiprotein Complexes|Protein Conformation|Proteins|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000833', '20617196', 'Many protein functions can be directly linked to conformational changes. Inside cells, the equilibria and transition rates between different conformations may be affected by macromolecular crowding. We have recently developed a new approach for modeling crowding effects, which enables an atomistic representation of test proteins. Here this approach is applied to study how crowding affects the equilibria and transition rates between open and closed conformations of seven proteins: yeast protein disulfide isomerase (yPDI), adenylate kinase (AdK), orotidine phosphate decarboxylase (ODCase), Trp repressor (TrpR), hemoglobin, DNA beta-glucosyltransferase, and Ap(4)A hydrolase. For each protein, molecular dynamics simulations of the open and closed states are separately run. Representative open and closed conformations are then used to calculate the crowding-induced changes in chemical potential for the two states. The difference in chemical-potential change between the two states finally predicts the effects of crowding on the population ratio of the two states. Crowding is found to reduce the open population to various extents. In the presence of crowders with a 15 A radius and occupying 35% of volume, the open-to-closed population ratios of yPDI, AdK, ODCase and TrpR are reduced by 79%, 78%, 62% and 55%, respectively. The reductions for the remaining three proteins are 20-44%. As expected, the four proteins experiencing the stronger crowding effects are those with larger conformational changes between open and closed states (e.g., as measured by the change in radius of gyration). Larger proteins also tend to experience stronger crowding effects than smaller ones [e.g., comparing yPDI (480 residues) and TrpR (98 residues)]. The potentials of mean force along the open-closed reaction coordinate of apo and ligand-bound ODCase are altered by crowding, suggesting that transition rates are also affected. These quantitative results and qualitative trends will serve as valuable guides for expected crowding effects on protein conformation changes inside cells.'),
(84675, 2010, 'plos', 'The energy landscape, folding pathways and the kinetics of a knotted protein', 'Prentiss, Michael C|Wales, David J|Wolynes, Peter G', 'Department of Chemistry, Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America. mcprentiss@gmail.com|Department of Chemistry, Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America. mcprentiss@gmail.com|Department of Chemistry, Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America. mcprentiss@gmail.com', 'United States|United States|United States', 33, 'Kinetics|Molecular Dynamics Simulation|Protein Conformation|Protein Folding|Proteins|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000835', '20617197', 'The folding pathway and rate coefficients of the folding of a knotted protein are calculated for a potential energy function with minimal energetic frustration. A kinetic transition network is constructed using the discrete path sampling approach, and the resulting potential energy surface is visualized by constructing disconnectivity graphs. Owing to topological constraints, the low-lying portion of the landscape consists of three distinct regions, corresponding to the native knotted state and to configurations where either the N or C terminus is not yet folded into the knot. The fastest folding pathways from denatured states exhibit early formation of the N terminus portion of the knot and a rate-determining step where the C terminus is incorporated. The low-lying minima with the N terminus knotted and the C terminus free therefore constitute an off-pathway intermediate for this model. The insertion of both the N and C termini into the knot occurs late in the folding process, creating large energy barriers that are the rate limiting steps in the folding process. When compared to other protein folding proteins of a similar length, this system folds over six orders of magnitude more slowly.'),
(84676, 2010, 'plos', 'Patterns of subnet usage reveal distinct scales of regulation in the transcriptional regulatory network of Escherichia coli', 'Marr, Carsten|Theis, Fabian J|Liebovitch, Larry S|Hütt, Marc-Thorsten', 'Institute for Bioinformatics and Systems Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. carsten.marr@helmholtz-muenchen.de|Institute for Bioinformatics and Systems Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. carsten.marr@helmholtz-muenchen.de|Institute for Bioinformatics and Systems Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. carsten.marr@helmholtz-muenchen.de|Institute for Bioinformatics and Systems Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. carsten.marr@helmholtz-muenchen.de', 'Germany|Germany|Germany|Germany', 12, 'Amino Acid Motifs|Cluster Analysis|Computational Biology|Escherichia coli|Gene Expression Regulation, Bacterial|Gene Regulatory Networks|RNA|Transcription Factors|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000836', '20617198', 'The set of regulatory interactions between genes, mediated by transcription factors, forms a species transcriptional regulatory network (TRN). By comparing this network with measured gene expression data, one can identify functional properties of the TRN and gain general insight into transcriptional control. We define the subnet of a node as the subgraph consisting of all nodes topologically downstream of the node, including itself. Using a large set of microarray expression data of the bacterium Escherichia coli, we find that the gene expression in different subnets exhibits a structured pattern in response to environmental changes and genotypic mutation. Subnets with fewer changes in their expression pattern have a higher fraction of feed-forward loop motifs and a lower fraction of small RNA targets within them. Our study implies that the TRN consists of several scales of regulatory organization: (1) subnets with more varying gene expression controlled by both transcription factors and post-transcriptional RNA regulation and (2) subnets with less varying gene expression having more feed-forward loops and less post-transcriptional RNA regulation.'),
(84677, 2010, 'plos', 'RNAcontext: a new method for learning the sequence and structure binding preferences of RNA-binding proteins', 'Kazan, Hilal|Ray, Debashish|Chan, Esther T|Hughes, Timothy R|Morris, Quaid', 'Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.|Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.|Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.|Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.|Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.', 'Canada|Canada|Canada|Canada|Canada', 120, 'Algorithms|Amino Acid Motifs|Amino Acid Sequence|Area Under Curve|Base Sequence|Binding Sites|Databases, Protein|Models, Genetic|Models, Statistical|Nucleic Acid Conformation|Protein Binding|Protein Conformation|RNA, Messenger|RNA-Binding Proteins', 'Journal Article', '10.1371/journal.pcbi.1000832', '20617199', 'Metazoan genomes encode hundreds of RNA-binding proteins (RBPs). These proteins regulate post-transcriptional gene expression and have critical roles in numerous cellular processes including mRNA splicing, export, stability and translation. Despite their ubiquity and importance, the binding preferences for most RBPs are not well characterized. In vitro and in vivo studies, using affinity selection-based approaches, have successfully identified RNA sequence associated with specific RBPs, however, it is difficult to infer RBP sequence and structural preferences without specifically designed motif finding methods. In this study, we introduce a new motif-finding method, RNAcontext, designed to elucidate RBP-specific sequence and structural preferences with greater accuracy than existing approaches. We evaluated RNAcontext on recently published in vitro and in vivo RNA affinity selected data and demonstrate that RNAcontext identifies known binding preferences for several control proteins including HuR, PTB, and Vts1p and predicts new RNA structure preferences for SF2/ASF, RBM4, FUSIP1 and SLM2. The predicted preferences for SF2/ASF are consistent with its recently reported in vivo binding sites. RNAcontext is an accurate and efficient motif finding method ideally suited for using large-scale RNA-binding affinity datasets to determine the relative binding preferences of RBPs for a wide range of RNA sequences and structures.'),
(84678, 2010, 'plos', 'A comprehensive benchmark of kernel methods to extract protein-protein interactions from literature', 'Tikk, Domonkos|Thomas, Philippe|Palaga, Peter|Hakenberg, Jörg|Leser, Ulf', 'Knowledge Management in Bioinformatics, Computer Science Department, Humboldt-Universität zu Berlin, Berlin, Germany. tikk@informatik.hu-berlin.de|Knowledge Management in Bioinformatics, Computer Science Department, Humboldt-Universität zu Berlin, Berlin, Germany. tikk@informatik.hu-berlin.de|Knowledge Management in Bioinformatics, Computer Science Department, Humboldt-Universität zu Berlin, Berlin, Germany. tikk@informatik.hu-berlin.de|Knowledge Management in Bioinformatics, Computer Science Department, Humboldt-Universität zu Berlin, Berlin, Germany. tikk@informatik.hu-berlin.de|Knowledge Management in Bioinformatics, Computer Science Department, Humboldt-Universität zu Berlin, Berlin, Germany. tikk@informatik.hu-berlin.de', 'Germany|Germany|Germany|Germany|Germany', 106, 'Algorithms|Area Under Curve|Data Mining|Databases, Protein|Decision Trees|Models, Molecular|Natural Language Processing|Protein Interaction Mapping|Proteins|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000837', '20617200', 'The most important way of conveying new findings in biomedical research is scientific publication. Extraction of protein-protein interactions (PPIs) reported in scientific publications is one of the core topics of text mining in the life sciences. Recently, a new class of such methods has been proposed - convolution kernels that identify PPIs using deep parses of sentences. However, comparing published results of different PPI extraction methods is impossible due to the use of different evaluation corpora, different evaluation metrics, different tuning procedures, etc. In this paper, we study whether the reported performance metrics are robust across different corpora and learning settings and whether the use of deep parsing actually leads to an increase in extraction quality. Our ultimate goal is to identify the one method that performs best in real-life scenarios, where information extraction is performed on unseen text and not on specifically prepared evaluation data. We performed a comprehensive benchmarking of nine different methods for PPI extraction that use convolution kernels on rich linguistic information. Methods were evaluated on five different public corpora using cross-validation, cross-learning, and cross-corpus evaluation. Our study confirms that kernels using dependency trees generally outperform kernels based on syntax trees. However, our study also shows that only the best kernel methods can compete with a simple rule-based approach when the evaluation prevents information leakage between training and test corpora. Our results further reveal that the F-score of many approaches drops significantly if no corpus-specific parameter optimization is applied and that methods reaching a good AUC score often perform much worse in terms of F-score. We conclude that for most kernels no sensible estimation of PPI extraction performance on new text is possible, given the current heterogeneity in evaluation data. Nevertheless, our study shows that three kernels are clearly superior to the other methods.'),
(84679, 2010, 'plos', 'Dual coding with STDP in a spiking recurrent neural network model of the hippocampus', 'Bush, Daniel|Philippides, Andrew|Husbands, Phil|OShea, Michael', 'Centre for Computational Neuroscience and Robotics, University of Sussex, Falmer, Brighton, United Kingdom. d.bush@sussex.ac.uk|Centre for Computational Neuroscience and Robotics, University of Sussex, Falmer, Brighton, United Kingdom. d.bush@sussex.ac.uk|Centre for Computational Neuroscience and Robotics, University of Sussex, Falmer, Brighton, United Kingdom. d.bush@sussex.ac.uk|Centre for Computational Neuroscience and Robotics, University of Sussex, Falmer, Brighton, United Kingdom. d.bush@sussex.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 21, 'Axons|CA3 Region, Hippocampal|Computer Simulation|Learning|Memory|Models, Neurological|Nerve Net|Neuronal Plasticity|Statistics, Nonparametric|Synapses|Theta Rhythm', 'Journal Article', '10.1371/journal.pcbi.1000839', '20617201', 'The firing rate of single neurons in the mammalian hippocampus has been demonstrated to encode for a range of spatial and non-spatial stimuli. It has also been demonstrated that phase of firing, with respect to the theta oscillation that dominates the hippocampal EEG during stereotype learning behaviour, correlates with an animals spatial location. These findings have led to the hypothesis that the hippocampus operates using a dual (rate and temporal) coding system. To investigate the phenomenon of dual coding in the hippocampus, we examine a spiking recurrent network model with theta coded neural dynamics and an STDP rule that mediates rate-coded Hebbian learning when pre- and post-synaptic firing is stochastic. We demonstrate that this plasticity rule can generate both symmetric and asymmetric connections between neurons that fire at concurrent or successive theta phase, respectively, and subsequently produce both pattern completion and sequence prediction from partial cues. This unifies previously disparate auto- and hetero-associative network models of hippocampal function and provides them with a firmer basis in modern neurobiology. Furthermore, the encoding and reactivation of activity in mutually exciting Hebbian cell assemblies demonstrated here is believed to represent a fundamental mechanism of cognitive processing in the brain.'),
(84680, 2010, 'plos', 'Action potential energy efficiency varies among neuron types in vertebrates and invertebrates', 'Sengupta, Biswa|Stemmler, Martin|Laughlin, Simon B|Niven, Jeremy E', 'Neural Circuit Design Group, Department of Zoology, University of Cambridge, Cambridge, United Kingdom.|Neural Circuit Design Group, Department of Zoology, University of Cambridge, Cambridge, United Kingdom.|Neural Circuit Design Group, Department of Zoology, University of Cambridge, Cambridge, United Kingdom.|Neural Circuit Design Group, Department of Zoology, University of Cambridge, Cambridge, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 151, 'Action Potentials|Animals|Brachyura|Electric Conductivity|Energy Metabolism|Loligo|Mice|Models, Neurological|Neurons|Potassium Channels|Rats|Sodium Channels|Temperature', 'Journal Article', '10.1371/journal.pcbi.1000840', '20617202', 'The initiation and propagation of action potentials (APs) places high demands on the energetic resources of neural tissue. Each AP forces ATP-driven ion pumps to work harder to restore the ionic concentration gradients, thus consuming more energy. Here, we ask whether the ionic currents underlying the AP can be predicted theoretically from the principle of minimum energy consumption. A long-held supposition that APs are energetically wasteful, based on theoretical analysis of the squid giant axon AP, has recently been overturned by studies that measured the currents contributing to the AP in several mammalian neurons. In the single compartment models studied here, AP energy consumption varies greatly among vertebrate and invertebrate neurons, with several mammalian neuron models using close to the capacitive minimum of energy needed. Strikingly, energy consumption can increase by more than ten-fold simply by changing the overlap of the Na(+) and K(+) currents during the AP without changing the APs shape. As a consequence, the height and width of the AP are poor predictors of energy consumption. In the Hodgkin-Huxley model of the squid axon, optimizing the kinetics or number of Na(+) and K(+) channels can whittle down the number of ATP molecules needed for each AP by a factor of four. In contrast to the squid AP, the temporal profile of the currents underlying APs of some mammalian neurons are nearly perfectly matched to the optimized properties of ionic conductances so as to minimize the ATP cost.'),
(84681, 2010, 'plos', 'Conductance ratios and cellular identity', 'Hudson, Amber E|Prinz, Astrid A', 'Bioengineering, Georgia Institute of Technology, Atlanta, Georgia, USA. aehudson@gatech.edu|Bioengineering, Georgia Institute of Technology, Atlanta, Georgia, USA. aehudson@gatech.edu', 'Georgia|Georgia', 52, 'Action Potentials|Animals|Calcium Channels|Chi-Square Distribution|Crustacea|Databases, Factual|Gastrointestinal Tract|Models, Neurological|Motor Neurons|Neural Conduction', 'Journal Article', '10.1371/journal.pcbi.1000838', '20628472', 'Recent experimental evidence suggests that coordinated expression of ion channels plays a role in constraining neuronal electrical activity. In particular, each neuronal cell type of the crustacean stomatogastric ganglion exhibits a unique set of positive linear correlations between ionic membrane conductances. These data suggest a causal relationship between expressed conductance correlations and features of cellular identity, namely electrical activity type. To test this idea, we used an existing database of conductance-based model neurons. We partitioned this database based on various measures of intrinsic activity, to approximate distinctions between biological cell types. We then tested individual conductance pairs for linear dependence to identify correlations. Contrary to experimental evidence, in which all conductance correlations are positive, 32% of correlations seen in this database were negative relationships. In addition, 80% of correlations seen here involved at least one calcium conductance, which have been difficult to measure experimentally. Similar to experimental results, each activity type investigated had a unique combination of correlated conductances. Finally, we found that populations of models that conform to a specific conductance correlation have a higher likelihood of exhibiting a particular feature of electrical activity. We conclude that regulating conductance ratios can support proper electrical activity of a wide range of cell types, particularly when the identity of the cell is well-defined by one or two features of its activity. Furthermore, we predict that previously unseen negative correlations and correlations involving calcium conductances are biologically plausible.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84682, 2010, 'plos', 'Statistical analysis of 3D images detects regular spatial distributions of centromeres and chromocenters in animal and plant nuclei', 'Andrey, Philippe|Kiêu, Kiên|Kress, Clémence|Lehmann, Gaëtan|Tirichine, Leïla|Liu, Zichuan|Biot, Eric|Adenot, Pierre-Gaël|Hue-Beauvais, Cathy|Houba-Hérin, Nicole|Duranthon, Véronique|Devinoy, Eve|Beaujean, Nathalie|Gaudin, Valérie|Maurin, Yves|Debey, Pascale', 'INRA, UMR1197 Neurobiologie de lOlfaction et de la Prise Alimentaire, Jouy-en-Josas, France.|INRA, UMR1197 Neurobiologie de lOlfaction et de la Prise Alimentaire, Jouy-en-Josas, France.|INRA, UMR1197 Neurobiologie de lOlfaction et de la Prise Alimentaire, Jouy-en-Josas, France.|INRA, UMR1197 Neurobiologie de lOlfaction et de la Prise Alimentaire, Jouy-en-Josas, France.|INRA, UMR1197 Neurobiologie de lOlfaction et de la Prise Alimentaire, Jouy-en-Josas, France.|INRA, UMR1197 Neurobiologie de lOlfaction et de la Prise Alimentaire, Jouy-en-Josas, France.|INRA, UMR1197 Neurobiologie de lOlfaction et de la Prise Alimentaire, Jouy-en-Josas, France.|INRA, UMR1197 Neurobiologie de lOlfaction et de la Prise Alimentaire, Jouy-en-Josas, France.|INRA, UMR1197 Neurobiologie de lOlfaction et de la Prise Alimentaire, Jouy-en-Josas, France.|INRA, UMR1197 Neurobiologie de lOlfaction et de la Prise Alimentaire, Jouy-en-Josas, France.|INRA, UMR1197 Neurobiologie de lOlfaction et de la Prise Alimentaire, Jouy-en-Josas, France.|INRA, UMR1197 Neurobiologie de lOlfaction et de la Prise Alimentaire, Jouy-en-Josas, France.|INRA, UMR1197 Neurobiologie de lOlfaction et de la Prise Alimentaire, Jouy-en-Josas, France.|INRA, UMR1197 Neurobiologie de lOlfaction et de la Prise Alimentaire, Jouy-en-Josas, France.|INRA, UMR1197 Neurobiologie de lOlfaction et de la Prise Alimentaire, Jouy-en-Josas, France.|INRA, UMR1197 Neurobiologie de lOlfaction et de la Prise Alimentaire, Jouy-en-Josas, France.', 'France|France|France|France|France|France|France|France|France|France|France|France|France|France|Fr', 58, 'Animals|Arabidopsis|Cell Nucleus|Centromere|Embryo, Mammalian|Female|Heterochromatin|Imaging, Three-Dimensional|Mammary Glands, Animal|Microscopy, Confocal|Models, Statistical|Monte Carlo Method|Nuclear Proteins|Rabbits', 'Journal Article', '10.1371/journal.pcbi.1000853', '20628576', 'In eukaryotes, the interphase nucleus is organized in morphologically and/or functionally distinct nuclear compartments. Numerous studies highlight functional relationships between the spatial organization of the nucleus and gene regulation. This raises the question of whether nuclear organization principles exist and, if so, whether they are identical in the animal and plant kingdoms. We addressed this issue through the investigation of the three-dimensional distribution of the centromeres and chromocenters. We investigated five very diverse populations of interphase nuclei at different differentiation stages in their physiological environment, belonging to rabbit embryos at the 8-cell and blastocyst stages, differentiated rabbit mammary epithelial cells during lactation, and differentiated cells of Arabidopsis thaliana plantlets. We developed new tools based on the processing of confocal images and a new statistical approach based on G- and F- distance functions used in spatial statistics. Our original computational scheme takes into account both size and shape variability by comparing, for each nucleus, the observed distribution against a reference distribution estimated by Monte-Carlo sampling over the same nucleus. This implicit normalization allowed similar data processing and extraction of rules in the five differentiated nuclei populations of the three studied biological systems, despite differences in chromosome number, genome organization and heterochromatin content. We showed that centromeres/chromocenters form significantly more regularly spaced patterns than expected under a completely random situation, suggesting that repulsive constraints or spatial inhomogeneities underlay the spatial organization of heterochromatic compartments. The proposed technique should be useful for identifying further spatial features in a wide range of cell types.'),
(84683, 2010, 'plos', 'Promoter complexity and tissue-specific expression of stress response components in Mytilus galloprovincialis, a sessile marine invertebrate species', 'Pantzartzi, Chrysa|Drosopoulou, Elena|Yiangou, Minas|Drozdov, Ignat|Tsoka, Sophia|Ouzounis, Christos A|Scouras, Zacharias G', 'Department of Genetics, Development & Molecular Biology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.|Department of Genetics, Development & Molecular Biology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.|Department of Genetics, Development & Molecular Biology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.|Department of Genetics, Development & Molecular Biology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.|Department of Genetics, Development & Molecular Biology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.|Department of Genetics, Development & Molecular Biology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.|Department of Genetics, Development & Molecular Biology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.', 'Greece|Greece|Greece|Greece|Greece|Greece|Greece', 0, 'Analysis of Variance|Animals|Base Sequence|Cluster Analysis|Conserved Sequence|Gene Expression Profiling|HSP90 Heat-Shock Proteins|Long Interspersed Nucleotide Elements|Models, Genetic|Models, Statistical|Molecular Sequence Data|Mytilus|Neoplasms|Organ Specificity|Principal Component Analysis|Promoter Regions, Genetic|Sequence Alignment|Stress, Physiological|Tumor Suppressor Protein p53', 'Journal Article', '10.1371/journal.pcbi.1000847', '20628614', 'The mechanisms of stress tolerance in sessile animals, such as molluscs, can offer fundamental insights into the adaptation of organisms for a wide range of environmental challenges. One of the best studied processes at the molecular level relevant to stress tolerance is the heat shock response in the genus Mytilus. We focus on the upstream region of Mytilus galloprovincialis Hsp90 genes and their structural and functional associations, using comparative genomics and network inference. Sequence comparison of this region provides novel evidence that the transcription of Hsp90 is regulated via a dense region of transcription factor binding sites, also containing a region with similarity to the Gamera family of LINE-like repetitive sequences and a genus-specific element of unknown function. Furthermore, we infer a set of gene networks from tissue-specific expression data, and specifically extract an Hsp class-associated network, with 174 genes and 2,226 associations, exhibiting a complex pattern of expression across multiple tissue types. Our results (i) suggest that the heat shock response in the genus Mytilus is regulated by an unexpectedly complex upstream region, and (ii) provide new directions for the use of the heat shock process as a biosensor system for environmental monitoring.'),
(84684, 2010, 'plos', 'Avalanches in a stochastic model of spiking neurons', 'Benayoun, Marc|Cowan, Jack D|van Drongelen, Wim|Wallace, Edward', 'Department of Pediatrics, University of Chicago, Chicago, Illinois, USA.|Department of Pediatrics, University of Chicago, Chicago, Illinois, USA.|Department of Pediatrics, University of Chicago, Chicago, Illinois, USA.|Department of Pediatrics, University of Chicago, Chicago, Illinois, USA.', 'United States|United States|United States|United States', 0, 'Action Potentials|Algorithms|Animals|Computer Simulation|Markov Chains|Models, Neurological|Nerve Net|Rats|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1000846', '20628615', 'Neuronal avalanches are a form of spontaneous activity widely observed in cortical slices and other types of nervous tissue, both in vivo and in vitro. They are characterized by irregular, isolated population bursts when many neurons fire together, where the number of spikes per burst obeys a power law distribution. We simulate, using the Gillespie algorithm, a model of neuronal avalanches based on stochastic single neurons. The network consists of excitatory and inhibitory neurons, first with all-to-all connectivity and later with random sparse connectivity. Analyzing our model using the system size expansion, we show that the model obeys the standard Wilson-Cowan equations for large network sizes ( neurons). When excitation and inhibition are closely balanced, networks of thousands of neurons exhibit irregular synchronous activity, including the characteristic power law distribution of avalanche size. We show that these avalanches are due to the balanced network having weakly stable functionally feedforward dynamics, which amplifies some small fluctuations into the large population bursts. Balanced networks are thought to underlie a variety of observed network behaviours and have useful computational properties, such as responding quickly to changes in input. Thus, the appearance of avalanches in such functionally feedforward networks indicates that avalanches may be a simple consequence of a widely present network structure, when neuron dynamics are noisy. An important implication is that a network need not be critical for the production of avalanches, so experimentally observed power laws in burst size may be a signature of noisy functionally feedforward structure rather than of, for example, self-organized criticality.'),
(84685, 2010, 'plos', 'Computational analysis of whole-genome differential allelic expression data in human', 'Wagner, James R|Ge, Bing|Pokholok, Dmitry|Gunderson, Kevin L|Pastinen, Tomi|Blanchette, Mathieu', 'School of Computer Science, McGill University, Montreal, Quebec, Canada.|School of Computer Science, McGill University, Montreal, Quebec, Canada.|School of Computer Science, McGill University, Montreal, Quebec, Canada.|School of Computer Science, McGill University, Montreal, Quebec, Canada.|School of Computer Science, McGill University, Montreal, Quebec, Canada.|School of Computer Science, McGill University, Montreal, Quebec, Canada.', 'Canada|Canada|Canada|Canada|Canada|Canada', 0, 'Algorithms|Allelic Imbalance|Gene Expression Profiling|Gene Expression Regulation|Genome|Genomics|Humans|Markov Chains|Oligonucleotide Array Sequence Analysis|Polymorphism, Single Nucleotide', 'Journal Article', '10.1371/journal.pcbi.1000849', '20628616', 'Allelic imbalance (AI) is a phenomenon where the two alleles of a given gene are expressed at different levels in a given cell, either because of epigenetic inactivation of one of the two alleles, or because of genetic variation in regulatory regions. Recently, Bing et al. have described the use of genotyping arrays to assay AI at a high resolution (approximately 750,000 SNPs across the autosomes). In this paper, we investigate computational approaches to analyze this data and identify genomic regions with AI in an unbiased and robust statistical manner. We propose two families of approaches: (i) a statistical approach based on z-score computations, and (ii) a family of machine learning approaches based on Hidden Markov Models. Each method is evaluated using previously published experimental data sets as well as with permutation testing. When applied to whole genome data from 53 HapMap samples, our approaches reveal that allelic imbalance is widespread (most expressed genes show evidence of AI in at least one of our 53 samples) and that most AI regions in a given individual are also found in at least a few other individuals. While many AI regions identified in the genome correspond to known protein-coding transcripts, others overlap with recently discovered long non-coding RNAs. We also observe that genomic regions with AI not only include complete transcripts with consistent differential expression levels, but also more complex patterns of allelic expression such as alternative promoters and alternative 3 end. The approaches developed not only shed light on the incidence and mechanisms of allelic expression, but will also help towards mapping the genetic causes of allelic expression and identify cases where this variation may be linked to diseases.'),
(84686, 2010, 'plos', 'Redundancy and the evolution of cis-regulatory element multiplicity', 'Paixão, Tiago|Azevedo, Ricardo B R', 'Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA.|Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA.', 'United States|United States', 0, 'Binding Sites|Cluster Analysis|Evolution, Molecular|Gene Expression Regulation, Fungal|Genome, Fungal|Models, Genetic|Models, Statistical|Protein Binding|Recombination, Genetic|Regulatory Elements, Transcriptional|Transcription Factors|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1000848', '20628617', 'The promoter regions of many genes contain multiple binding sites for the same transcription factor (TF). One possibility is that this multiplicity evolved through transitional forms showing redundant cis-regulation. To evaluate this hypothesis, we must disentangle the relative contributions of different evolutionary mechanisms to the evolution of binding site multiplicity. Here, we attempt to do this using a model of binding site evolution. Our model considers binding sequences and their interactions with TFs explicitly, and allows us to cast the evolution of gene networks into a neutral network framework. We then test some of the models predictions using data from yeast. Analysis of the model suggested three candidate nonadaptive processes favoring the evolution of cis-regulatory element redundancy and multiplicity: neutral evolution in long promoters, recombination and TF promiscuity. We find that recombination rate is positively associated with binding site multiplicity in yeast. Our model also indicated that weak direct selection for multiplicity (partial redundancy) can play a major role in organisms with large populations. Our data suggest that selection for changes in gene expression level may have contributed to the evolution of multiple binding sites in yeast. We conclude that the evolution of cis-regulatory element redundancy and multiplicity is impacted by many aspects of the biology of an organism: both adaptive and nonadaptive processes, both changes in cis to binding sites and in trans to the TFs that interact with them, both the functional setting of the promoter and the population genetic context of the individuals carrying them.'),
(84687, 2010, 'plos', 'Large-scale analysis of network bistability for human cancers', 'Shiraishi, Tetsuya|Matsuyama, Shinako|Kitano, Hiroaki', 'Sony Computer Science Laboratories, Shinagawa-ku, Tokyo, Japan. Tetsuya.Shiraishi@jp.sony.com|Sony Computer Science Laboratories, Shinagawa-ku, Tokyo, Japan. Tetsuya.Shiraishi@jp.sony.com|Sony Computer Science Laboratories, Shinagawa-ku, Tokyo, Japan. Tetsuya.Shiraishi@jp.sony.com', 'Japan|Japan|Japan', 48, 'Biomarkers, Tumor|Computational Biology|Drug Discovery|Gene Expression Profiling|Gene Regulatory Networks|Humans|Models, Biological|Neoplasms|Oligonucleotide Array Sequence Analysis|Protein Interaction Mapping|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000851', '20628618', 'Protein-protein interaction and gene regulatory networks are likely to be locked in a state corresponding to a disease by the behavior of one or more bistable circuits exhibiting switch-like behavior. Sets of genes could be over-expressed or repressed when anomalies due to disease appear, and the circuits responsible for this over- or under-expression might persist for as long as the disease state continues. This paper shows how a large-scale analysis of network bistability for various human cancers can identify genes that can potentially serve as drug targets or diagnosis biomarkers.'),
(84688, 2010, 'plos', 'A threshold equation for action potential initiation', 'Platkiewicz, Jonathan|Brette, Romain', 'Laboratoire Psychologie de la Perception, CNRS and Université Paris Descartes, Paris, France.|Laboratoire Psychologie de la Perception, CNRS and Université Paris Descartes, Paris, France.', 'France|France', 109, 'Action Potentials|Algorithms|Computer Simulation|Models, Neurological|Reproducibility of Results|Sodium Channels', 'Journal Article', '10.1371/journal.pcbi.1000850', '20628619', 'In central neurons, the threshold for spike initiation can depend on the stimulus and varies between cells and between recording sites in a given cell, but it is unclear what mechanisms underlie this variability. Properties of ionic channels are likely to play a role in threshold modulation. We examined in models the influence of Na channel activation, inactivation, slow voltage-gated channels and synaptic conductances on spike threshold. We propose a threshold equation which quantifies the contribution of all these mechanisms. It provides an instantaneous time-varying value of the threshold, which applies to neurons with fluctuating inputs. We deduce a differential equation for the threshold, similar to the equations of gating variables in the Hodgkin-Huxley formalism, which describes how the spike threshold varies with the membrane potential, depending on channel properties. We find that spike threshold depends logarithmically on Na channel density, and that Na channel inactivation and K channels can dynamically modulate it in an adaptive way: the threshold increases with membrane potential and after every action potential. Our equation was validated with simulations of a previously published multicompartemental model of spike initiation. Finally, we observed that threshold variability in models depends crucially on the shape of the Na activation function near spike initiation (about -55 mV), while its parameters are adjusted near half-activation voltage (about -30 mV), which might explain why many models exhibit little threshold variability, contrary to experimental observations. We conclude that ionic channels can account for large variations in spike threshold.'),
(84689, 2010, 'plos', 'Reliability of transcriptional cycles and the yeast cell-cycle oscillator', 'Sevim, Volkan|Gong, Xinwei|Socolar, Joshua E S', 'Physics Department and Center for Nonlinear and Complex Systems, Duke University, Durham, North Carolina, USA. volkan.sevim@duke.edu|Physics Department and Center for Nonlinear and Complex Systems, Duke University, Durham, North Carolina, USA. volkan.sevim@duke.edu|Physics Department and Center for Nonlinear and Complex Systems, Duke University, Durham, North Carolina, USA. volkan.sevim@duke.edu', 'United States|United States|United States', 0, 'Cell Cycle|Computational Biology|Feedback, Physiological|Gene Regulatory Networks|Models, Genetic|Models, Statistical|Transcription, Genetic|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1000842', '20628620', 'A recently published transcriptional oscillator associated with the yeast cell cycle provides clues and raises questions about the mechanisms underlying autonomous cyclic processes in cells. Unlike other biological and synthetic oscillatory networks in the literature, this one does not seem to rely on a constitutive signal or positive auto-regulation, but rather to operate through stable transmission of a pulse on a slow positive feedback loop that determines its period. We construct a continuous-time Boolean model of this network, which permits the modeling of noise through small fluctuations in the timing of events, and show that it can sustain stable oscillations. Analysis of simpler network models shows how a few building blocks can be arranged to provide stability against fluctuations. Our findings suggest that the transcriptional oscillator in yeast belongs to a new class of biological oscillators.'),
(84690, 2010, 'plos', 'The effects of alignment quality, distance calculation method, sequence filtering, and region on the analysis of 16S rRNA gene-based studies', 'Schloss, Patrick D', 'Department of Microbiology & Immunology, The University of Michigan, Ann Arbor, Michigan, USA. pschloss@umich.edu', 'United States', 221, 'Computational Biology|Databases, Genetic|Escherichia coli|Genes, Bacterial|Genetic Variation|Phylogeny|RNA, Ribosomal, 16S|Regression Analysis|Sequence Alignment', 'Journal Article', '10.1371/journal.pcbi.1000844', '20628621', 'Pyrosequencing of PCR-amplified fragments that target variable regions within the 16S rRNA gene has quickly become a powerful method for analyzing the membership and structure of microbial communities. This approach has revealed and introduced questions that were not fully appreciated by those carrying out traditional Sanger sequencing-based methods. These include the effects of alignment quality, the best method of calculating pairwise genetic distances for 16S rRNA genes, whether it is appropriate to filter variable regions, and how the choice of variable region relates to the genetic diversity observed in full-length sequences. I used a diverse collection of 13,501 high-quality full-length sequences to assess each of these questions. First, alignment quality had a significant impact on distance values and downstream analyses. Specifically, the greengenes alignment, which does a poor job of aligning variable regions, predicted higher genetic diversity, richness, and phylogenetic diversity than the SILVA and RDP-based alignments. Second, the effect of different gap treatments in determining pairwise genetic distances was strongly affected by the variation in sequence length for a region, however, the effect of different calculation methods was subtle when determining the samples richness or phylogenetic diversity for a region. Third, applying a sequence mask to remove variable positions had a profound impact on genetic distances by muting the observed richness and phylogenetic diversity. Finally, the genetic distances calculated for each of the variable regions did a poor job of correlating with the full-length gene. Thus, while it is tempting to apply traditional cutoff levels derived for full-length sequences to these shorter sequences, it is not advisable. Analysis of beta-diversity metrics showed that each of these factors can have a significant impact on the comparison of community membership and structure. Taken together, these results urge caution in the design and interpretation of analyses using pyrosequencing data.'),
(84691, 2010, 'plos', 'Predicting important residues and interaction pathways in proteins using Gaussian Network Model: binding and stability of HLA proteins', 'Haliloglu, Turkan|Gul, Ahmet|Erman, Burak', 'Polymer Research Center, Bogazici University, Bebek, Istanbul, Turkey. turkan@prc.boun.edu.tr|Polymer Research Center, Bogazici University, Bebek, Istanbul, Turkey. turkan@prc.boun.edu.tr|Polymer Research Center, Bogazici University, Bebek, Istanbul, Turkey. turkan@prc.boun.edu.tr', 'Turkey|Turkey|Turkey', 0, 'Amino Acids|Computational Biology|Genes, MHC Class I|HLA-B27 Antigen|Humans|Models, Statistical|Normal Distribution|Protein Conformation|Protein Interaction Domains and Motifs|Sequence Analysis, Protein|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000845', '20628622', 'A statistical thermodynamics approach is proposed to determine structurally and functionally important residues in native proteins that are involved in energy exchange with a ligand and other residues along an interaction pathway. The structure-function relationships, ligand binding and allosteric activities of ten structures of HLA Class I proteins of the immune system are studied by the Gaussian Network Model. Five of these models are associated with inflammatory rheumatic disease and the remaining five are properly functioning. In the Gaussian Network Model, the protein structures are modeled as an elastic network where the inter-residue interactions are harmonic. Important residues and the interaction pathways in the proteins are identified by focusing on the largest eigenvalue of the residue interaction matrix. Predicted important residues match those known from previous experimental and clinical work. Graph perturbation is used to determine the response of the important residues along the interaction pathway. Differences in response patterns of the two sets of proteins are identified and their relations to disease are discussed.'),
(84692, 2010, 'plos', 'Learning a weighted sequence model of the nucleosome core and linker yields more accurate predictions in Saccharomyces cerevisiae and Homo sapiens', 'Reynolds, Sheila M|Bilmes, Jeff A|Noble, William Stafford', 'Department of Electrical Engineering, University of Washington, Seattle, Washington, USA.|Department of Electrical Engineering, University of Washington, Seattle, Washington, USA.|Department of Electrical Engineering, University of Washington, Seattle, Washington, USA.', 'United States|United States|United States', 0, 'Alu Elements|Base Composition|Base Sequence|CCCTC-Binding Factor|DNA|DNA, Fungal|Humans|Nucleic Acid Conformation|Nucleosomes|ROC Curve|Repressor Proteins|Reproducibility of Results|Saccharomyces cerevisiae|Sequence Alignment|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1000834', '20628623', 'DNA in eukaryotes is packaged into a chromatin complex, the most basic element of which is the nucleosome. The precise positioning of the nucleosome cores allows for selective access to the DNA, and the mechanisms that control this positioning are important pieces of the gene expression puzzle. We describe a large-scale nucleosome pattern that jointly characterizes the nucleosome core and the adjacent linkers and is predominantly characterized by long-range oscillations in the mono, di- and tri-nucleotide content of the DNA sequence, and we show that this pattern can be used to predict nucleosome positions in both Homo sapiens and Saccharomyces cerevisiae more accurately than previously published methods. Surprisingly, in both H. sapiens and S. cerevisiae, the most informative individual features are the mono-nucleotide patterns, although the inclusion of di- and tri-nucleotide features results in improved performance. Our approach combines a much longer pattern than has been previously used to predict nucleosome positioning from sequence-301 base pairs, centered at the position to be scored-with a novel discriminative classification approach that selectively weights the contributions from each of the input features. The resulting scores are relatively insensitive to local AT-content and can be used to accurately discriminate putative dyad positions from adjacent linker regions without requiring an additional dynamic programming step and without the attendant edge effects and assumptions about linker length modeling and overall nucleosome density. Our approach produces the best dyad-linker classification results published to date in H. sapiens, and outperforms two recently published models on a large set of S. cerevisiae nucleosome positions. Our results suggest that in both genomes, a comparable and relatively small fraction of nucleosomes are well-positioned and that these positions are predictable based on sequence alone. We believe that the bulk of the remaining nucleosomes follow a statistical positioning model.'),
(84693, 2010, 'plos', 'Risk-sensitive optimal feedback control accounts for sensorimotor behavior under uncertainty', 'Nagengast, Arne J|Braun, Daniel A|Wolpert, Daniel M', 'Computational and Biological Learning Lab, Department of Engineering, University of Cambridge, Cambridge, United Kingdom. an261@cam.ac.uk|Computational and Biological Learning Lab, Department of Engineering, University of Cambridge, Cambridge, United Kingdom. an261@cam.ac.uk|Computational and Biological Learning Lab, Department of Engineering, University of Cambridge, Cambridge, United Kingdom. an261@cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Adult|Algorithms|Analysis of Variance|Computer Simulation|Feedback, Sensory|Female|Humans|Linear Models|Male|Models, Biological|Risk-Taking|Uncertainty', 'Journal Article', '10.1371/journal.pcbi.1000857', '20657657', 'Many aspects of human motor behavior can be understood using optimality principles such as optimal feedback control. However, these proposed optimal control models are risk-neutral, that is, they are indifferent to the variability of the movement cost. Here, we propose the use of a risk-sensitive optimal controller that incorporates movement cost variance either as an added cost (risk-averse controller) or as an added value (risk-seeking controller) to model human motor behavior in the face of uncertainty. We use a sensorimotor task to test the hypothesis that subjects are risk-sensitive. Subjects controlled a virtual ball undergoing Brownian motion towards a target. Subjects were required to minimize an explicit cost, in points, that was a combination of the final positional error of the ball and the integrated control cost. By testing subjects on different levels of Brownian motion noise and relative weighting of the position and control cost, we could distinguish between risk-sensitive and risk-neutral control. We show that subjects change their movement strategy pessimistically in the face of increased uncertainty in accord with the predictions of a risk-averse optimal controller. Our results suggest that risk-sensitivity is a fundamental attribute that needs to be incorporated into optimal feedback control models.'),
(84694, 2010, 'plos', 'Sampling the solution space in genome-scale metabolic networks reveals transcriptional regulation in key enzymes', 'Bordel, Sergio|Agren, Rasmus|Nielsen, Jens', 'Systems Biology, Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.|Systems Biology, Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.|Systems Biology, Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.', 'Sweden|Sweden|Sweden', 108, 'Aerobiosis|Algorithms|Anaerobiosis|Enzymes|Gene Expression Profiling|Gene Expression Regulation|Genome|Metabolic Networks and Pathways|Models, Biological|Mutation|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Signal Transduction|Systems Biology|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000859', '20657658', 'Genome-scale metabolic models are available for an increasing number of organisms and can be used to define the region of feasible metabolic flux distributions. In this work we use as constraints a small set of experimental metabolic fluxes, which reduces the region of feasible metabolic states. Once the region of feasible flux distributions has been defined, a set of possible flux distributions is obtained by random sampling and the averages and standard deviations for each of the metabolic fluxes in the genome-scale model are calculated. These values allow estimation of the significance of change for each reaction rate between different conditions and comparison of it with the significance of change in gene transcription for the corresponding enzymes. The comparison of flux change and gene expression allows identification of enzymes showing a significant correlation between flux change and expression change (transcriptional regulation) as well as reactions whose flux change is likely to be driven only by changes in the metabolite concentrations (metabolic regulation). The changes due to growth on four different carbon sources and as a consequence of five gene deletions were analyzed for Saccharomyces cerevisiae. The enzymes with transcriptional regulation showed enrichment in certain transcription factors. This has not been previously reported. The information provided by the presented method could guide the discovery of new metabolic engineering strategies or the identification of drug targets for treatment of metabolic diseases.'),
(84695, 2010, 'plos', 'The construction and use of log-odds substitution scores for multiple sequence alignment', 'Altschul, Stephen F|Wootton, John C|Zaslavsky, Elena|Yu, Yi-Kuo', 'National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America. altschul@ncbi.nlm.nih.gov|National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America. altschul@ncbi.nlm.nih.gov|National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America. altschul@ncbi.nlm.nih.gov|National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America. altschul@ncbi.nlm.nih.gov', 'United States|United States|United States|United States', 45, 'Algorithms|Amino Acid Sequence|Base Sequence|Bayes Theorem|Computational Biology|Consensus Sequence|DNA-Binding Proteins|Databases, Genetic|Models, Statistical|Pattern Recognition, Automated|Plasmodium|Protein Structure, Tertiary|Sequence Alignment|Toxoplasma', 'Journal Article', '10.1371/journal.pcbi.1000852', '20657661', 'Most pairwise and multiple sequence alignment programs seek alignments with optimal scores. Central to defining such scores is selecting a set of substitution scores for aligned amino acids or nucleotides. For local pairwise alignment, substitution scores are implicitly of log-odds form. We now extend the log-odds formalism to multiple alignments, using Bayesian methods to construct BILD (Bayesian Integral Log-odds) substitution scores from prior distributions describing columns of related letters. This approach has been used previously only to define scores for aligning individual sequences to sequence profiles, but it has much broader applicability. We describe how to calculate BILD scores efficiently, and illustrate their uses in Gibbs sampling optimization procedures, gapped alignment, and the construction of hidden Markov model profiles. BILD scores enable automated selection of optimal motif and domain model widths, and can inform the decision of whether to include a sequence in a multiple alignment, and the selection of insertion and deletion locations. Other applications include the classification of related sequences into subfamilies, and the definition of profile-profile alignment scores. Although a fully realized multiple alignment program must rely upon more than substitution scores, many existing multiple alignment programs can be modified to employ BILD scores. We illustrate how simple BILD score based strategies can enhance the recognition of DNA binding domains, including the Api-AP2 domain in Toxoplasma gondii and Plasmodium falciparum.'),
(84696, 2010, 'plos', 'Intrinsically disordered regions may lower the hydration free energy in proteins: a case study of nudix hydrolase in the bacterium Deinococcus radiodurans', 'Awile, Omar|Krisko, Anita|Sbalzarini, Ivo F|Zagrovic, Bojan', 'Mediterranean Institute for Life Sciences, Split, Croatia.|Mediterranean Institute for Life Sciences, Split, Croatia.|Mediterranean Institute for Life Sciences, Split, Croatia.|Mediterranean Institute for Life Sciences, Split, Croatia.', 'Croatia|Croatia|Croatia|Croatia', 0, 'Bacterial Proteins|Deinococcus|Desiccation|Hydrophobic and Hydrophilic Interactions|Molecular Dynamics Simulation|Protein Conformation|Pyrophosphatases|Sequence Analysis, Protein|Surface Properties|Thermodynamics|Water', 'Journal Article', '10.1371/journal.pcbi.1000854', '20657662', 'The proteome of the radiation- and desiccation-resistant bacterium D. radiodurans features a group of proteins that contain significant intrinsically disordered regions that are not present in non-extremophile homologues. Interestingly, this group includes a number of housekeeping and repair proteins such as DNA polymerase III, nudix hydrolase and rotamase. Here, we focus on a member of the nudix hydrolase family from D. radiodurans possessing low-complexity N- and C-terminal tails, which exhibit sequence signatures of intrinsic disorder and have unknown function. The enzyme catalyzes the hydrolysis of oxidatively damaged and mutagenic nucleotides, and it is thought to play an important role in D. radiodurans during the recovery phase after exposure to ionizing radiation or desiccation. We use molecular dynamics simulations to study the dynamics of the protein, and study its hydration free energy using the GB/SA formalism. We show that the presence of disordered tails significantly decreases the hydration free energy of the whole protein. We hypothesize that the tails increase the chances of the protein to be located in the remaining water patches in the desiccated cell, where it is protected from the desiccation effects and can function normally. We extrapolate this to other intrinsically disordered regions in proteins, and propose a novel function for them: intrinsically disordered regions increase the surface-properties of the folded domains they are attached to, making them on the whole more hydrophilic and potentially influencing, in this way, their localization and cellular activity.'),
(84697, 2010, 'plos', 'Organization of cellular receptors into a nanoscale junction during HIV-1 adhesion', 'Dobrowsky, Terrence M|Daniels, Brian R|Siliciano, Robert F|Sun, Sean X|Wirtz, Denis', 'Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, United States of America.', 'United States|United States|United States|United States|United States', 13, 'CD4 Antigens|Cell Membrane|HIV Envelope Protein gp120|HIV-1|Markov Chains|Models, Biological|Molecular Dynamics Simulation|Multiprotein Complexes|Protein Binding|Receptors, CCR5|Stochastic Processes|Thermodynamics|Virion|Virus Attachment', 'Journal Article', '10.1371/journal.pcbi.1000855', '20657663', 'The fusion of the human immunodeficiency virus type 1 (HIV-1) with its host cell is the target for new antiretroviral therapies. Viral particles interact with the flexible plasma membrane via viral surface protein gp120 which binds its primary cellular receptor CD4 and subsequently the coreceptor CCR5. However, whether and how these receptors become organized at the adhesive junction between cell and virion are unknown. Here, stochastic modeling predicts that, regarding binding to gp120, cellular receptors CD4 and CCR5 form an organized, ring-like, nanoscale structure beneath the virion, which locally deforms the plasma membrane. This organized adhesive junction between cell and virion, which we name the viral junction, is reminiscent of the well-characterized immunological synapse, albeit at much smaller length scales. The formation of an organized viral junction under multiple physiopathologically relevant conditions may represent a novel intermediate step in productive infection.'),
(84698, 2010, 'plos', 'Do humans optimally exploit redundancy to control step variability in walking?', 'Dingwell, Jonathan B|John, Joby|Cusumano, Joseph P', 'Department of Kinesiology, University of Texas, Austin, Texas, United States of America. jdingwell@mail.utexas.edu|Department of Kinesiology, University of Texas, Austin, Texas, United States of America. jdingwell@mail.utexas.edu|Department of Kinesiology, University of Texas, Austin, Texas, United States of America. jdingwell@mail.utexas.edu', 'United States|United States|United States', 0, 'Adolescent|Adult|Algorithms|Analysis of Variance|Female|Gait|Humans|Male|Models, Biological|Stochastic Processes|Walking', 'Journal Article', '10.1371/journal.pcbi.1000856', '20657664', 'It is widely accepted that humans and animals minimize energetic cost while walking. While such principles predict average behavior, they do not explain the variability observed in walking. For robust performance, walking movements must adapt at each step, not just on average. Here, we propose an analytical framework that reconciles issues of optimality, redundancy, and stochasticity. For human treadmill walking, we defined a goal function to formulate a precise mathematical definition of one possible control strategy: maintain constant speed at each stride. We recorded stride times and stride lengths from healthy subjects walking at five speeds. The specified goal function yielded a decomposition of stride-to-stride variations into new gait variables explicitly related to achieving the hypothesized strategy. Subjects exhibited greatly decreased variability for goal-relevant gait fluctuations directly related to achieving this strategy, but far greater variability for goal-irrelevant fluctuations. More importantly, humans immediately corrected goal-relevant deviations at each successive stride, while allowing goal-irrelevant deviations to persist across multiple strides. To demonstrate that this was not the only strategy people could have used to successfully accomplish the task, we created three surrogate data sets. Each tested a specific alternative hypothesis that subjects used a different strategy that made no reference to the hypothesized goal function. Humans did not adopt any of these viable alternative strategies. Finally, we developed a sequence of stochastic control models of stride-to-stride variability for walking, based on the Minimum Intervention Principle. We demonstrate that healthy humans are not precisely optimal, but instead consistently slightly over-correct small deviations in walking speed at each stride. Our results reveal a new governing principle for regulating stride-to-stride fluctuations in human walking that acts independently of, but in parallel with, minimizing energetic cost. Thus, humans exploit task redundancies to achieve robust control while minimizing effort and allowing potentially beneficial motor variability.'),
(84699, 2010, 'plos', 'Coding efficiency of fly motion processing is set by firing rate, not firing precision', 'Spavieri, Deusdedit Lineu|Eichner, Hubert|Borst, Alexander', 'Department of System and Computational Neurobiology, Max-Planck-Institute of Neurobiology, Martinsried, Germany.|Department of System and Computational Neurobiology, Max-Planck-Institute of Neurobiology, Martinsried, Germany.|Department of System and Computational Neurobiology, Max-Planck-Institute of Neurobiology, Martinsried, Germany.', 'Germany|Germany|Germany', 0, 'Action Potentials|Animals|Diptera|Evoked Potentials, Visual|Female|Flight, Animal|Information Theory|Luminescence|Models, Neurological|Movement|Nervous System Physiological Phenomena|Photic Stimulation|Systems Biology|Temperature|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1000860', '20661305', 'To comprehend the principles underlying sensory information processing, it is important to understand how the nervous system deals with various sources of perturbation. Here, we analyze how the representation of motion information in the flys nervous system changes with temperature and luminance. Although these two environmental variables have a considerable impact on the flys nervous system, they do not impede the fly to behave suitably over a wide range of conditions. We recorded responses from a motion-sensitive neuron, the H1-cell, to a time-varying stimulus at many different combinations of temperature and luminance. We found that the mean firing rate, but not firing precision, changes with temperature, while both were affected by mean luminance. Because we also found that information rate and coding efficiency are mainly set by the mean firing rate, our results suggest that, in the face of environmental perturbations, the coding efficiency is improved by an increase in the mean firing rate, rather than by an increased firing precision.'),
(84700, 2010, 'plos', 'Categorial compositionality: a category theory explanation for the systematicity of human cognition', 'Phillips, Steven|Wilson, William H', 'Mathematical Neuroinformatics Group, Human Technology Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan. steve@ni.aist.go.jp|Mathematical Neuroinformatics Group, Human Technology Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan. steve@ni.aist.go.jp', 'Japan|Japan', 0, 'Algorithms|Cognition|Cognitive Science|Humans|Models, Psychological|Psychological Theory', 'Journal Article', '10.1371/journal.pcbi.1000858', '20661306', 'Classical and Connectionist theories of cognitive architecture seek to explain systematicity (i.e., the property of human cognition whereby cognitive capacity comes in groups of related behaviours) as a consequence of syntactically and functionally compositional representations, respectively. However, both theories depend on ad hoc assumptions to exclude specific instances of these forms of compositionality (e.g. grammars, networks) that do not account for systematicity. By analogy with the Ptolemaic (i.e. geocentric) theory of planetary motion, although either theory can be made to be consistent with the data, both nonetheless fail to fully explain it. Category theory, a branch of mathematics, provides an alternative explanation based on the formal concept of adjunction, which relates a pair of structure-preserving maps, called functors. A functor generalizes the notion of a map between representational states to include a map between state transformations (or processes). In a formal sense, systematicity is a necessary consequence of a higher-order theory of cognitive architecture, in contrast to the first-order theories derived from Classicism or Connectionism. Category theory offers a re-conceptualization for cognitive science, analogous to the one that Copernicus provided for astronomy, where representational states are no longer the center of the cognitive universe--replaced by the relationships between the maps that transform them.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84701, 2010, 'plos', 'Defining the plasticity of transcription factor binding sites by Deconstructing DNA consensus sequences: the PhoP-binding sites among gamma/enterobacteria', 'Harari, Oscar|Park, Sun-Yang|Huang, Henry|Groisman, Eduardo A|Zwir, Igor', 'Department of Computer Science and Artificial Intelligence, University of Granada, Granada, Spain.|Department of Computer Science and Artificial Intelligence, University of Granada, Granada, Spain.|Department of Computer Science and Artificial Intelligence, University of Granada, Granada, Spain.|Department of Computer Science and Artificial Intelligence, University of Granada, Granada, Spain.|Department of Computer Science and Artificial Intelligence, University of Granada, Granada, Spain.', 'Spain|Spain|Spain|Spain|Spain', 0, 'Artificial Intelligence|Bacterial Proteins|Base Sequence|Binding Sites|Chromatin Immunoprecipitation|Cluster Analysis|Computational Biology|Consensus Sequence|DNA, Bacterial|Enterobacteriaceae|Evolution, Molecular|Gene Expression Profiling|Genome, Bacterial|Models, Genetic|Molecular Sequence Data|Nucleic Acid Conformation|Oligonucleotide Array Sequence Analysis|Pattern Recognition, Automated|Sequence Alignment|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000862', '20661307', 'Transcriptional regulators recognize specific DNA sequences. Because these sequences are embedded in the background of genomic DNA, it is hard to identify the key cis-regulatory elements that determine disparate patterns of gene expression. The detection of the intra- and inter-species differences among these sequences is crucial for understanding the molecular basis of both differential gene expression and evolution. Here, we address this problem by investigating the target promoters controlled by the DNA-binding PhoP protein, which governs virulence and Mg(2+) homeostasis in several bacterial species. PhoP is particularly interesting, it is highly conserved in different gamma/enterobacteria, regulating not only ancestral genes but also governing the expression of dozens of horizontally acquired genes that differ from species to species. Our approach consists of decomposing the DNA binding site sequences for a given regulator into families of motifs (i.e., termed submotifs) using a machine learning method inspired by the Divide & Conquer strategy. By partitioning a motif into sub-patterns, computational advantages for classification were produced, resulting in the discovery of new members of a regulon, and alleviating the problem of distinguishing functional sites in chromatin immunoprecipitation and DNA microarray genome-wide analysis. Moreover, we found that certain partitions were useful in revealing biological properties of binding site sequences, including modular gains and losses of PhoP binding sites through evolutionary turnover events, as well as conservation in distant species. The high conservation of PhoP submotifs within gamma/enterobacteria, as well as the regulatory protein that recognizes them, suggests that the major cause of divergence between related species is not due to the binding sites, as was previously suggested for other regulators. Instead, the divergence may be attributed to the fast evolution of orthologous target genes and/or the promoter architectures resulting from the interaction of those binding sites with the RNA polymerase.'),
(84702, 2010, 'plos', 'G-quadruplex DNA sequences are evolutionarily conserved and associated with distinct genomic features in Saccharomyces cerevisiae', 'Capra, John A|Paeschke, Katrin|Singh, Mona|Zakian, Virginia A', 'Department of Computer Science, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.|Department of Computer Science, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.|Department of Computer Science, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.|Department of Computer Science, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.', 'Jersey|Jersey|Jersey|Jersey', 128, 'Base Sequence|Conserved Sequence|DNA Breaks, Double-Stranded|DNA, Fungal|G-Quadruplexes|Genome, Fungal|Markov Chains|Models, Genetic|Molecular Sequence Data|Nucleic Acid Conformation|Phylogeny|Saccharomyces cerevisiae|Sequence Analysis, DNA|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1000861', '20676380', 'G-quadruplex DNA is a four-stranded DNA structure formed by non-Watson-Crick base pairing between stacked sets of four guanines. Many possible functions have been proposed for this structure, but its in vivo role in the cell is still largely unresolved. We carried out a genome-wide survey of the evolutionary conservation of regions with the potential to form G-quadruplex DNA structures (G4 DNA motifs) across seven yeast species. We found that G4 DNA motifs were significantly more conserved than expected by chance, and the nucleotide-level conservation patterns suggested that the motif conservation was the result of the formation of G4 DNA structures. We characterized the association of conserved and non-conserved G4 DNA motifs in Saccharomyces cerevisiae with more than 40 known genome features and gene classes. Our comprehensive, integrated evolutionary and functional analysis confirmed the previously observed associations of G4 DNA motifs with promoter regions and the rDNA, and it identified several previously unrecognized associations of G4 DNA motifs with genomic features, such as mitotic and meiotic double-strand break sites (DSBs). Conserved G4 DNA motifs maintained strong associations with promoters and the rDNA, but not with DSBs. We also performed the first analysis of G4 DNA motifs in the mitochondria, and surprisingly found a tenfold higher concentration of the motifs in the AT-rich yeast mitochondrial DNA than in nuclear DNA. The evolutionary conservation of the G4 DNA motif and its association with specific genome features supports the hypothesis that G4 DNA has in vivo functions that are under evolutionary constraint.'),
(84703, 2010, 'plos', 'Patterns of HIV-1 protein interaction identify perturbed host-cellular subsystems', 'MacPherson, Jamie I|Dickerson, Jonathan E|Pinney, John W|Robertson, David L', 'Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.|Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.|Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.|Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Cluster Analysis|Computational Biology|Databases, Protein|HIV-1|Host-Pathogen Interactions|Humans|Protein Interaction Mapping|RNA, Small Interfering|Reproducibility of Results|Signal Transduction|T-Lymphocytes|Viral Proteins', 'Journal Article', '10.1371/journal.pcbi.1000863', '20686668', 'Human immunodeficiency virus type 1 (HIV-1) exploits a diverse array of host cell functions in order to replicate. This is mediated through a network of virus-host interactions. A variety of recent studies have catalogued this information. In particular the HIV-1, Human Protein Interaction Database (HHPID) has provided a unique depth of protein interaction detail. However, as a map of HIV-1 infection, the HHPID is problematic, as it contains curation error and redundancy, in addition, it is based on a heterogeneous set of experimental methods. Based on identifying shared patterns of HIV-host interaction, we have developed a novel methodology to delimit the core set of host-cellular functions and their associated perturbation from the HHPID. Initially, using biclustering, we identify 279 significant sets of host proteins that undergo the same types of interaction. The functional cohesiveness of these protein sets was validated using a human protein-protein interaction network, gene ontology annotation and sequence similarity. Next, using a distance measure, we group host protein sets and identify 37 distinct higher-level subsystems. We further demonstrate the biological significance of these subsystems by cross-referencing with global siRNA screens that have been used to detect host factors necessary for HIV-1 replication, and investigate the seemingly small intersect between these data sets. Our results highlight significant host-cell subsystems that are perturbed during the course of HIV-1 infection. Moreover, we characterise the patterns of interaction that contribute to these perturbations. Thus, our work disentangles the complex set of HIV-1-host protein interactions in the HHPID, reconciles these with siRNA screens and provides an accessible and interpretable map of infection.'),
(84704, 2010, 'plos', 'The roots of bioinformatics in protein evolution', 'Doolittle, Russell F', 'Department of Chemistry & Biochemistry, University of California, San Diego, La Jolla, California, United States of America. rdoolittle@ucsd.edu', 'United States', 0, 'Amino Acid Sequence|Animals|Computational Biology|Evolution, Molecular|Fibrinopeptide A|Fibrinopeptide B|Humans|Molecular Sequence Data|Phylogeny|Proteins|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1000875', '20686682', '-'),
(84705, 2010, 'plos', 'Knotted vs unknotted proteins: evidence of knot-promoting loops', 'Potestio, Raffaello|Micheletti, Cristian|Orland, Henri', 'SISSA - Scuola Internazionale Superiore di Studi Avanzati, Trieste, Italy.|SISSA - Scuola Internazionale Superiore di Studi Avanzati, Trieste, Italy.|SISSA - Scuola Internazionale Superiore di Studi Avanzati, Trieste, Italy.', 'Italy|Italy|Italy', 0, 'Animals|Carbonic Anhydrase II|Computational Biology|Databases, Protein|Humans|Isomerism|Models, Molecular|Nuclear Proteins|Phylogeny|Protein Conformation|Protein Structure, Tertiary|Proteins|RNA-Binding Proteins|Sequence Alignment|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1000864', '20686683', 'Knotted proteins, because of their ability to fold reversibly in the same topologically entangled conformation, are the object of an increasing number of experimental and theoretical studies. The aim of the present investigation is to assess, on the basis of presently available structural data, the extent to which knotted proteins are isolated instances in sequence or structure space, and to use comparative schemes to understand whether specific protein segments can be associated to the occurrence of a knot in the native state. A significant sequence homology is found among a sizeable group of knotted and unknotted proteins. In this family, knotted members occupy a primary sub-branch of the phylogenetic tree and differ from unknotted ones only by additional loop segments. These knot-promoting loops, whose virtual bridging eliminates the knot, are found in various types of knotted proteins. Valuable insight into how knots form, or are encoded, in proteins could be obtained by targeting these regions in future computational studies or excision experiments.'),
(84706, 2010, 'plos', 'A comprehensive, quantitative, and genome-wide model of translation', 'Siwiak, Marlena|Zielenkiewicz, Piotr', 'Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.|Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.', 'Poland|Poland', 0, 'Algorithms|Computational Biology|Gene Expression Regulation|Genome, Fungal|Models, Genetic|Protein Biosynthesis|Proteins|RNA, Messenger|Ribosomes|Saccharomyces|Temperature', 'Journal Article', '10.1371/journal.pcbi.1000865', '20686685', 'Translation is still poorly characterised at the level of individual proteins and its role in regulation of gene expression has been constantly underestimated. To better understand the process of protein synthesis we developed a comprehensive and quantitative model of translation, characterising protein synthesis separately for individual genes. The main advantage of the model is that basing it on only a few datasets and general assumptions allows the calculation of many important translational parameters, which are extremely difficult to measure experimentally. In the model, each gene is attributed with a set of translational parameters, namely the absolute number of transcripts, ribosome density, mean codon translation time, total transcript translation time, total time required for translation initiation and elongation, translation initiation rate, mean mRNA lifetime, and absolute number of proteins produced by gene transcripts. Most parameters were calculated based on only one experimental dataset of genome-wide ribosome profiling. The model was implemented in Saccharomyces cerevisiae, and its results were compared with available data, yielding reasonably good correlations. The calculated coefficients were used to perform a global analysis of translation in yeast, revealing some interesting aspects of the process. We have shown that two commonly used measures of translation efficiency - ribosome density and number of protein molecules produced - are affected by two distinct factors. High values of both measures are caused, i.a., by very short times of translation initiation, however, the origins of initiation time reduction are completely different in both cases. The model is universal and can be applied to any organism, if the necessary input data are available. The model allows us to better integrate transcriptomic and proteomic data. A few other possibilities of the model utilisation are discussed concerning the example of the yeast system.'),
(84707, 2010, 'plos', 'Mechanism of microRNA-target interaction: molecular dynamics simulations and thermodynamics analysis', 'Wang, Yonghua|Li, Yan|Ma, Zhi|Yang, Wei|Ai, Chunzhi', 'Center of Bioinformatics, Northwest A&F University, Yangling, Shaanxi, China. yh_wang@nwsuaf.edu.cn|Center of Bioinformatics, Northwest A&F University, Yangling, Shaanxi, China. yh_wang@nwsuaf.edu.cn|Center of Bioinformatics, Northwest A&F University, Yangling, Shaanxi, China. yh_wang@nwsuaf.edu.cn|Center of Bioinformatics, Northwest A&F University, Yangling, Shaanxi, China. yh_wang@nwsuaf.edu.cn|Center of Bioinformatics, Northwest A&F University, Yangling, Shaanxi, China. yh_wang@nwsuaf.edu.cn', 'China|China|China|China|China', 60, 'Bacterial Proteins|Magnesium|MicroRNAs|Molecular Dynamics Simulation|Poisson Distribution|Principal Component Analysis|Protein Binding|Protein Conformation|Protein Structure, Tertiary|Proteins|Thermodynamics|Thermus thermophilus', 'Journal Article', '10.1371/journal.pcbi.1000866', '20686687', 'MicroRNAs (miRNAs) are endogenously produced approximately 21-nt riboregulators that associate with Argonaute (Ago) proteins to direct mRNA cleavage or repress the translation of complementary RNAs. Capturing the molecular mechanisms of miRNA interacting with its target will not only reinforce the understanding of underlying RNA interference but also fuel the design of more effective small-interfering RNA strands. To address this, in the present work the RNA-bound (Ago-miRNA, Ago-miRNA-target) and RNA-free Ago forms were analyzed by performing both molecular dynamics simulations and thermodynamic analysis. Based on the principal component analysis results of the simulation trajectories as well as the correlation analysis in fluctuations of residues, we discover that: 1) three important (PAZ, Mid and PIWI) domains exist in Argonaute which define the global dynamics of the protein, 2) the interdomain correlated movements are so crucial for the interaction of Ago-RNAs that they not only facilitate the relaxation of the interactions between residues surrounding the RNA binding channel but also induce certain conformational changes, and 3) it is just these conformational changes that expand the cavity of the active site and open putative pathways for both the substrate uptake and product release. In addition, by thermodynamic analysis we also discover that for both the guide RNA 5-end recognition and the facilitated site-specific cleavage of the target, the presence of two metal ions (of Mg(2+)) plays a predominant role, and this conclusion is consistent with the observed enzyme catalytic cleavage activity in the ternary complex (Ago-miRNA-mRNA). Our results find that it is the set of arginine amino acids concentrated in the nucleotide-binding channel in Ago, instead of the conventionally-deemed seed base-paring, that makes greater contributions in stabilizing the binding of the nucleic acids to Ago.'),
(84708, 2010, 'plos', 'More than 1,001 problems with protein domain databases: transmembrane regions, signal peptides and the issue of sequence homology', 'Wong, Wing-Cheong|Maurer-Stroh, Sebastian|Eisenhaber, Frank', 'Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore. wongwc@bii-sg.org|Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore. wongwc@bii-sg.org|Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore. wongwc@bii-sg.org', 'Singapore|Singapore|Singapore', 0, 'Animals|Computational Biology|Databases, Protein|Humans|Markov Chains|Membrane Proteins|Pattern Recognition, Automated|Protein Folding|Protein Sorting Signals|Protein Structure, Tertiary|Proteins|Reproducibility of Results|Sequence Homology, Amino Acid', 'Journal Article', '10.1371/journal.pcbi.1000867', '20686689', 'Large-scale genome sequencing gained general importance for life science because functional annotation of otherwise experimentally uncharacterized sequences is made possible by the theory of biomolecular sequence homology. Historically, the paradigm of similarity of protein sequences implying common structure, function and ancestry was generalized based on studies of globular domains. Having the same fold imposes strict conditions over the packing in the hydrophobic core requiring similarity of hydrophobic patterns. The implications of sequence similarity among non-globular protein segments have not been studied to the same extent, nevertheless, homology considerations are silently extended for them. This appears especially detrimental in the case of transmembrane helices (TMs) and signal peptides (SPs) where sequence similarity is necessarily a consequence of physical requirements rather than common ancestry. Thus, matching of SPs/TMs creates the illusion of matching hydrophobic cores. Therefore, inclusion of SPs/TMs into domain models can give rise to wrong annotations. More than 1001 domains among the 10,340 models of Pfam release 23 and 18 domains of SMART version 6 (out of 809) contain SP/TM regions. As expected, fragment-mode HMM searches generate promiscuous hits limited to solely the SP/TM part among clearly unrelated proteins. More worryingly, we show explicit examples that the scores of clearly false-positive hits, even in global-mode searches, can be elevated into the significance range just by matching the hydrophobic runs. In the PIR iProClass database v3.74 using conservative criteria, we find that at least between 2.1% and 13.6% of its annotated Pfam hits appear unjustified for a set of validated domain models. Thus, false-positive domain hits enforced by SP/TM regions can lead to dramatic annotation errors where the hit has nothing in common with the problematic domain model except the SP/TM region itself. We suggest a workflow of flagging problematic hits arising from SP/TM-containing models for critical reconsideration by annotation users.'),
(84709, 2010, 'plos', 'A Bayesian approach to the evolution of metabolic networks on a phylogeny', 'Mithani, Aziz|Preston, Gail M|Hein, Jotun', 'Department of Statistics, University of Oxford, Oxford, United Kingdom. mithani@stats.ox.ac.uk|Department of Statistics, University of Oxford, Oxford, United Kingdom. mithani@stats.ox.ac.uk|Department of Statistics, University of Oxford, Oxford, United Kingdom. mithani@stats.ox.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 18, 'Bayes Theorem|Biological Evolution|Computer Simulation|Genome, Bacterial|Metabolic Networks and Pathways|Models, Biological|Models, Statistical|Phylogeny|Pseudomonas', 'Journal Article', '10.1371/journal.pcbi.1000868', '20700467', 'The availability of genomes of many closely related bacteria with diverse metabolic capabilities offers the possibility of tracing metabolic evolution on a phylogeny relating the genomes to understand the evolutionary processes and constraints that affect the evolution of metabolic networks. Using simple (independent loss/gain of reactions) or complex (incorporating dependencies among reactions) stochastic models of metabolic evolution, it is possible to study how metabolic networks evolve over time. Here, we describe a model that takes the reaction neighborhood into account when modeling metabolic evolution. The model also allows estimation of the strength of the neighborhood effect during the course of evolution. We present Gibbs samplers for sampling networks at the internal node of a phylogeny and for estimating the parameters of evolution over a phylogeny without exploring the whole search space by iteratively sampling from the conditional distributions of the internal networks and parameters. The samplers are used to estimate the parameters of evolution of metabolic networks of bacteria in the genus Pseudomonas and to infer the metabolic networks of the ancestral pseudomonads. The results suggest that pathway maps that are conserved across the Pseudomonas phylogeny have a stronger neighborhood structure than those which have a variable distribution of reactions across the phylogeny, and that some Pseudomonas lineages are going through genome reduction resulting in the loss of a number of reactions from their metabolic networks.'),
(84710, 2010, 'plos', 'Continuous attractors with morphed/correlated maps', 'Romani, Sandro|Tsodyks, Misha', 'Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.|Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel', 14, 'Animals|Computer Simulation|Discrimination (Psychology)|Hippocampus|Models, Biological|Neural Networks (Computer)|Numerical Analysis, Computer-Assisted', 'Journal Article', '10.1371/journal.pcbi.1000869', '20700490', 'Continuous attractor networks are used to model the storage and representation of analog quantities, such as position of a visual stimulus. The storage of multiple continuous attractors in the same network has previously been studied in the context of self-position coding. Several uncorrelated maps of environments are stored in the synaptic connections, and a position in a given environment is represented by a localized pattern of neural activity in the corresponding map, driven by a spatially tuned input. Here we analyze networks storing a pair of correlated maps, or a morph sequence between two uncorrelated maps. We find a novel state in which the network activity is simultaneously localized in both maps. In this state, a fixed cue presented to the network does not determine uniquely the location of the bump, i.e. the response is unreliable, with neurons not always responding when their preferred input is present. When the tuned input varies smoothly in time, the neuronal responses become reliable and selective for the environment: the subset of neurons responsive to a moving input in one map changes almost completely in the other map. This form of remapping is a non-trivial transformation between the tuned input to the network and the resulting tuning curves of the neurons. The new state of the network could be related to the formation of direction selectivity in one-dimensional environments and hippocampal remapping. The applicability of the model is not confined to self-position representations, we show an instance of the network solving a simple delayed discrimination task.'),
(84711, 2010, 'plos', 'A simple self-maintaining metabolic system: robustness, autocatalysis, bistability', 'Piedrafita, Gabriel|Montero, Francisco|Morán, Federico|Cárdenas, María Luz|Cornish-Bowden, Athel', 'Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain.|Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain.|Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain.|Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain.|Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain.', 'Spain|Spain|Spain|Spain|Spain', 0, 'Catalysis|Enzymes|Metabolism|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1000872', '20700491', 'A living organism must not only organize itself from within, it must also maintain its organization in the face of changes in its environment and degradation of its components. We show here that a simple (M,R)-system consisting of three interlocking catalytic cycles, with every catalyst produced by the system itself, can both establish a non-trivial steady state and maintain this despite continuous loss of the catalysts by irreversible degradation. As long as at least one catalyst is present at a sufficient concentration in the initial state, the others can be produced and maintained. The system shows bistability, because if the amount of catalyst in the initial state is insufficient to reach the non-trivial steady state the system collapses to a trivial steady state in which all fluxes are zero. It is also robust, because if one catalyst is catastrophically lost when the system is in steady state it can recreate the same state. There are three elementary flux modes, but none of them is an enzyme-maintaining mode, the entire network being necessary to maintain the two catalysts.'),
(84712, 2010, 'plos', 'Evolution of gene regulatory networks by fluctuating selection and intrinsic constraints', 'Tsuda, Masaki E|Kawata, Masakado', 'Division of Ecology and Evolutionary Biology, Graduate School of Life Sciences, Tohoku University, Sendai, Japan. teuder@gmail.com|Division of Ecology and Evolutionary Biology, Graduate School of Life Sciences, Tohoku University, Sendai, Japan. teuder@gmail.com', 'Japan|Japan', 14, 'Adaptation, Physiological|Biological Evolution|Computer Simulation|Environment|Gene Expression|Gene Regulatory Networks|Gene Transfer, Horizontal|Genes, Bacterial|Genes, Duplicate|Humans|Models, Genetic|Mutation|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000873', '20700492', 'Various characteristics of complex gene regulatory networks (GRNs) have been discovered during the last decade, e.g., redundancy, exponential indegree distributions, scale-free outdegree distributions, mutational robustness, and evolvability. Although progress has been made in this field, it is not well understood whether these characteristics are the direct products of selection or those of other evolutionary forces such as mutational biases and biophysical constraints. To elucidate the causal factors that promoted the evolution of complex GRNs, we examined the effect of fluctuating environmental selection and some intrinsic constraining factors on GRN evolution by using an individual-based model. We found that the evolution of complex GRNs is remarkably promoted by fixation of beneficial gene duplications under unpredictably fluctuating environmental conditions and that some internal factors inherent in organisms, such as mutational bias, gene expression costs, and constraints on expression dynamics, are also important for the evolution of GRNs. The results indicate that various biological properties observed in GRNs could evolve as a result of not only adaptation to unpredictable environmental changes but also non-adaptive processes owing to the properties of the organisms themselves. Our study emphasizes that evolutionary models considering such intrinsic constraining factors should be used as null models to analyze the effect of selection on GRN evolution.'),
(84713, 2010, 'plos', 'Probability matching as a computational strategy used in perception', 'Wozny, David R|Beierholm, Ulrik R|Shams, Ladan', 'Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.|Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.|Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.', 'Germany|Germany|Germany', 111, 'Decision Making|Female|Humans|Male|Probability Learning|Sound Localization|Visual Perception|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1000871', '20700493', 'The question of which strategy is employed in human decision making has been studied extensively in the context of cognitive tasks, however, this question has not been investigated systematically in the context of perceptual tasks. The goal of this study was to gain insight into the decision-making strategy used by human observers in a low-level perceptual task. Data from more than 100 individuals who participated in an auditory-visual spatial localization task was evaluated to examine which of three plausible strategies could account for each observers behavior the best. This task is very suitable for exploring this question because it involves an implicit inference about whether the auditory and visual stimuli were caused by the same object or independent objects, and provides different strategies of how using the inference about causes can lead to distinctly different spatial estimates and response patterns. For example, employing the commonly used cost function of minimizing the mean squared error of spatial estimates would result in a weighted averaging of estimates corresponding to different causal structures. A strategy that would minimize the error in the inferred causal structure would result in the selection of the most likely causal structure and sticking with it in the subsequent inference of location-model selection. A third strategy is one that selects a causal structure in proportion to its probability, thus attempting to match the probability of the inferred causal structure. This type of probability matching strategy has been reported to be used by participants predominantly in cognitive tasks. Comparing these three strategies, the behavior of the vast majority of observers in this perceptual task was most consistent with probability matching. While this appears to be a suboptimal strategy and hence a surprising choice for the perceptual system to adopt, we discuss potential advantages of such a strategy for perception.'),
(84714, 2010, 'plos', 'Connectivity, cycles, and persistence thresholds in metapopulation networks', 'Artzy-Randrup, Yael|Stone, Lewi', 'Department of Ecology and Evolution, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Ecology and Evolution, University of Michigan, Ann Arbor, Michigan, United States of America.', 'United States|United States', 0, 'Animal Migration|Animals|Aquatic Organisms|Conservation of Natural Resources|Ecosystem|Larva|Models, Biological|Population Dynamics', 'Journal Article', '10.1371/journal.pcbi.1000876', '20700494', 'Synthesising the relationships between complexity, connectivity, and the stability of large biological systems has been a longstanding fundamental quest in theoretical biology and ecology. With the many exciting developments in modern network theory, interest in these issues has recently come to the forefront in a range of multidisciplinary areas. Here we outline a new theoretical analysis specifically relevant for the study of ecological metapopulations focusing primarily on marine systems, where subpopulations are generally connected via larval dispersal. Our work determines the qualitative and quantitative conditions by which dispersal and network structure control the persistence of a set of age-structured patch populations. Mathematical modelling combined with a graph theoretic analysis demonstrates that persistence depends crucially on the topology of cycles in the dispersal network which tend to enhance the effect of larvae returning home. Our method clarifies the impact directly due to network structure, but this almost by definition can only be achieved by examining the simplified case in which patches are identical, an assumption that we later relax. The methodology identifies critical migration routes, whose presence are vital to overall stability, and therefore should have high conservation priority. In contrast, lonely links, or links in the network that do not participate in a cyclical component, have no impact on persistence and thus have low conservation priority. A number of other intriguing criteria for persistence are derived. Our modelling framework reveals new insights regarding the determinants of persistence, stability, and thresholds in complex metapopulations. In particular, while theoretical arguments have, in the past, suggested that increasing connectivity is a destabilizing feature in complex systems, this is not evident in metapopulation networks where connectivity, cycles, coherency, and heterogeneity all tend to enhance persistence. The results should be of interest for many other scientific contexts that make use of network theory.'),
(84715, 2010, 'plos', 'One rule to grow them all: a general theory of neuronal branching and its practical application', 'Cuntz, Hermann|Forstner, Friedrich|Borst, Alexander|Häusser, Michael', 'Wolfson Institute for Biomedical Research and Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom. h.cuntz@ucl.ac.uk|Wolfson Institute for Biomedical Research and Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom. h.cuntz@ucl.ac.uk|Wolfson Institute for Biomedical Research and Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom. h.cuntz@ucl.ac.uk|Wolfson Institute for Biomedical Research and Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom. h.cuntz@ucl.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 155, 'Axons|Brain|Computer Simulation|Dendrites|Humans|Models, Neurological|Nerve Net|Neurons', 'Journal Article', '10.1371/journal.pcbi.1000877', '20700495', 'Understanding the principles governing axonal and dendritic branching is essential for unravelling the functionality of single neurons and the way in which they connect. Nevertheless, no formalism has yet been described which can capture the general features of neuronal branching. Here we propose such a formalism, which is derived from the expression of dendritic arborizations as locally optimized graphs. Inspired by Ramón y Cajals laws of conservation of cytoplasm and conduction time in neural circuitry, we show that this graphical representation can be used to optimize these variables. This approach allows us to generate synthetic branching geometries which replicate morphological features of any tested neuron. The essential structure of a neuronal tree is thereby captured by the density profile of its spanning field and by a single parameter, a balancing factor weighing the costs for material and conduction time. This balancing factor determines a neurons electrotonic compartmentalization. Additions to this rule, when required in the construction process, can be directly attributed to developmental processes or a neurons computational role within its neural circuit. The simulations presented here are implemented in an open-source software package, the TREES toolbox, which provides a general set of tools for analyzing, manipulating, and generating dendritic structure, including a tool to create synthetic members of any particular cell group and an approach for a model-based supervised automatic morphological reconstruction from fluorescent image stacks. These approaches provide new insights into the constraints governing dendritic architectures. They also provide a novel framework for modelling and analyzing neuronal branching structures and for constructing realistic synthetic neural networks.'),
(84716, 2010, 'plos', 'Lysine120 interactions with p53 response elements can allosterically direct p53 organization', 'Pan, Yongping|Nussinov, Ruth', 'Basic Science Program, Science Applications International Corporation-Frederick, Inc., Center for Cancer Research Nanobiology Program, National Cancer Institute-Frederick, Frederick, Maryland, United States of America.|Basic Science Program, Science Applications International Corporation-Frederick, Inc., Center for Cancer Research Nanobiology Program, National Cancer Institute-Frederick, Frederick, Maryland, United States of America.', 'United States|United States', 14, 'Allosteric Regulation|Apoptosis|Binding Sites|DNA|Humans|Lysine|Models, Molecular|Protein Binding|Protein Interaction Domains and Motifs|Response Elements|Tumor Suppressor Protein p53', 'Journal Article', '10.1371/journal.pcbi.1000878', '20700496', 'p53 can serve as a paradigm in studies aiming to figure out how allosteric perturbations in transcription factors (TFs) triggered by small changes in DNA response element (RE) sequences, can spell selectivity in co-factor recruitment. p53-REs are 20-base pair (bp) DNA segments specifying diverse functions. They may be located near the transcription start sites or thousands of bps away in the genome. Their number has been estimated to be in the thousands, and they all share a common motif. A key question is then how does the p53 protein recognize a particular p53-RE sequence among all the similar ones? Here, representative p53-REs regulating diverse functions including cell cycle arrest, DNA repair, and apoptosis were simulated in explicit solvent. Among the major interactions between p53 and its REs involving Lys120, Arg280 and Arg248, the bps interacting with Lys120 vary while the interacting partners of other residues are less so. We observe that each p53-RE quarter site sequence has a unique pattern of interactions with p53 Lys120. The allosteric, DNA sequence-induced conformational and dynamic changes of the altered Lys120 interactions are amplified by the perturbation of other p53-DNA interactions. The combined subtle RE sequence-specific allosteric effects propagate in the p53 and in the DNA. The resulting amplified allosteric effects far away are reflected in changes in the overall p53 organization and in the p53 surface topology and residue fluctuations which play key roles in selective co-factor recruitment. As such, these observations suggest how similar p53-RE sequences can spell the preferred co-factor binding, which is the key to the selective gene transactivation and consequently different functional effects.'),
(84717, 2010, 'plos', 'Calcium signals driven by single channel noise', 'Skupin, Alexander|Kettenmann, Helmut|Falcke, Martin', 'Max-Planck-Institute of Molecular Plant Physiology, Potsdam, Germany. skupin@mpimp-golm.mpg.de|Max-Planck-Institute of Molecular Plant Physiology, Potsdam, Germany. skupin@mpimp-golm.mpg.de|Max-Planck-Institute of Molecular Plant Physiology, Potsdam, Germany. skupin@mpimp-golm.mpg.de', 'Germany|Germany|Germany', 0, 'Animals|Astrocytes|Calcium|Calcium Channels|Calcium Signaling|Computer Simulation|Diffusion|Inositol 1,4,5-Trisphosphate Receptors|Markov Chains|Mice|Models, Biological|Models, Statistical|Rats', 'Journal Article', '10.1371/journal.pcbi.1000870', '20700497', 'Usually, the occurrence of random cell behavior is appointed to small copy numbers of molecules involved in the stochastic process. Recently, we demonstrated for a variety of cell types that intracellular Ca2+ oscillations are sequences of random spikes despite the involvement of many molecules in spike generation. This randomness arises from the stochastic state transitions of individual Ca2+ release channels and does not average out due to the existence of steep concentration gradients. The system is hierarchical due to the structural levels channel--channel cluster--cell and a corresponding strength of coupling. Concentration gradients introduce microdomains which couple channels of a cluster strongly. But they couple clusters only weakly, too weak to establish deterministic behavior on cell level. Here, we present a multi-scale modelling concept for stochastic hierarchical systems. It simulates active molecules individually as Markov chains and their coupling by deterministic diffusion. Thus, we are able to follow the consequences of random single molecule state changes up to the signal on cell level. To demonstrate the potential of the method, we simulate a variety of experiments. Comparisons of simulated and experimental data of spontaneous oscillations in astrocytes emphasize the role of spatial concentration gradients in Ca2+ signalling. Analysis of extensive simulations indicates that frequency encoding described by the relation between average and standard deviation of interspike intervals is surprisingly robust. This robustness is a property of the random spiking mechanism and not a result of control.'),
(84718, 2010, 'plos', 'A model for a correlated random walk based on the ordered extension of pseudopodia', 'Van Haastert, Peter J M', 'Department of Cell Biochemistry, University of Groningen, Haren, the Netherlands. P.J.M.van.haastert@rug.nl', 'Netherlands', 20, 'Computer Simulation|Dictyostelium|Models, Biological|Models, Statistical|Monte Carlo Method|Movement|Pseudopodia', 'Journal Article', '10.1371/journal.pcbi.1000874', '20711349', 'Cell migration in the absence of external cues is well described by a correlated random walk. Most single cells move by extending protrusions called pseudopodia. To deduce how cells walk, we have analyzed the formation of pseudopodia by Dictyostelium cells. We have observed that the formation of pseudopodia is highly ordered with two types of pseudopodia: First, de novo formation of pseudopodia at random positions on the cell body, and therefore in random directions. Second, pseudopod splitting near the tip of the current pseudopod in alternating right/left directions, leading to a persistent zig-zag trajectory. Here we analyzed the probability frequency distributions of the angles between pseudopodia and used this information to design a stochastic model for cell movement. Monte Carlo simulations show that the critical elements are the ratio of persistent splitting pseudopodia relative to random de novo pseudopodia, the Left/Right alternation, the angle between pseudopodia and the variance of this angle. Experiments confirm predictions of the model, showing reduced persistence in mutants that are defective in pseudopod splitting and in mutants with an irregular cell surface.'),
(84719, 2010, 'plos', 'Computational models of HIV-1 resistance to gene therapy elucidate therapy design principles', 'Aviran, Sharon|Shah, Priya S|Schaffer, David V|Arkin, Adam P', 'Department of Bioengineering, University of California Berkeley, Berkeley, California, USA.|Department of Bioengineering, University of California Berkeley, Berkeley, California, USA.|Department of Bioengineering, University of California Berkeley, Berkeley, California, USA.|Department of Bioengineering, University of California Berkeley, Berkeley, California, USA.', 'United States|United States|United States|United States', 15, 'Anti-HIV Agents|Antiretroviral Therapy, Highly Active|Cell Proliferation|Drug Resistance, Viral|Genetic Fitness|Genetic Therapy|HIV Infections|HIV-1|Humans|Models, Genetic|Mutation|Time|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.1000883', '20711350', 'Gene therapy is an emerging alternative to conventional anti-HIV-1 drugs, and can potentially control the virus while alleviating major limitations of current approaches. Yet, HIV-1s ability to rapidly acquire mutations and escape therapy presents a critical challenge to any novel treatment paradigm. Viral escape is thus a key consideration in the design of any gene-based technique. We develop a computational model of HIVs evolutionary dynamics in vivo in the presence of a genetic therapy to explore the impact of therapy parameters and strategies on the development of resistance. Our model is generic and captures the properties of a broad class of gene-based agents that inhibit early stages of the viral life cycle. We highlight the differences in viral resistance dynamics between gene and standard antiretroviral therapies, and identify key factors that impact long-term viral suppression. In particular, we underscore the importance of mutationally-induced viral fitness losses in cells that are not genetically modified, as these can severely constrain the replication of resistant virus. We also propose and investigate a novel treatment strategy that leverages upon gene therapys unique capacity to deliver different genes to distinct cell populations, and we find that such a strategy can dramatically improve efficacy when used judiciously within a certain parametric regime. Finally, we revisit a previously-suggested idea of improving clinical outcomes by boosting the proliferation of the genetically-modified cells, but we find that such an approach has mixed effects on resistance dynamics. Our results provide insights into the short- and long-term effects of gene therapy and the role of its key properties in the evolution of resistance, which can serve as guidelines for the choice and optimization of effective therapeutic agents.'),
(84720, 2010, 'plos', 'Induced effects of sodium ions on dopaminergic G-protein coupled receptors', 'Selent, Jana|Sanz, Ferran|Pastor, Manuel|De Fabritiis, Gianni', 'Computer-Assisted Drug Design Laboratory, Research Unit on Biomedical Informatics, IMIM, Universitat Pompeu Fabra, Barcelona, Spain.|Computer-Assisted Drug Design Laboratory, Research Unit on Biomedical Informatics, IMIM, Universitat Pompeu Fabra, Barcelona, Spain.|Computer-Assisted Drug Design Laboratory, Research Unit on Biomedical Informatics, IMIM, Universitat Pompeu Fabra, Barcelona, Spain.|Computer-Assisted Drug Design Laboratory, Research Unit on Biomedical Informatics, IMIM, Universitat Pompeu Fabra, Barcelona, Spain.', 'Spain|Spain|Spain|Spain', 74, 'Allosteric Regulation|Allosteric Site|Humans|Molecular Dynamics Simulation|Protein Conformation|Receptors, Adrenergic, beta-2|Receptors, Dopamine D2|Receptors, G-Protein-Coupled|Sodium', 'Journal Article', '10.1371/journal.pcbi.1000884', '20711351', 'G-protein coupled receptors, the largest family of proteins in the human genome, are involved in many complex signal transduction pathways, typically activated by orthosteric ligand binding and subject to allosteric modulation. Dopaminergic receptors, belonging to the class A family of G-protein coupled receptors, are known to be modulated by sodium ions from an allosteric binding site, although the details of sodium effects on the receptor have not yet been described. In an effort to understand these effects, we performed microsecond scale all-atom molecular dynamics simulations on the dopaminergic D(2) receptor, finding that sodium ions enter the receptor from the extracellular side and bind at a deep allosteric site (Asp2.50). Remarkably, the presence of a sodium ion at this allosteric site induces a conformational change of the rotamer toggle switch Trp6.48 which locks in a conformation identical to the one found in the partially inactive state of the crystallized human beta(2) adrenergic receptor. This study provides detailed quantitative information about binding of sodium ions in the D(2) receptor and reports a possibly important sodium-induced conformational change for modulation of D(2) receptor function.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84721, 2010, 'plos', 'Stochastic ion channel gating in dendritic neurons: morphology dependence and probabilistic synaptic activation of dendritic spikes', 'Cannon, Robert C|ODonnell, Cian|Nolan, Matthew F', 'Textensor Limited, Edinburgh, United Kingdom.|Textensor Limited, Edinburgh, United Kingdom.|Textensor Limited, Edinburgh, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 59, 'Action Potentials|Axons|CA1 Region, Hippocampal|Dendrites|Humans|Ion Channel Gating|Ion Channels|Membrane Potentials|Models, Neurological|Stochastic Processes|Synapses', 'Journal Article', '10.1371/journal.pcbi.1000886', '20711353', 'Neuronal activity is mediated through changes in the probability of stochastic transitions between open and closed states of ion channels. While differences in morphology define neuronal cell types and may underlie neurological disorders, very little is known about influences of stochastic ion channel gating in neurons with complex morphology. We introduce and validate new computational tools that enable efficient generation and simulation of models containing stochastic ion channels distributed across dendritic and axonal membranes. Comparison of five morphologically distinct neuronal cell types reveals that when all simulated neurons contain identical densities of stochastic ion channels, the amplitude of stochastic membrane potential fluctuations differs between cell types and depends on sub-cellular location. For typical neurons, the amplitude of membrane potential fluctuations depends on channel kinetics as well as open probability. Using a detailed model of a hippocampal CA1 pyramidal neuron, we show that when intrinsic ion channels gate stochastically, the probability of initiation of dendritic or somatic spikes by dendritic synaptic input varies continuously between zero and one, whereas when ion channels gate deterministically, the probability is either zero or one. At physiological firing rates, stochastic gating of dendritic ion channels almost completely accounts for probabilistic somatic and dendritic spikes generated by the fully stochastic model. These results suggest that the consequences of stochastic ion channel gating differ globally between neuronal cell-types and locally between neuronal compartments. Whereas dendritic neurons are often assumed to behave deterministically, our simulations suggest that a direct consequence of stochastic gating of intrinsic ion channels is that spike output may instead be a probabilistic function of patterns of synaptic input to dendrites.'),
(84722, 2010, 'plos', 'Computational analysis of phosphopeptide binding to the polo-box domain of the mitotic kinase PLK1 using molecular dynamics simulation', 'Huggins, David J|McKenzie, Grahame J|Robinson, Daniel D|Narváez, Ana J|Hardwick, Bryn|Roberts-Thomson, Meredith|Venkitaraman, Ashok R|Grant, Guy H|Payne, Mike C', 'TCM Group, Cavendish Laboratory, University of Cambridge, Cambridge, United Kingdom. djh210@cam.ac.uk|TCM Group, Cavendish Laboratory, University of Cambridge, Cambridge, United Kingdom. djh210@cam.ac.uk|TCM Group, Cavendish Laboratory, University of Cambridge, Cambridge, United Kingdom. djh210@cam.ac.uk|TCM Group, Cavendish Laboratory, University of Cambridge, Cambridge, United Kingdom. djh210@cam.ac.uk|TCM Group, Cavendish Laboratory, University of Cambridge, Cambridge, United Kingdom. djh210@cam.ac.uk|TCM Group, Cavendish Laboratory, University of Cambridge, Cambridge, United Kingdom. djh210@cam.ac.uk|TCM Group, Cavendish Laboratory, University of Cambridge, Cambridge, United Kingdom. djh210@cam.ac.uk|TCM Group, Cavendish Laboratory, University of Cambridge, Cambridge, United Kingdom. djh210@cam.ac.uk|TCM Group, Cavendish Laboratory, University of Cambridge, Cambridge, United Kingdom. djh210@cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 26, 'Binding Sites|Cell Cycle Proteins|Humans|Molecular Dynamics Simulation|Phosphopeptides|Phosphorylation|Phosphothreonine|Protein Binding|Protein Interaction Domains and Motifs|Protein-Serine-Threonine Kinases|Proto-Oncogene Proteins|Substrate Specificity|cdc25 Phosphatases', 'Journal Article', '10.1371/journal.pcbi.1000880', '20711360', 'The Polo-Like Kinase 1 (PLK1) acts as a central regulator of mitosis and is over-expressed in a wide range of human tumours where high levels of expression correlate with a poor prognosis. PLK1 comprises two structural elements, a kinase domain and a polo-box domain (PBD). The PBD binds phosphorylated substrates to control substrate phosphorylation by the kinase domain. Although the PBD preferentially binds to phosphopeptides, it has a relatively broad sequence specificity in comparison with other phosphopeptide binding domains. We analysed the molecular determinants of recognition by performing molecular dynamics simulations of the PBD with one of its natural substrates, CDC25c. Predicted binding free energies were calculated using a molecular mechanics, Poisson-Boltzmann surface area approach. We calculated the per-residue contributions to the binding free energy change, showing that the phosphothreonine residue and the mainchain account for the vast majority of the interaction energy. This explains the very broad sequence specificity with respect to other sidechain residues. Finally, we considered the key role of bridging water molecules at the binding interface. We employed inhomogeneous fluid solvation theory to consider the free energy of water molecules on the protein surface with respect to bulk water molecules. Such an analysis highlights binding hotspots created by elimination of water molecules from hydrophobic surfaces. It also predicts that a number of water molecules are stabilized by the presence of the charged phosphate group, and that this will have a significant effect on the binding affinity. Our findings suggest a molecular rationale for the promiscuous binding of the PBD and highlight a role for bridging water molecules at the interface. We expect that this method of analysis will be very useful for probing other protein surfaces to identify binding hotspots for natural binding partners and small molecule inhibitors.'),
(84723, 2010, 'plos', 'Correlation of influenza virus excess mortality with antigenic variation: application to rapid estimation of influenza mortality burden', 'Wu, Aiping|Peng, Yousong|Du, Xiangjun|Shu, Yuelong|Jiang, Taijiao', 'National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.', 'China|China|China|China|China', 14, 'Antigenic Variation|Antigens, Viral|Host-Pathogen Interactions|Humans|Influenza A Virus, H1N1 Subtype|Influenza Vaccines|Influenza, Human|Orthomyxoviridae|Population Surveillance', 'Journal Article', '10.1371/journal.pcbi.1000882', '20711361', 'The variants of human influenza virus have caused, and continue to cause, substantial morbidity and mortality. Timely and accurate assessment of their impact on human death is invaluable for influenza planning but presents a substantial challenge, as current approaches rely mostly on intensive and unbiased influenza surveillance. In this study, by proposing a novel host-virus interaction model, we have established a positive correlation between the excess mortalities caused by viral strains of distinct antigenicity and their antigenic distances to their previous strains for each (sub)type of seasonal influenza viruses. Based on this relationship, we further develop a method to rapidly assess the mortality burden of influenza A(H1N1) virus by accurately predicting the antigenic distance between A(H1N1) strains. Rapid estimation of influenza mortality burden for new seasonal strains should help formulate a cost-effective response for influenza control and prevention.'),
(84724, 2010, 'plos', 'CodonTest: modeling amino acid substitution preferences in coding sequences', 'Delport, Wayne|Scheffler, Konrad|Botha, Gordon|Gravenor, Mike B|Muse, Spencer V|Kosakovsky Pond, Sergei L', 'Department of Pathology, University of California, San Diego, La Jolla, California, United States of America.|Department of Pathology, University of California, San Diego, La Jolla, California, United States of America.|Department of Pathology, University of California, San Diego, La Jolla, California, United States of America.|Department of Pathology, University of California, San Diego, La Jolla, California, United States of America.|Department of Pathology, University of California, San Diego, La Jolla, California, United States of America.|Department of Pathology, University of California, San Diego, La Jolla, California, United States of America.', 'United States|United States|United States|United States|United States|United States', 53, 'Algorithms|Amino Acid Substitution|Codon|Computer Simulation|DNA-Directed DNA Polymerase|Evolution, Molecular|HIV-1|Hemagglutinins|Humans|Markov Chains|Models, Genetic|Sequence Alignment', 'Journal Article', '10.1371/journal.pcbi.1000885', '20808876', 'Codon models of evolution have facilitated the interpretation of selective forces operating on genomes. These models, however, assume a single rate of non-synonymous substitution irrespective of the nature of amino acids being exchanged. Recent developments have shown that models which allow for amino acid pairs to have independent rates of substitution offer improved fit over single rate models. However, these approaches have been limited by the necessity for large alignments in their estimation. An alternative approach is to assume that substitution rates between amino acid pairs can be subdivided into rate classes, dependent on the information content of the alignment. However, given the combinatorially large number of such models, an efficient model search strategy is needed. Here we develop a Genetic Algorithm (GA) method for the estimation of such models. A GA is used to assign amino acid substitution pairs to a series of rate classes, where is estimated from the alignment. Other parameters of the phylogenetic Markov model, including substitution rates, character frequencies and branch lengths are estimated using standard maximum likelihood optimization procedures. We apply the GA to empirical alignments and show improved model fit over existing models of codon evolution. Our results suggest that current models are poor approximations of protein evolution and thus gene and organism specific multi-rate models that incorporate amino acid substitution biases are preferred. We further anticipate that the clustering of amino acid substitution rates into classes will be biologically informative, such that genes with similar functions exhibit similar clustering, and hence this clustering will be useful for the evolutionary fingerprinting of genes.'),
(84725, 2010, 'plos', 'Spike-timing theory of working memory', 'Szatmáry, Botond|Izhikevich, Eugene M', 'The Neurosciences Institute, San Diego, California, United States of America.|The Neurosciences Institute, San Diego, California, United States of America.', 'United States|United States', 87, 'Animals|Brain|Computer Simulation|Memory, Long-Term|Memory, Short-Term|Models, Neurological|Nerve Net|Neuronal Plasticity|Neurons|Synapses|Synaptic Transmission|Time Perception', 'Journal Article', '10.1371/journal.pcbi.1000879', '20808877', 'Working memory (WM) is the part of the brains memory system that provides temporary storage and manipulation of information necessary for cognition. Although WM has limited capacity at any given time, it has vast memory content in the sense that it acts on the brains nearly infinite repertoire of lifetime long-term memories. Using simulations, we show that large memory content and WM functionality emerge spontaneously if we take the spike-timing nature of neuronal processing into account. Here, memories are represented by extensively overlapping groups of neurons that exhibit stereotypical time-locked spatiotemporal spike-timing patterns, called polychronous patterns, and synapses forming such polychronous neuronal groups (PNGs) are subject to associative synaptic plasticity in the form of both long-term and short-term spike-timing dependent plasticity. While long-term potentiation is essential in PNG formation, we show how short-term plasticity can temporarily strengthen the synapses of selected PNGs and lead to an increase in the spontaneous reactivation rate of these PNGs. This increased reactivation rate, consistent with in vivo recordings during WM tasks, results in high interspike interval variability and irregular, yet systematically changing, elevated firing rate profiles within the neurons of the selected PNGs. Additionally, our theory explains the relationship between such slowly changing firing rates and precisely timed spikes, and it reveals a novel relationship between WM and the perception of time on the order of seconds.'),
(84726, 2010, 'plos', 'Mathematical description of bacterial traveling pulses', 'Saragosti, Jonathan|Calvez, Vincent|Bournaveas, Nikolaos|Buguin, Axel|Silberzan, Pascal|Perthame, Benoît', 'Physico-Chimie-Curie, Institut Curie, UMR CNRS 168, Paris, France. jonathan.saragosti@curie.fr|Physico-Chimie-Curie, Institut Curie, UMR CNRS 168, Paris, France. jonathan.saragosti@curie.fr|Physico-Chimie-Curie, Institut Curie, UMR CNRS 168, Paris, France. jonathan.saragosti@curie.fr|Physico-Chimie-Curie, Institut Curie, UMR CNRS 168, Paris, France. jonathan.saragosti@curie.fr|Physico-Chimie-Curie, Institut Curie, UMR CNRS 168, Paris, France. jonathan.saragosti@curie.fr|Physico-Chimie-Curie, Institut Curie, UMR CNRS 168, Paris, France. jonathan.saragosti@curie.fr', 'France|France|France|France|France|France', 58, 'Chemotaxis|Computer Simulation|Escherichia coli|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1000890', '20808878', 'The Keller-Segel system has been widely proposed as a model for bacterial waves driven by chemotactic processes. Current experiments on Escherichia coli have shown the precise structure of traveling pulses. We present here an alternative mathematical description of traveling pulses at the macroscopic scale. This modeling task is complemented with numerical simulations in accordance with the experimental observations. Our model is derived from an accurate kinetic description of the mesoscopic run-and-tumble process performed by bacteria. This can account for recent experimental observations with E. coli. Qualitative agreements include the asymmetry of the pulse and transition in the collective behaviour (clustered motion versus dispersion). In addition, we can capture quantitatively the traveling speed of the pulse as well as its characteristic length. This work opens several experimental and theoretical perspectives since coefficients at the macroscopic level are derived from considerations at the cellular scale. For instance, the particular response of a single cell to chemical cues turns out to have a strong effect on collective motion. Furthermore, the bottom-up scaling allows us to perform preliminary mathematical analysis and write efficient numerical schemes. This model is intended as a predictive tool for the investigation of bacterial collective motion.'),
(84727, 2010, 'plos', 'Use of data-biased random walks on graphs for the retrieval of context-specific networks from genomic data', 'Komurov, Kakajan|White, Michael A|Ram, Prahlad T', 'Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America. kkomurov@mdanderson.org|Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America. kkomurov@mdanderson.org|Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America. kkomurov@mdanderson.org', 'United States|United States|United States', 70, 'Algorithms|Apoptosis|Breast Neoplasms|Cell Cycle|Cell Line, Tumor|Computational Biology|Doxorubicin|Female|Gene Expression Profiling|Gene Regulatory Networks|Genes, p53|Genomics|Humans|Models, Biological|Oligonucleotide Array Sequence Analysis|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1000889', '20808879', 'Extracting network-based functional relationships within genomic datasets is an important challenge in the computational analysis of large-scale data. Although many methods, both public and commercial, have been developed, the problem of identifying networks of interactions that are most relevant to the given input data still remains an open issue. Here, we have leveraged the method of random walks on graphs as a powerful platform for scoring network components based on simultaneous assessment of the experimental data as well as local network connectivity. Using this method, NetWalk, we can calculate distribution of Edge Flux values associated with each interaction in the network, which reflects the relevance of interactions based on the experimental data. We show that network-based analyses of genomic data are simpler and more accurate using NetWalk than with some of the currently employed methods. We also present NetWalk analysis of microarray gene expression data from MCF7 cells exposed to different doses of doxorubicin, which reveals a switch-like pattern in the p53 regulated network in cell cycle arrest and apoptosis. Our analyses demonstrate the use of NetWalk as a valuable tool in generating high-confidence hypotheses from high-content genomic data.'),
(84728, 2010, 'plos', 'Reduction in learning rates associated with anterograde interference results from interactions between different timescales in motor adaptation', 'Sing, Gary C|Smith, Maurice A', 'School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.|School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.', 'United States|United States', 52, 'Adaptation, Physiological|Arm|Humans|Learning Curve|Memory|Models, Biological|Motor Skills|Movement|Psychomotor Performance', 'Journal Article', '10.1371/journal.pcbi.1000893', '20808880', 'Prior experiences can influence future actions. These experiences can not only drive adaptive changes in motor output, but they can also modulate the rate at which these adaptive changes occur. Here we studied anterograde interference in motor adaptation--the ability of a previously learned motor task (Task A) to reduce the rate of subsequently learning a different (and usually opposite) motor task (Task B). We examined the formation of the motor systems capacity for anterograde interference in the adaptive control of human reaching-arm movements by determining the amount of interference after varying durations of exposure to Task A (13, 41, 112, 230, and 369 trials). We found that the amount of anterograde interference observed in the learning of Task B increased with the duration of Task A. However, this increase did not continue indefinitely, instead, the interference reached asymptote after 15-40 trials of Task A. Interestingly, we found that a recently proposed multi-rate model of motor adaptation, composed of two distinct but interacting adaptive processes, predicts several key features of the interference patterns we observed. Specifically, this computational model (without any free parameters) predicts the initial growth and leveling off of anterograde interference that we describe, as well as the asymptotic amount of interference that we observe experimentally (R(2) = 0.91). Understanding the mechanisms underlying anterograde interference in motor adaptation may enable the development of improved training and rehabilitation paradigms that mitigate unwanted interference.'),
(84729, 2010, 'plos', 'Quantitative test of the barrier nucleosome model for statistical positioning of nucleosomes up- and downstream of transcription start sites', 'Möbius, Wolfram|Gerland, Ulrich', 'Arnold Sommerfeld Center for Theoretical Physics and Center for NanoScience, Ludwig-Maximilians Universität München, Munich, Germany.|Arnold Sommerfeld Center for Theoretical Physics and Center for NanoScience, Ludwig-Maximilians Universität München, Munich, Germany.', 'Germany|Germany', 51, 'Base Sequence|Genome, Fungal|Insulator Elements|Models, Biological|Models, Statistical|Nucleosomes|Saccharomyces cerevisiae|Transcription Factors|Transcription Initiation Site|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000891', '20808881', 'The positions of nucleosomes in eukaryotic genomes determine which parts of the DNA sequence are readily accessible for regulatory proteins and which are not. Genome-wide maps of nucleosome positions have revealed a salient pattern around transcription start sites, involving a nucleosome-free region (NFR) flanked by a pronounced periodic pattern in the average nucleosome density. While the periodic pattern clearly reflects well-positioned nucleosomes, the positioning mechanism is less clear. A recent experimental study by Mavrich et al. argued that the pattern observed in Saccharomyces cerevisiae is qualitatively consistent with a barrier nucleosome model, in which the oscillatory pattern is created by the statistical positioning mechanism of Kornberg and Stryer. On the other hand, there is clear evidence for intrinsic sequence preferences of nucleosomes, and it is unclear to what extent these sequence preferences affect the observed pattern. To test the barrier nucleosome model, we quantitatively analyze yeast nucleosome positioning data both up- and downstream from NFRs. Our analysis is based on the Tonks model of statistical physics which quantifies the interplay between the excluded-volume interaction of nucleosomes and their positional entropy. We find that although the typical patterns on the two sides of the NFR are different, they are both quantitatively described by the same physical model with the same parameters, but different boundary conditions. The inferred boundary conditions suggest that the first nucleosome downstream from the NFR (the +1 nucleosome) is typically directly positioned while the first nucleosome upstream is statistically positioned via a nucleosome-repelling DNA region. These boundary conditions, which can be locally encoded into the genome sequence, significantly shape the statistical distribution of nucleosomes over a range of up to approximately 1,000 bp to each side.'),
(84730, 2010, 'plos', 'A cervid vocal fold model suggests greater glottal efficiency in calling at high frequencies', 'Titze, Ingo R|Riede, Tobias', 'National Center for Voice and Speech, University of Utah, Salt Lake City, Utah, United States of America.|National Center for Voice and Speech, University of Utah, Salt Lake City, Utah, United States of America.', 'United States|United States', 33, 'Animals|Computer Simulation|Deer|Female|Finite Element Analysis|Male|Models, Biological|Vocal Cords|Vocalization, Animal', 'Journal Article', '10.1371/journal.pcbi.1000897', '20808882', 'Male Rocky Mountain elk (Cervus elaphus nelsoni) produce loud and high fundamental frequency bugles during the mating season, in contrast to the male European Red Deer (Cervus elaphus scoticus) who produces loud and low fundamental frequency roaring calls. A critical step in understanding vocal communication is to relate sound complexity to anatomy and physiology in a causal manner. Experimentation at the sound source, often difficult in vivo in mammals, is simulated here by a finite element model of the larynx and a wave propagation model of the vocal tract, both based on the morphology and biomechanics of the elk. The model can produce a wide range of fundamental frequencies. Low fundamental frequencies require low vocal fold strain, but large lung pressure and large glottal flow if sound intensity level is to exceed 70 dB at 10 m distance. A high-frequency bugle requires both large muscular effort (to strain the vocal ligament) and high lung pressure (to overcome phonation threshold pressure), but at least 10 dB more intensity level can be achieved. Glottal efficiency, the ration of radiated sound power to aerodynamic power at the glottis, is higher in elk, suggesting an advantage of high-pitched signaling. This advantage is based on two aspects, first, the lower airflow required for aerodynamic power and, second, an acoustic radiation advantage at higher frequencies. Both signal types are used by the respective males during the mating season and probably serve as honest signals. The two signal types relate differently to physical qualities of the sender. The low-frequency sound (Red Deer call) relates to overall body size via a strong relationship between acoustic parameters and the size of vocal organs and body size. The high-frequency bugle may signal muscular strength and endurance, via a vocalizing at the edge mechanism, for which efficiency is critical.'),
(84731, 2010, 'plos', 'Reinforcement learning on slow features of high-dimensional input streams', 'Legenstein, Robert|Wilbert, Niko|Wiskott, Laurenz', 'Institute for Theoretical Computer Science, Graz University of Technology, Graz, Austria. legi@igi.tugraz.at|Institute for Theoretical Computer Science, Graz University of Technology, Graz, Austria. legi@igi.tugraz.at|Institute for Theoretical Computer Science, Graz University of Technology, Graz, Austria. legi@igi.tugraz.at', 'Austria|Austria|Austria', 46, 'Algorithms|Animals|Brain|Computer Simulation|Humans|Learning|Models, Biological|Neural Networks (Computer)|Psychomotor Performance|Rats|Reinforcement (Psychology)|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1000894', '20808883', 'Humans and animals are able to learn complex behaviors based on a massive stream of sensory information from different modalities. Early animal studies have identified learning mechanisms that are based on reward and punishment such that animals tend to avoid actions that lead to punishment whereas rewarded actions are reinforced. However, most algorithms for reward-based learning are only applicable if the dimensionality of the state-space is sufficiently small or its structure is sufficiently simple. Therefore, the question arises how the problem of learning on high-dimensional data is solved in the brain. In this article, we propose a biologically plausible generic two-stage learning system that can directly be applied to raw high-dimensional input streams. The system is composed of a hierarchical slow feature analysis (SFA) network for preprocessing and a simple neural network on top that is trained based on rewards. We demonstrate by computer simulations that this generic architecture is able to learn quite demanding reinforcement learning tasks on high-dimensional visual input streams in a time that is comparable to the time needed when an explicit highly informative low-dimensional state-space representation is given instead of the high-dimensional visual input. The learning speed of the proposed architecture in a task similar to the Morris water maze task is comparable to that found in experimental studies with rats. This study thus supports the hypothesis that slowness learning is one important unsupervised learning principle utilized in the brain to form efficient state representations for behavioral learning.'),
(84732, 2010, 'plos', 'Adaptive contact networks change effective disease infectiousness and dynamics', 'Van Segbroeck, Sven|Santos, Francisco C|Pacheco, Jorge M', 'COMO, Vrije Universiteit Brussel, Brussels, Belgium.|COMO, Vrije Universiteit Brussel, Brussels, Belgium.|COMO, Vrije Universiteit Brussel, Brussels, Belgium.', 'Belgium|Belgium|Belgium', 0, 'Communicable Diseases|Computer Simulation|Disease Outbreaks|Humans|Models, Biological|Numerical Analysis, Computer-Assisted|Population Density|Social Support', 'Journal Article', '10.1371/journal.pcbi.1000895', '20808884', 'Human societies are organized in complex webs that are constantly reshaped by a social dynamic which is influenced by the information individuals have about others. Similarly, epidemic spreading may be affected by local information that makes individuals aware of the health status of their social contacts, allowing them to avoid contact with those infected and to remain in touch with the healthy. Here we study disease dynamics in finite populations in which infection occurs along the links of a dynamical contact network whose reshaping may be biased based on each individuals health status. We adopt some of the most widely used epidemiological models, investigating the impact of the reshaping of the contact network on the disease dynamics. We derive analytical results in the limit where network reshaping occurs much faster than disease spreading and demonstrate numerically that this limit extends to a much wider range of time scales than one might anticipate. Specifically, we show that from a population-level description, disease propagation in a quickly adapting network can be formulated equivalently as disease spreading on a well-mixed population but with a rescaled infectiousness. We find that for all models studied here--SI, SIS and SIR--the effective infectiousness of a disease depends on the population size, the number of infected in the population, and the capacity of healthy individuals to sever contacts with the infected. Importantly, we indicate how the use of available information hinders disease progression, either by reducing the average time required to eradicate a disease (in case recovery is possible), or by increasing the average time needed for a disease to spread to the entire population (in case recovery or immunity is impossible).'),
(84733, 2010, 'plos', 'Modeling chemotaxis reveals the role of reversed phosphotransfer and a bi-functional kinase-phosphatase', 'Tindall, Marcus J|Porter, Steven L|Maini, Philip K|Armitage, Judith P', 'Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, United Kingdom. m.tindall@reading.ac.uk|Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, United Kingdom. m.tindall@reading.ac.uk|Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, United Kingdom. m.tindall@reading.ac.uk|Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, United Kingdom. m.tindall@reading.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Bacterial Proteins|Chemotaxis|Flagella|Histidine Kinase|Membrane Proteins|Models, Biological|Phosphoric Monoester Hydrolases|Phosphorylation|Protein Kinases|Rhodobacter sphaeroides|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000896', '20808885', 'Understanding how multiple signals are integrated in living cells to produce a balanced response is a major challenge in biology. Two-component signal transduction pathways, such as bacterial chemotaxis, comprise histidine protein kinases (HPKs) and response regulators (RRs). These are used to sense and respond to changes in the environment. Rhodobacter sphaeroides has a complex chemosensory network with two signaling clusters, each containing a HPK, CheA. Here we demonstrate, using a mathematical model, how the outputs of the two signaling clusters may be integrated. We use our mathematical model supported by experimental data to predict that: (1) the main RR controlling flagellar rotation, CheY(6), aided by its specific phosphatase, the bifunctional kinase CheA(3), acts as a phosphate sink for the other RRs, and (2) a phosphorelay pathway involving CheB(2) connects the cytoplasmic cluster kinase CheA(3) with the polar localised kinase CheA(2), and allows CheA(3)-P to phosphorylate non-cognate chemotaxis RRs. These two mechanisms enable the bifunctional kinase/phosphatase activity of CheA(3) to integrate and tune the sensory output of each signaling cluster to produce a balanced response. The signal integration mechanisms identified here may be widely used by other bacteria, since like R. sphaeroides, over 50% of chemotactic bacteria have multiple cheA homologues and need to integrate signals from different sources.'),
(84734, 2010, 'plos', 'Dendritic spikes amplify the synaptic signal to enhance detection of motion in a simulation of the direction-selective ganglion cell', 'Schachter, Michael J|Oesch, Nicholas|Smith, Robert G|Taylor, W Rowland', 'Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.', 'United States|United States|United States|United States', 0, 'Animals|Computer Simulation|Dendrites|Mice|Models, Neurological|Motion Perception|NAV1.6 Voltage-Gated Sodium Channel|Nerve Tissue Proteins|Rabbits|Retina|Retinal Ganglion Cells|Sodium Channels|Synaptic Potentials', 'Journal Article', '10.1371/journal.pcbi.1000899', '20808894', 'The On-Off direction-selective ganglion cell (DSGC) in mammalian retinas responds most strongly to a stimulus moving in a specific direction. The DSGC initiates spikes in its dendritic tree, which are thought to propagate to the soma with high probability. Both dendritic and somatic spikes in the DSGC display strong directional tuning, whereas somatic PSPs (postsynaptic potentials) are only weakly directional, indicating that spike generation includes marked enhancement of the directional signal. We used a realistic computational model based on anatomical and physiological measurements to determine the source of the enhancement. Our results indicate that the DSGC dendritic tree is partitioned into separate electrotonic regions, each summing its local excitatory and inhibitory synaptic inputs to initiate spikes. Within each local region the local spike threshold nonlinearly amplifies the preferred response over the null response on the basis of PSP amplitude. Using inhibitory conductances previously measured in DSGCs, the simulation results showed that inhibition is only sufficient to prevent spike initiation and cannot affect spike propagation. Therefore, inhibition will only act locally within the dendritic arbor. We identified the role of three mechanisms that generate directional selectivity (DS) in the local dendritic regions. First, a mechanism for DS intrinsic to the dendritic structure of the DSGC enhances DS on the null side of the cells dendritic tree and weakens it on the preferred side. Second, spatially offset postsynaptic inhibition generates robust DS in the isolated dendritic tips but weak DS near the soma. Third, presynaptic DS is apparently necessary because it is more robust across the dendritic tree. The pre- and postsynaptic mechanisms together can overcome the local intrinsic DS. These local dendritic mechanisms can perform independent nonlinear computations to make a decision, and there could be analogous mechanisms within cortical circuitry.'),
(84735, 2010, 'plos', 'Characterizing the metabolism of Dehalococcoides with a constraint-based model', 'Ahsanul Islam, M|Edwards, Elizabeth A|Mahadevan, Radhakrishnan', 'Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.|Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.|Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.', 'Canada|Canada|Canada', 40, 'Biological Evolution|Chloroflexi|Genome, Bacterial|Metabolic Networks and Pathways|Models, Biological|Molecular Sequence Data', 'Journal Article', '10.1371/journal.pcbi.1000887', '20811585', 'Dehalococcoides strains respire a wide variety of chloro-organic compounds and are important for the bioremediation of toxic, persistent, carcinogenic, and ubiquitous ground water pollutants. In order to better understand metabolism and optimize their application, we have developed a pan-genome-scale metabolic network and constraint-based metabolic model of Dehalococcoides. The pan-genome was constructed from publicly available complete genome sequences of Dehalococcoides sp. strain CBDB1, strain 195, strain BAV1, and strain VS. We found that Dehalococcoides pan-genome consisted of 1118 core genes (shared by all), 457 dispensable genes (shared by some), and 486 unique genes (found in only one genome). The model included 549 metabolic genes that encoded 356 proteins catalyzing 497 gene-associated model reactions. Of these 497 reactions, 477 were associated with core metabolic genes, 18 with dispensable genes, and 2 with unique genes. This study, in addition to analyzing the metabolism of an environmentally important phylogenetic group on a pan-genome scale, provides valuable insights into Dehalococcoides metabolic limitations, low growth yields, and energy conservation. The model also provides a framework to anchor and compare disparate experimental data, as well as to give insights on the physiological impact of incomplete pathways, such as the TCA-cycle, CO(2) fixation, and cobalamin biosynthesis pathways. The model, referred to as iAI549, highlights the specialized and highly conserved nature of Dehalococcoides metabolism, and suggests that evolution of Dehalococcoides species is driven by the electron acceptor availability.'),
(84736, 2010, 'plos', 'VASP: a volumetric analysis of surface properties yields insights into protein-ligand binding specificity', 'Chen, Brian Y|Honig, Barry', 'Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Columbia University, New York, New York, United States of America.|Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Columbia University, New York, New York, United States of America.', 'United States|United States', 0, 'Algorithms|Amino Acid Motifs|Amino Acids|Binding Sites|Humans|Ligands|Models, Molecular|Phosphoproteins|Protein Binding|Protein Interaction Domains and Motifs|Serine Proteases|Substrate Specificity|Surface Properties', 'Journal Article', '10.1371/journal.pcbi.1000881', '20814581', 'Many algorithms that compare protein structures can reveal similarities that suggest related biological functions, even at great evolutionary distances. Proteins with related function often exhibit differences in binding specificity, but few algorithms identify structural variations that effect specificity. To address this problem, we describe the Volumetric Analysis of Surface Properties (VASP), a novel volumetric analysis tool for the comparison of binding sites in aligned protein structures. VASP uses solid volumes to represent protein shape and the shape of surface cavities, clefts and tunnels that are defined with other methods. Our approach, inspired by techniques from constructive solid geometry, enables the isolation of volumetrically conserved and variable regions within three dimensionally superposed volumes. We applied VASP to compute a comparative volumetric analysis of the ligand binding sites formed by members of the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domains and the serine proteases. Within both families, VASP isolated individual amino acids that create structural differences between ligand binding cavities that are known to influence differences in binding specificity. Also, VASP isolated cavity subregions that differ between ligand binding cavities which are essential for differences in binding specificity. As such, VASP should prove a valuable tool in the study of protein-ligand binding specificity.'),
(84737, 2010, 'plos', 'Forcing versus feedback: epidemic malaria and monsoon rains in northwest India', 'Laneri, Karina|Bhadra, Anindya|Ionides, Edward L|Bouma, Menno|Dhiman, Ramesh C|Yadav, Rajpal S|Pascual, Mercedes', 'Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, USA.|Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, USA.|Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, USA.|Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, USA.|Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, USA.|Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, USA.|Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, USA.', 'United States|United States|United States|United States|United States|United States|United States', 0, 'Animals|Computer Simulation|Culicidae|Databases, Factual|Epidemics|Feedback, Physiological|Host-Parasite Interactions|Humans|India|Insect Vectors|Malaria, Falciparum|Models, Biological|Models, Statistical|Plasmodium falciparum|Rain|Seasons|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000898', '20824122', 'Malaria epidemics in regions with seasonal windows of transmission can vary greatly in size from year to year. A central question has been whether these interannual cycles are driven by climate, are instead generated by the intrinsic dynamics of the disease, or result from the resonance of these two mechanisms. This corresponds to the more general inverse problem of identifying the respective roles of external forcings vs. internal feedbacks from time series for nonlinear and noisy systems. We propose here a quantitative approach to formally compare rival hypotheses on climate vs. disease dynamics, or external forcings vs. internal feedbacks, that combines dynamical models with recently developed, computational inference methods. The interannual patterns of epidemic malaria are investigated here for desert regions of northwest India, with extensive epidemiological records for Plasmodium falciparum malaria for the past two decades. We formulate a dynamical model of malaria transmission that explicitly incorporates rainfall, and we rely on recent advances on parameter estimation for nonlinear and stochastic dynamical systems based on sequential Monte Carlo methods. Results show a significant effect of rainfall in the inter-annual variability of epidemic malaria that involves a threshold in the disease response. The model exhibits high prediction skill for yearly cases in the malaria transmission season following the monsoonal rains. Consideration of a more complex model with clinical immunity demonstrates the robustness of the findings and suggests a role of infected individuals that lack clinical symptoms as a reservoir for transmission. Our results indicate that the nonlinear dynamics of the disease itself play a role at the seasonal, but not the interannual, time scales. They illustrate the feasibility of forecasting malaria epidemics in desert and semi-arid regions of India based on climate variability. This approach should be applicable to malaria in other locations, to other infectious diseases, and to other nonlinear systems under forcing.'),
(84738, 2010, 'plos', 'Regression analysis for constraining free parameters in electrophysiological models of cardiac cells', 'Sarkar, Amrita X|Sobie, Eric A', 'Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York, USA.|Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York, USA.', 'United States|United States', 0, 'Action Potentials|Animals|Bayes Theorem|Cardiac Electrophysiology|Computational Biology|Computer Simulation|Dogs|Heart Failure|Heart Ventricles|Humans|Models, Cardiovascular|Multivariate Analysis|Myocytes, Cardiac|Regression Analysis', 'Journal Article', '10.1371/journal.pcbi.1000914', '20824123', 'A major challenge in computational biology is constraining free parameters in mathematical models. Adjusting a parameter to make a given model output more realistic sometimes has unexpected and undesirable effects on other model behaviors. Here, we extend a regression-based method for parameter sensitivity analysis and show that a straightforward procedure can uniquely define most ionic conductances in a well-known model of the human ventricular myocyte. The models parameter sensitivity was analyzed by randomizing ionic conductances, running repeated simulations to measure physiological outputs, then collecting the randomized parameters and simulation results as input and output matrices, respectively. Multivariable regression derived a matrix whose elements indicate how changes in conductances influence model outputs. We show here that if the number of linearly-independent outputs equals the number of inputs, the regression matrix can be inverted. This is significant, because it implies that the inverted matrix can specify the ionic conductances that are required to generate a particular combination of model outputs. Applying this idea to the myocyte model tested, we found that most ionic conductances could be specified with precision (R(2) > 0.77 for 12 out of 16 parameters). We also applied this method to a test case of changes in electrophysiology caused by heart failure and found that changes in most parameters could be well predicted. We complemented our findings using a Bayesian approach to demonstrate that model parameters cannot be specified using limited outputs, but they can be successfully constrained if multiple outputs are considered. Our results place on a solid mathematical footing the intuition-based procedure simultaneously matching a models output to several data sets. More generally, this method shows promise as a tool to define model parameters, in electrophysiology and in other biological fields.'),
(84739, 2010, 'plos', 'Diversity and plasticity of Th cell types predicted from regulatory network modelling', 'Naldi, Aurélien|Carneiro, Jorge|Chaouiya, Claudine|Thieffry, Denis', 'Technological Advances for Genomics and Clinics, INSERM U928, Marseille, France.|Technological Advances for Genomics and Clinics, INSERM U928, Marseille, France.|Technological Advances for Genomics and Clinics, INSERM U928, Marseille, France.|Technological Advances for Genomics and Clinics, INSERM U928, Marseille, France.', 'France|France|France|France', 0, 'Animals|Cell Differentiation|Humans|Interleukins|Lymphocyte Activation|Mice|Models, Immunological|Signal Transduction|Systems Biology|T-Lymphocytes, Helper-Inducer|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000912', '20824124', 'Alternative cell differentiation pathways are believed to arise from the concerted action of signalling pathways and transcriptional regulatory networks. However, the prediction of mammalian cell differentiation from the knowledge of the presence of specific signals and transcriptional factors is still a daunting challenge. In this respect, the vertebrate hematopoietic system, with its many branching differentiation pathways and cell types, is a compelling case study. In this paper, we propose an integrated, comprehensive model of the regulatory network and signalling pathways controlling Th cell differentiation. As most available data are qualitative, we rely on a logical formalism to perform extensive dynamical analyses. To cope with the size and complexity of the resulting network, we use an original model reduction approach together with a stable state identification algorithm. To assess the effects of heterogeneous environments on Th cell differentiation, we have performed a systematic series of simulations considering various prototypic environments. Consequently, we have identified stable states corresponding to canonical Th1, Th2, Th17 and Treg subtypes, but these were found to coexist with other transient hybrid cell types that co-express combinations of Th1, Th2, Treg and Th17 markers in an environment-dependent fashion. In the process, our logical analysis highlights the nature of these cell types and their relationships with canonical Th subtypes. Finally, our logical model can be used to explore novel differentiation pathways in silico.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84740, 2010, 'plos', 'Occurrence and treatment of bone atrophic non-unions investigated by an integrative approach', 'Geris, Liesbet|Reed, Anita A C|Vander Sloten, Jos|Simpson, A Hamish R W|Van Oosterwyck, Hans', 'Division of Biomechanics and Engineering Design, Department of Mechanical Engineering, Katholieke Universiteit Leuven, Leuven, Belgium. liesbet.geris@mech.kuleuven.be|Division of Biomechanics and Engineering Design, Department of Mechanical Engineering, Katholieke Universiteit Leuven, Leuven, Belgium. liesbet.geris@mech.kuleuven.be|Division of Biomechanics and Engineering Design, Department of Mechanical Engineering, Katholieke Universiteit Leuven, Leuven, Belgium. liesbet.geris@mech.kuleuven.be|Division of Biomechanics and Engineering Design, Department of Mechanical Engineering, Katholieke Universiteit Leuven, Leuven, Belgium. liesbet.geris@mech.kuleuven.be|Division of Biomechanics and Engineering Design, Department of Mechanical Engineering, Katholieke Universiteit Leuven, Leuven, Belgium. liesbet.geris@mech.kuleuven.be', 'Belgium|Belgium|Belgium|Belgium|Belgium', 37, 'Animals|Bone Marrow Cells|Bone Regeneration|Bone and Bones|Cell Movement|Cell Proliferation|Cell Transplantation|Chondrogenesis|Computer Simulation|Disease Models, Animal|Fractures, Bone|Histocytochemistry|Intercellular Signaling Peptides and Proteins|Models, Biological|Neovascularization, Physiologic|Proliferating Cell Nuclear Antigen|Rats|Rats, Inbred WKY|Statistics, Nonparametric|Wound Healing', 'Journal Article', '10.1371/journal.pcbi.1000915', '20824125', 'Recently developed atrophic non-union models are a good representation of the clinical situation in which many non-unions develop. Based on previous experimental studies with these atrophic non-union models, it was hypothesized that in order to obtain successful fracture healing, blood vessels, growth factors, and (proliferative) precursor cells all need to be present in the callus at the same time. This study uses a combined in vivo-in silico approach to investigate these different aspects (vasculature, growth factors, cell proliferation). The mathematical model, initially developed for the study of normal fracture healing, is able to capture essential aspects of the in vivo atrophic non-union model despite a number of deviations that are mainly due to simplifications in the in silico model. The mathematical model is subsequently used to test possible treatment strategies for atrophic non-unions (i.e. cell transplant at post-osteotomy, week 3). Preliminary in vivo experiments corroborate the numerical predictions. Finally, the mathematical model is applied to explain experimental observations and identify potentially crucial steps in the treatments and can thereby be used to optimize experimental and clinical studies in this area. This study demonstrates the potential of the combined in silico-in vivo approach and its clinical implications for the early treatment of patients with problematic fractures.'),
(84741, 2010, 'plos', 'Current estimates for HIV-1 production imply rapid viral clearance in lymphoid tissues', 'De Boer, Rob J|Ribeiro, Ruy M|Perelson, Alan S', 'Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, The Netherlands. r.j.deboer@uu.nl|Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, The Netherlands. r.j.deboer@uu.nl|Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, The Netherlands. r.j.deboer@uu.nl', 'Netherlands|Netherlands|Netherlands', 0, 'Animals|Blood Component Removal|Computer Simulation|Dendritic Cells, Follicular|Disease Models, Animal|HIV Infections|HIV-1|Humans|Lymphoid Tissue|Macaca mulatta|Models, Immunological|Plasma|RNA, Viral|Simian Acquired Immunodeficiency Syndrome|Simian Immunodeficiency Virus|Tissue Distribution|Virion', 'Journal Article', '10.1371/journal.pcbi.1000906', '20824126', 'It has recently been estimated that a single HIV-1 infected cell produces between and more than viral particles over its life span. Since body-wide estimates of the ratio of free virus to productively infected cells are smaller than and much smaller than , individual virions must be cleared rapidly. This seems difficult to reconcile with the fact that most of the total body virus is trapped on follicular dendritic cells where it can survive for many months. It has also been difficult to reconcile the vast difference in the rates at which the virus is cleared from the blood in rhesus macaques and in chronically infected patients. Here we attempt to reconcile these seemingly contradictory observations by considering the virion clearance rate in various organs and the virion exchange rates between them. The main results are that the per capita clearance rate of free virus in lymphoid tissue should be fast, the virion exchange rate between lymphoid tissue and the blood should be slow, and the comparatively slow previous estimates for the virion clearance rate from the blood correspond to the rate of virion efflux from the blood to other organs where the virus is ultimately cleared.'),
(84742, 2010, 'plos', 'Differences in nutrient requirements imply a non-linear emergence of leaders in animal groups', 'Sueur, Cédric|Deneubourg, Jean-Louis|Petit, Odile|Couzin, Iain D', 'Unit of Social Ecology, The Free University of Brussels, Brussels, Belgium. cedric.sueur@c-strasbourg.fr|Unit of Social Ecology, The Free University of Brussels, Brussels, Belgium. cedric.sueur@c-strasbourg.fr|Unit of Social Ecology, The Free University of Brussels, Brussels, Belgium. cedric.sueur@c-strasbourg.fr|Unit of Social Ecology, The Free University of Brussels, Brussels, Belgium. cedric.sueur@c-strasbourg.fr', 'Belgium|Belgium|Belgium|Belgium', 0, 'Algorithms|Animals|Behavior, Animal|Body Weight|Computational Biology|Computer Simulation|Female|Leadership|Macaca mulatta|Male|Nonlinear Dynamics|Nutritional Requirements|Social Dominance|Statistics, Nonparametric', 'Journal Article', '10.1371/journal.pcbi.1000917', '20824127', 'Collective decision making and especially leadership in groups are among the most studied topics in natural, social, and political sciences. Previous studies have shown that some individuals are more likely to be leaders because of their social power or the pertinent information they possess. One challenge for all group members, however, is to satisfy their needs. In many situations, we do not yet know how individuals within groups distribute leadership decisions between themselves in order to satisfy time-varying individual requirements. To gain insight into this problem, we build a dynamic model where group members have to satisfy different needs but are not aware of each others needs. Data about needs of animals come from real data observed in macaques. Several studies showed that a collective movement may be initiated by a single individual. This individual may be the dominant one, the oldest one, but also the one having the highest physiological needs. In our model, the individual with the lowest reserve initiates movements and decides for all its conspecifics. This simple rule leads to a viable decision-making system where all individuals may lead the group at one moment and thus suit their requirements. However, a single individual becomes the leader in 38% to 95% of cases and the leadership is unequally (according to an exponential law) distributed according to the heterogeneity of needs in the group. The results showed that this non-linearity emerges when one group member reaches physiological requirements, mainly the nutrient ones - protein, energy and water depending on weight - superior to those of its conspecifics. This amplification may explain why some leaders could appear in animal groups without any despotism, complex signalling, or developed cognitive ability.'),
(84743, 2010, 'plos', 'Latent factor analysis to discover pathway-associated putative segmental aneuploidies in human cancers', 'Lucas, Joseph E|Kung, Hsiu-Ni|Chi, Jen-Tsan A', 'Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, USA. joe@stat.duke.edu|Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, USA. joe@stat.duke.edu|Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, USA. joe@stat.duke.edu', 'United States|United States|United States', 26, 'Acidosis, Lactic|Aneuploidy|Breast Neoplasms|Cell Hypoxia|Cell Line, Tumor|Cluster Analysis|Comparative Genomic Hybridization|Computational Biology|DNA Copy Number Variations|Databases, Genetic|Female|Gene Dosage|Gene Expression Profiling|Gene Expression Regulation, Neoplastic|Humans|Models, Statistical|Organ Specificity|RNA, Messenger|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000920', '20824128', 'Tumor microenvironmental stresses, such as hypoxia and lactic acidosis, play important roles in tumor progression. Although gene signatures reflecting the influence of these stresses are powerful approaches to link expression with phenotypes, they do not fully reflect the complexity of human cancers. Here, we describe the use of latent factor models to further dissect the stress gene signatures in a breast cancer expression dataset. The genes in these latent factors are coordinately expressed in tumors and depict distinct, interacting components of the biological processes. The genes in several latent factors are highly enriched in chromosomal locations. When these factors are analyzed in independent datasets with gene expression and array CGH data, the expression values of these factors are highly correlated with copy number alterations (CNAs) of the corresponding BAC clones in both the cell lines and tumors. Therefore, variation in the expression of these pathway-associated factors is at least partially caused by variation in gene dosage and CNAs among breast cancers. We have also found the expression of two latent factors without any chromosomal enrichment is highly associated with 12q CNA, likely an instance of trans-variations in which CNA leads to the variations in gene expression outside of the CNA region. In addition, we have found that factor 26 (1q CNA) is negatively correlated with HIF-1alpha protein and hypoxia pathways in breast tumors and cell lines. This agrees with, and for the first time links, known good prognosis associated with both a low hypoxia signature and the presence of CNA in this region. Taken together, these results suggest the possibility that tumor segmental aneuploidy makes significant contributions to variation in the lactic acidosis/hypoxia gene signatures in human cancers and demonstrate that latent factor analysis is a powerful means to uncover such a linkage.'),
(84744, 2010, 'plos', 'Graph-based analysis of the metabolic exchanges between two co-resident intracellular symbionts, Baumannia cicadellinicola and Sulcia muelleri, with their insect host, Homalodisca coagulata', 'Cottret, Ludovic|Milreu, Paulo Vieira|Acuña, Vicente|Marchetti-Spaccamela, Alberto|Stougie, Leen|Charles, Hubert|Sagot, Marie-France', 'INRA, UMR1089 Xénobiotiques, Toulouse, France. Ludovic.Cottret@toulouse.inra.fr|INRA, UMR1089 Xénobiotiques, Toulouse, France. Ludovic.Cottret@toulouse.inra.fr|INRA, UMR1089 Xénobiotiques, Toulouse, France. Ludovic.Cottret@toulouse.inra.fr|INRA, UMR1089 Xénobiotiques, Toulouse, France. Ludovic.Cottret@toulouse.inra.fr|INRA, UMR1089 Xénobiotiques, Toulouse, France. Ludovic.Cottret@toulouse.inra.fr|INRA, UMR1089 Xénobiotiques, Toulouse, France. Ludovic.Cottret@toulouse.inra.fr|INRA, UMR1089 Xénobiotiques, Toulouse, France. Ludovic.Cottret@toulouse.inra.fr', 'France|France|France|France|France|France|France', 0, 'Animals|Bacteroidetes|Computational Biology|Gammaproteobacteria|Hemiptera|Host-Pathogen Interactions|Metabolic Networks and Pathways|Metabolome|Models, Biological|Symbiosis', 'Journal Article', '10.1371/journal.pcbi.1000904', '20838465', 'Endosymbiotic bacteria from different species can live inside cells of the same eukaryotic organism. Metabolic exchanges occur between host and bacteria but also between different endocytobionts. Since a complete genome annotation is available for both, we built the metabolic network of two endosymbiotic bacteria, Sulcia muelleri and Baumannia cicadellinicola, that live inside specific cells of the sharpshooter Homalodisca coagulata and studied the metabolic exchanges involving transfers of carbon atoms between the three. We automatically determined the set of metabolites potentially exogenously acquired (seeds) for both metabolic networks. We show that the number of seeds needed by both bacteria in the carbon metabolism is extremely reduced. Moreover, only three seeds are common to both metabolic networks, indicating that the complementarity of the two metabolisms is not only manifested in the metabolic capabilities of each bacterium, but also by their different use of the same environment. Furthermore, our results show that the carbon metabolism of S. muelleri may be completely independent of the metabolic network of B. cicadellinicola. On the contrary, the carbon metabolism of the latter appears dependent on the metabolism of S. muelleri, at least for two essential amino acids, threonine and lysine. Next, in order to define which subsets of seeds (precursor sets) are sufficient to produce the metabolites involved in a symbiotic function, we used a graph-based method, PITUFO, that we recently developed. Our results highly refine our knowledge about the complementarity between the metabolisms of the two bacteria and their host. We thus indicate seeds that appear obligatory in the synthesis of metabolites are involved in the symbiotic function. Our results suggest both B. cicadellinicola and S. muelleri may be completely independent of the metabolites provided by the co-resident endocytobiont to produce the carbon backbone of the metabolites provided to the symbiotic system (., thr and lys are only exploited by B. cicadellinicola to produce its proteins).'),
(84745, 2010, 'plos', 'Minimal mesoscale model for protein-mediated vesiculation in clathrin-dependent endocytosis', 'Agrawal, Neeraj J|Nukpezah, Jonathan|Radhakrishnan, Ravi', 'Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.', 'United States|United States|United States', 33, 'Adaptor Protein Complex 2|Adaptor Proteins, Vesicular Transport|Animals|Biomechanical Phenomena|Clathrin|Clathrin-Coated Vesicles|Computational Biology|Endocytosis|Eukaryotic Cells|Mammals|Models, Biological|Particle Size|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000926', '20838575', 'In eukaryotic cells, the internalization of extracellular cargo via the endocytic machinery is an important regulatory process required for many essential cellular functions. The role of cooperative protein-protein and protein-membrane interactions in the ubiquitous endocytic pathway in mammalian cells, namely the clathrin-dependent endocytosis, remains unresolved. We employ the Helfrich membrane Hamiltonian together with surface evolution methodology to address how the shapes and energetics of vesicular-bud formation in a planar membrane are stabilized by presence of the clathrin-coat assembly. Our results identify a unique dual role for the tubulating protein epsin: multiple epsins localized spatially and orientationally collectively play the role of a curvature inducing capsid, in addition, epsin serves the role of an adapter in binding the clathrin coat to the membrane. Our results also suggest an important role for the clathrin lattice, namely in the spatial- and orientational-templating of epsins. We suggest that there exists a critical size of the coat above which a vesicular bud with a constricted neck resembling a mature vesicle is stabilized. Based on the observed strong dependence of the vesicle diameter on the bending rigidity, we suggest that the variability in bending stiffness due to variations in membrane composition with cell type can explain the experimentally observed variability on the size of clathrin-coated vesicles, which typically range 50-100 nm. Our model also provides estimates for the number of epsins involved in stabilizing a coated vesicle, and without any direct fitting reproduces the experimentally observed shapes of vesicular intermediates as well as their probability distributions quantitatively, in wildtype as well as CLAP IgG injected neuronal cell experiments. We have presented a minimal mesoscale model which quantitatively explains several experimental observations on the process of vesicle nucleation induced by the clathrin-coated assembly prior to vesicle scission in clathrin dependent endocytosis.'),
(84746, 2010, 'plos', 'The distinct conformational dynamics of K-Ras and H-Ras A59G', 'Lukman, Suryani|Grant, Barry J|Gorfe, Alemayehu A|Grant, Guy H|McCammon, J Andrew', 'Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. sl471@cam.ac.uk|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. sl471@cam.ac.uk|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. sl471@cam.ac.uk|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. sl471@cam.ac.uk|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. sl471@cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 63, 'Amino Acid Sequence|Catalytic Domain|Crystallography|Guanosine Diphosphate|Guanosine Triphosphate|Humans|Molecular Dynamics Simulation|Molecular Sequence Data|Mutation|Principal Component Analysis|Protein Isoforms|Signal Transduction|ras Proteins', 'Journal Article', '10.1371/journal.pcbi.1000922', '20838576', 'Ras proteins regulate signaling cascades crucial for cell proliferation and differentiation by switching between GTP- and GDP-bound conformations. Distinct Ras isoforms have unique physiological functions with individual isoforms associated with different cancers and developmental diseases. Given the small structural differences among isoforms and mutants, it is currently unclear how these functional differences and aberrant properties arise. Here we investigate whether the subtle differences among isoforms and mutants are associated with detectable dynamical differences. Extensive molecular dynamics simulations reveal that wild-type K-Ras and mutant H-Ras A59G are intrinsically more dynamic than wild-type H-Ras. The crucial switch 1 and switch 2 regions along with loop 3, helix 3, and loop 7 contribute to this enhanced flexibility. Removing the gamma-phosphate of the bound GTP from the structure of A59G led to a spontaneous GTP-to-GDP conformational transition in a 20-ns unbiased simulation. The switch 1 and 2 regions exhibit enhanced flexibility and correlated motion when compared to non-transitioning wild-type H-Ras over a similar timeframe. Correlated motions between loop 3 and helix 5 of wild-type H-Ras are absent in the mutant A59G reflecting the enhanced dynamics of the loop 3 region. Taken together with earlier findings, these results suggest the existence of a lower energetic barrier between GTP and GDP states of the mutant. Molecular dynamics simulations combined with principal component analysis of available Ras crystallographic structures can be used to discriminate ligand- and sequence-based dynamic perturbations with potential functional implications. Furthermore, the identification of specific conformations associated with distinct Ras isoforms and mutants provides useful information for efforts that attempt to selectively interfere with the aberrant functions of these species.'),
(84747, 2010, 'plos', 'Rescuing loading induced bone formation at senescence', 'Srinivasan, Sundar|Ausk, Brandon J|Prasad, Jitendra|Threet, Dewayne|Bain, Steven D|Richardson, Thomas S|Gross, Ted S', 'Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America. sundars@u.washington.edu|Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America. sundars@u.washington.edu|Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America. sundars@u.washington.edu|Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America. sundars@u.washington.edu|Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America. sundars@u.washington.edu|Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America. sundars@u.washington.edu|Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America. sundars@u.washington.edu', 'United States|United States|United States|United States|United States|United States|United States', 0, 'Aging|Analysis of Variance|Animals|Biomechanical Phenomena|Bone and Bones|Calcium|Cellular Senescence|Computational Biology|Cyclosporine|Female|Mice|Mice, Inbred C57BL|Models, Biological|NFATC Transcription Factors|Osteocytes|Osteogenesis|Osteoporosis|Reproducibility of Results|Tibia|Weight-Bearing', 'Journal Article', '10.1371/journal.pcbi.1000924', '20838577', 'The increasing incidence of osteoporosis worldwide requires anabolic treatments that are safe, effective, and, critically, inexpensive given the prevailing overburdened health care systems. While vigorous skeletal loading is anabolic and holds promise, deficits in mechanotransduction accrued with age markedly diminish the efficacy of readily complied, exercise-based strategies to combat osteoporosis in the elderly. Our approach to explore and counteract these age-related deficits was guided by cellular signaling patterns across hierarchical scales and by the insight that cell responses initiated during transient, rare events hold potential to exert high-fidelity control over temporally and spatially distant tissue adaptation. Here, we present an agent-based model of real-time Ca(2+)/NFAT signaling amongst bone cells that fully described periosteal bone formation induced by a wide variety of loading stimuli in young and aged animals. The model predicted age-related pathway alterations underlying the diminished bone formation at senescence, and hence identified critical deficits that were promising targets for therapy. Based upon model predictions, we implemented an in vivo intervention and show for the first time that supplementing mechanical stimuli with low-dose Cyclosporin A can completely rescue loading induced bone formation in the senescent skeleton. These pre-clinical data provide the rationale to consider this approved pharmaceutical alongside mild physical exercise as an inexpensive, yet potent therapy to augment bone mass in the elderly. Our analyses suggested that real-time cellular signaling strongly influences downstream bone adaptation to mechanical stimuli, and quantification of these otherwise inaccessible, transient events in silico yielded a novel intervention with clinical potential.'),
(84748, 2010, 'plos', 'A dynamic neural field model of mesoscopic cortical activity captured with voltage-sensitive dye imaging', 'Markounikau, Valentin|Igel, Christian|Grinvald, Amiram|Jancke, Dirk', 'Institut für Neuroinformatik, Ruhr-Universität Bochum, Bochum, Germany. valiantsin.markounikau@ruhr-uni-bochum.de|Institut für Neuroinformatik, Ruhr-Universität Bochum, Bochum, Germany. valiantsin.markounikau@ruhr-uni-bochum.de|Institut für Neuroinformatik, Ruhr-Universität Bochum, Bochum, Germany. valiantsin.markounikau@ruhr-uni-bochum.de|Institut für Neuroinformatik, Ruhr-Universität Bochum, Bochum, Germany. valiantsin.markounikau@ruhr-uni-bochum.de', 'Germany|Germany|Germany|Germany', 29, 'Animals|Cats|Computational Biology|Evoked Potentials, Visual|Feedback, Physiological|Models, Neurological|Nonlinear Dynamics|Visual Cortex|Voltage-Sensitive Dye Imaging', 'Journal Article', '10.1371/journal.pcbi.1000919', '20838578', 'A neural field model is presented that captures the essential non-linear characteristics of activity dynamics across several millimeters of visual cortex in response to local flashed and moving stimuli. We account for physiological data obtained by voltage-sensitive dye (VSD) imaging which reports mesoscopic population activity at high spatio-temporal resolution. Stimulation included a single flashed square, a single flashed bar, the line-motion paradigm--for which psychophysical studies showed that flashing a square briefly before a bar produces sensation of illusory motion within the bar--and moving squares controls. We consider a two-layer neural field (NF) model describing an excitatory and an inhibitory layer of neurons as a coupled system of non-linear integro-differential equations. Under the assumption that the aggregated activity of both layers is reflected by VSD imaging, our phenomenological model quantitatively accounts for the observed spatio-temporal activity patterns. Moreover, the model generalizes to novel similar stimuli as it matches activity evoked by moving squares of different speeds. Our results indicate that feedback from higher brain areas is not required to produce motion patterns in the case of the illusory line-motion paradigm. Physiological interpretation of the model suggests that a considerable fraction of the VSD signal may be due to inhibitory activity, supporting the notion that balanced intra-layer cortical interactions between inhibitory and excitatory populations play a major role in shaping dynamic stimulus representations in the early visual cortex.'),
(84749, 2010, 'plos', 'Drug-induced regulation of target expression', 'Iskar, Murat|Campillos, Monica|Kuhn, Michael|Jensen, Lars Juhl|van Noort, Vera|Bork, Peer', 'Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.|Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.|Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.|Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.|Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.|Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany', 87, 'Cell Line, Tumor|Databases, Genetic|Drug Discovery|Feedback, Physiological|Gene Expression Profiling|Genomics|HL-60 Cells|Humans|Molecular Targeted Therapy|Oligonucleotide Array Sequence Analysis|Pharmaceutical Preparations|Pharmacological Phenomena|Proteins|RNA, Messenger|Receptors, G-Protein-Coupled|Statistics, Nonparametric|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000925', '20838579', 'Drug perturbations of human cells lead to complex responses upon target binding. One of the known mechanisms is a (positive or negative) feedback loop that adjusts the expression level of the respective target protein. To quantify this mechanism systems-wide in an unbiased way, drug-induced differential expression of drug target mRNA was examined in three cell lines using the Connectivity Map. To overcome various biases in this valuable resource, we have developed a computational normalization and scoring procedure that is applicable to gene expression recording upon heterogeneous drug treatments. In 1290 drug-target relations, corresponding to 466 drugs acting on 167 drug targets studied, 8% of the targets are subject to regulation at the mRNA level. We confirmed systematically that in particular G-protein coupled receptors, when serving as known targets, are regulated upon drug treatment. We further newly identified drug-induced differential regulation of Lanosterol 14-alpha demethylase, Endoplasmin, DNA topoisomerase 2-alpha and Calmodulin 1. The feedback regulation in these and other targets is likely to be relevant for the success or failure of the molecular intervention.'),
(84750, 2010, 'plos', 'Pavlovian-instrumental interaction in observing behavior', 'Beierholm, Ulrik R|Dayan, Peter', 'Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom. beierh@gatsby.ucl.ac.uk|Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom. beierh@gatsby.ucl.ac.uk', 'United Kingdom|United Kingdom', 20, 'Algorithms|Animals|Behavior, Animal|Computational Biology|Conditioning, Classical|Learning|Macaca|Markov Chains|Models, Theoretical|Reinforcement (Psychology)|Stochastic Processes|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1000903', '20838580', 'Subjects typically choose to be presented with stimuli that predict the existence of future reinforcements. This so-called observing behavior is evident in many species under various experimental conditions, including if the choice is expensive, or if there is nothing that subjects can do to improve their lot with the information gained. A recent study showed that the activities of putative midbrain dopamine neurons reflect this preference for observation in a way that appears to challenge the common prediction-error interpretation of these neurons. In this paper, we provide an alternative account according to which observing behavior arises from a small, possibly Pavlovian, bias associated with the operation of working memory.'),
(84751, 2010, 'plos', 'Synaptic plasticity controls sensory responses through frequency-dependent gamma oscillation resonance', 'Paik, Se-Bum|Glaser, Donald A', 'Department of Physics, University of California Berkeley, Berkeley, California, United States of America. spaik@berkeley.edu|Department of Physics, University of California Berkeley, Berkeley, California, United States of America. spaik@berkeley.edu', 'United States|United States', 16, 'Animals|Cats|Computational Biology|Computer Simulation|Cortical Synchronization|Models, Neurological|Nerve Net|Neuronal Plasticity|Synapses|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1000927', '20838581', 'Synchronized gamma frequency oscillations in neural networks are thought to be important to sensory information processing, and their effects have been intensively studied. Here we describe a mechanism by which the nervous system can readily control gamma oscillation effects, depending selectively on visual stimuli. Using a model neural network simulation, we found that sensory response in the primary visual cortex is significantly modulated by the resonance between spontaneous and stimulus-driven oscillations. This gamma resonance can be precisely controlled by the synaptic plasticity of thalamocortical connections, and cortical response is regulated differentially according to the resonance condition. The mechanism produces a selective synchronization between the afferent and downstream neural population. Our simulation results explain experimental observations such as stimulus-dependent synchronization between the thalamus and the cortex at different oscillation frequencies. The model generally shows how sensory information can be selectively routed depending on its frequency components.'),
(84752, 2010, 'plos', 'High resolution models of transcription factor-DNA affinities improve in vitro and in vivo binding predictions', 'Agius, Phaedra|Arvey, Aaron|Chang, William|Noble, William Stafford|Leslie, Christina', 'Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.|Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.|Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.|Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.|Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.', 'United States|United States|United States|United States|United States', 44, 'Algorithms|Animals|Area Under Curve|Artificial Intelligence|Binding Sites|Chromatin Immunoprecipitation|Computational Biology|DNA|Databases, Protein|Fungal Proteins|Humans|Mice|Models, Molecular|Models, Statistical|Protein Array Analysis|Protein Binding|Reproducibility of Results|Sequence Analysis, Protein|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000916', '20838582', 'Accurately modeling the DNA sequence preferences of transcription factors (TFs), and using these models to predict in vivo genomic binding sites for TFs, are key pieces in deciphering the regulatory code. These efforts have been frustrated by the limited availability and accuracy of TF binding site motifs, usually represented as position-specific scoring matrices (PSSMs), which may match large numbers of sites and produce an unreliable list of target genes. Recently, protein binding microarray (PBM) experiments have emerged as a new source of high resolution data on in vitro TF binding specificities. PBM data has been analyzed either by estimating PSSMs or via rank statistics on probe intensities, so that individual sequence patterns are assigned enrichment scores (E-scores). This representation is informative but unwieldy because every TF is assigned a list of thousands of scored sequence patterns. Meanwhile, high-resolution in vivo TF occupancy data from ChIP-seq experiments is also increasingly available. We have developed a flexible discriminative framework for learning TF binding preferences from high resolution in vitro and in vivo data. We first trained support vector regression (SVR) models on PBM data to learn the mapping from probe sequences to binding intensities. We used a novel -mer based string kernel called the di-mismatch kernel to represent probe sequence similarities. The SVR models are more compact than E-scores, more expressive than PSSMs, and can be readily used to scan genomics regions to predict in vivo occupancy. Using a large data set of yeast and mouse TFs, we found that our SVR models can better predict probe intensity than the E-score method or PBM-derived PSSMs. Moreover, by using SVRs to score yeast, mouse, and human genomic regions, we were better able to predict genomic occupancy as measured by ChIP-chip and ChIP-seq experiments. Finally, we found that by training kernel-based models directly on ChIP-seq data, we greatly improved in vivo occupancy prediction, and by comparing a TFs in vitro and in vivo models, we could identify cofactors and disambiguate direct and indirect binding.'),
(84753, 2010, 'plos', 'An integrative multi-network and multi-classifier approach to predict genetic interactions', 'Pandey, Gaurav|Zhang, Bin|Chang, Aaron N|Myers, Chad L|Zhu, Jun|Kumar, Vipin|Schadt, Eric E', 'Department of Computer Science and Engineering, University of Minnesota, Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Computer Science and Engineering, University of Minnesota, Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Computer Science and Engineering, University of Minnesota, Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Computer Science and Engineering, University of Minnesota, Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Computer Science and Engineering, University of Minnesota, Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Computer Science and Engineering, University of Minnesota, Twin Cities, Minneapolis, Minnesota, United States of America.|Department of Computer Science and Engineering, University of Minnesota, Twin Cities, Minneapolis, Minnesota, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 47, 'Area Under Curve|Computational Biology|Databases, Genetic|Gene Regulatory Networks|Genes, Fungal|Phenotype|ROC Curve|Reproducibility of Results|Saccharomyces cerevisiae Proteins|Statistics, Nonparametric|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000928', '20838583', 'Genetic interactions occur when a combination of mutations results in a surprising phenotype. These interactions capture functional redundancy, and thus are important for predicting function, dissecting protein complexes into functional pathways, and exploring the mechanistic underpinnings of common human diseases. Synthetic sickness and lethality are the most studied types of genetic interactions in yeast. However, even in yeast, only a small proportion of gene pairs have been tested for genetic interactions due to the large number of possible combinations of gene pairs. To expand the set of known synthetic lethal (SL) interactions, we have devised an integrative, multi-network approach for predicting these interactions that significantly improves upon the existing approaches. First, we defined a large number of features for characterizing the relationships between pairs of genes from various data sources. In particular, these features are independent of the known SL interactions, in contrast to some previous approaches. Using these features, we developed a non-parametric multi-classifier system for predicting SL interactions that enabled the simultaneous use of multiple classification procedures. Several comprehensive experiments demonstrated that the SL-independent features in conjunction with the advanced classification scheme led to an improved performance when compared to the current state of the art method. Using this approach, we derived the first yeast transcription factor genetic interaction network, part of which was well supported by literature. We also used this approach to predict SL interactions between all non-essential gene pairs in yeast (http://sage.fhcrc.org/downloads/downloads/predicted_yeast_genetic_interactions.zip). This integrative approach is expected to be more effective and robust in uncovering new genetic interactions from the tens of millions of unknown gene pairs in yeast and from the hundreds of millions of gene pairs in higher organisms like mouse and human, in which very few genetic interactions have been identified to date.'),
(84754, 2010, 'plos', 'Evolution and optimality of similar neural mechanisms for perception and action during search', 'Zhang, Sheng|Eckstein, Miguel P', 'Vision and Image Understanding, Department of Psychology, University of California, Santa Barbara, California, United States of America.|Vision and Image Understanding, Department of Psychology, University of California, Santa Barbara, California, United States of America.', 'United States|United States', 14, 'Algorithms|Bayes Theorem|Biological Evolution|Computational Biology|Humans|Models, Genetic|Models, Neurological|Normal Distribution|Saccades|Visual Cortex|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1000930', '20838589', 'A prevailing theory proposes that the brains two visual pathways, the ventral and dorsal, lead to differing visual processing and world representations for conscious perception than those for action. Others have claimed that perception and action share much of their visual processing. But which of these two neural architectures is favored by evolution? Successful visual search is life-critical and here we investigate the evolution and optimality of neural mechanisms mediating perception and eye movement actions for visual search in natural images. We implement an approximation to the ideal Bayesian searcher with two separate processing streams, one controlling the eye movements and the other stream determining the perceptual search decisions. We virtually evolved the neural mechanisms of the searchers two separate pathways built from linear combinations of primary visual cortex receptive fields (V1) by making the simulated individuals probability of survival depend on the perceptual accuracy finding targets in cluttered backgrounds. We find that for a variety of targets, backgrounds, and dependence of target detectability on retinal eccentricity, the mechanisms of the searchers two processing streams converge to similar representations showing that mismatches in the mechanisms for perception and eye movements lead to suboptimal search. Three exceptions which resulted in partial or no convergence were a case of an organism for which the targets are equally detectable across the retina, an organism with sufficient time to foveate all possible target locations, and a strict two-pathway model with no interconnections and differential pre-filtering based on parvocellular and magnocellular lateral geniculate cell properties. Thus, similar neural mechanisms for perception and eye movement actions during search are optimal and should be expected from the effects of natural selection on an organism with limited time to search for food that is not equi-detectable across its retina and interconnected perception and action neural pathways.'),
(84755, 2010, 'plos', 'MetMap enables genome-scale Methyltyping for determining methylation states in populations', 'Singer, Meromit|Boffelli, Dario|Dhahbi, Joseph|Schönhuth, Alexander|Schroth, Gary P|Martin, David I K|Pachter, Lior', 'Computer Science Division, University of California at Berkeley, Berkeley, California, USA.|Computer Science Division, University of California at Berkeley, Berkeley, California, USA.|Computer Science Division, University of California at Berkeley, Berkeley, California, USA.|Computer Science Division, University of California at Berkeley, Berkeley, California, USA.|Computer Science Division, University of California at Berkeley, Berkeley, California, USA.|Computer Science Division, University of California at Berkeley, Berkeley, California, USA.|Computer Science Division, University of California at Berkeley, Berkeley, California, USA.', 'United States|United States|United States|United States|United States|United States|United States', 8, 'Bayes Theorem|CpG Islands|DNA Methylation|Genome, Human|Genomics|Humans|Models, Genetic|Neutrophils|Population|Sequence Analysis, DNA|Software|Sulfites', 'Journal Article', '10.1371/journal.pcbi.1000888', '20856582', 'The ability to assay genome-scale methylation patterns using high-throughput sequencing makes it possible to carry out association studies to determine the relationship between epigenetic variation and phenotype. While bisulfite sequencing can determine a methylome at high resolution, cost inhibits its use in comparative and population studies. MethylSeq, based on sequencing of fragment ends produced by a methylation-sensitive restriction enzyme, is a method for methyltyping (survey of methylation states) and is a site-specific and cost-effective alternative to whole-genome bisulfite sequencing. Despite its advantages, the use of MethylSeq has been restricted by biases in MethylSeq data that complicate the determination of methyltypes. Here we introduce a statistical method, MetMap, that produces corrected site-specific methylation states from MethylSeq experiments and annotates unmethylated islands across the genome. MetMap integrates genome sequence information with experimental data, in a statistically sound and cohesive Bayesian Network. It infers the extent of methylation at individual CGs and across regions, and serves as a framework for comparative methylation analysis within and among species. We validated MetMaps inferences with direct bisulfite sequencing, showing that the methylation status of sites and islands is accurately inferred. We used MetMap to analyze MethylSeq data from four human neutrophil samples, identifying novel, highly unmethylated islands that are invisible to sequence-based annotation strategies. The combination of MethylSeq and MetMap is a powerful and cost-effective tool for determining genome-scale methyltypes suitable for comparative and association studies.'),
(84756, 2010, 'plos', 'Instantaneous non-linear processing by pulse-coupled threshold units', 'Helias, Moritz|Deger, Moritz|Rotter, Stefan|Diesmann, Markus', 'RIKEN Brain Science Institute, Wako City, Japan. helias@brain.riken.jp|RIKEN Brain Science Institute, Wako City, Japan. helias@brain.riken.jp|RIKEN Brain Science Institute, Wako City, Japan. helias@brain.riken.jp|RIKEN Brain Science Institute, Wako City, Japan. helias@brain.riken.jp', 'Japan|Japan|Japan|Japan', 25, 'Action Potentials|Algorithms|Animals|Computational Biology|Computer Simulation|Models, Neurological|Nerve Net|Nonlinear Dynamics|Normal Distribution|Synapses', 'Journal Article', '10.1371/journal.pcbi.1000929', '20856583', 'Contemporary theory of spiking neuronal networks is based on the linear response of the integrate-and-fire neuron model derived in the diffusion limit. We find that for non-zero synaptic weights, the response to transient inputs differs qualitatively from this approximation. The response is instantaneous rather than exhibiting low-pass characteristics, non-linearly dependent on the input amplitude, asymmetric for excitation and inhibition, and is promoted by a characteristic level of synaptic background noise. We show that at threshold the probability density of the potential drops to zero within the range of one synaptic weight and explain how this shapes the response. The novel mechanism is exhibited on the network level and is a generic property of pulse-coupled networks of threshold units.'),
(84757, 2010, 'plos', 'Plasmodium falciparum erythrocyte membrane protein 1 diversity in seven genomes--divide and conquer', 'Rask, Thomas S|Hansen, Daniel A|Theander, Thor G|Gorm Pedersen, Anders|Lavstsen, Thomas', 'Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark. rask@cbs.dtu.dk|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark. rask@cbs.dtu.dk|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark. rask@cbs.dtu.dk|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark. rask@cbs.dtu.dk|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark. rask@cbs.dtu.dk', 'Denmark|Denmark|Denmark|Denmark|Denmark', 198, 'Amino Acid Sequence|Cluster Analysis|Computational Biology|Conserved Sequence|Genome, Protozoan|Markov Chains|Models, Molecular|Molecular Sequence Annotation|Molecular Sequence Data|Phylogeny|Plasmodium falciparum|Protein Structure, Tertiary|Protozoan Proteins|Sequence Analysis, Protein|Sequence Homology, Amino Acid', 'Journal Article', '10.1371/journal.pcbi.1000933', '20862303', 'The var gene encoded hyper-variable Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family mediates cytoadhesion of infected erythrocytes to human endothelium. Antibodies blocking cytoadhesion are important mediators of malaria immunity acquired by endemic populations. The development of a PfEMP1 based vaccine mimicking natural acquired immunity depends on a thorough understanding of the evolved PfEMP1 diversity, balancing antigenic variation against conserved receptor binding affinities. This study redefines and reclassifies the domains of PfEMP1 from seven genomes. Analysis of domains in 399 different PfEMP1 sequences allowed identification of several novel domain classes, and a high degree of PfEMP1 domain compositional order, including conserved domain cassettes not always associated with the established group A-E division of PfEMP1. A novel iterative homology block (HB) detection method was applied, allowing identification of 628 conserved minimal PfEMP1 building blocks, describing on average 83% of a PfEMP1 sequence. Using the HBs, similarities between domain classes were determined, and Duffy binding-like (DBL) domain subclasses were found in many cases to be hybrids of major domain classes. Related to this, a recombination hotspot was uncovered between DBL subdomains S2 and S3. The VarDom server is introduced, from which information on domain classes and homology blocks can be retrieved, and new sequences can be classified. Several conserved sequence elements were found, including: (1) residues conserved in all DBL domains predicted to interact and hold together the three DBL subdomains, (2) potential integrin binding sites in DBLxcexb1 domains, (3) an acylation motif conserved in group A var genes suggesting N-terminal N-myristoylation, (4) PfEMP1 inter-domain regions proposed to be elastic disordered structures, and (5) several conserved predicted phosphorylation sites. Ideally, this comprehensive categorization of PfEMP1 will provide a platform for future studies on var/PfEMP1 expression and function.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84758, 2010, 'plos', 'Role of Hsp70 ATPase domain intrinsic dynamics and sequence evolution in enabling its functional interactions with NEFs', 'Liu, Ying|Gierasch, Lila M|Bahar, Ivet', 'Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.', 'United States|United States|United States', 48, 'Adenosine Triphosphatases|Amino Acid Sequence|Animals|Binding Sites|Cattle|Computational Biology|Escherichia coli Proteins|Evolution, Molecular|HSP70 Heat-Shock Proteins|Humans|Molecular Chaperones|Molecular Dynamics Simulation|Multiprotein Complexes|Normal Distribution|Phylogeny|Protein Structure, Tertiary|Sequence Alignment', 'Journal Article', '10.1371/journal.pcbi.1000931', '20862304', 'Catalysis of ADP-ATP exchange by nucleotide exchange factors (NEFs) is central to the activity of Hsp70 molecular chaperones. Yet, the mechanism of interaction of this family of chaperones with NEFs is not well understood in the context of the sequence evolution and structural dynamics of Hsp70 ATPase domains. We studied the interactions of Hsp70 ATPase domains with four different NEFs on the basis of the evolutionary trace and co-evolution of the ATPase domain sequence, combined with elastic network modeling of the collective dynamics of the complexes. Our study reveals a subtle balance between the intrinsic (to the ATPase domain) and specific (to interactions with NEFs) mechanisms shared by the four complexes. Two classes of key residues are distinguished in the Hsp70 ATPase domain: (i) highly conserved residues, involved in nucleotide binding, which mediate, via a global hinge-bending, the ATPase domain opening irrespective of NEF binding, and (ii) not-conserved but co-evolved and highly mobile residues, engaged in specific interactions with NEFs (e.g., N57, R258, R262, E283, D285). The observed interplay between these respective intrinsic (pre-existing, structure-encoded) and specific (co-evolved, sequence-dependent) interactions provides us with insights into the allosteric dynamics and functional evolution of the modular Hsp70 ATPase domain.'),
(84759, 2010, 'plos', 'Correlated mutations: a hallmark of phenotypic amino acid substitutions', 'Kowarsch, Andreas|Fuchs, Angelika|Frishman, Dmitrij|Pagel, Philipp', 'Lehrstuhl für Genomorientierte Bioinformatik, Technische Universität München, Wissenschaftszentrum Weihenstephan, Freising, Germany.|Lehrstuhl für Genomorientierte Bioinformatik, Technische Universität München, Wissenschaftszentrum Weihenstephan, Freising, Germany.|Lehrstuhl für Genomorientierte Bioinformatik, Technische Universität München, Wissenschaftszentrum Weihenstephan, Freising, Germany.|Lehrstuhl für Genomorientierte Bioinformatik, Technische Universität München, Wissenschaftszentrum Weihenstephan, Freising, Germany.', 'Germany|Germany|Germany|Germany', 42, 'Adenylate Kinase|Algorithms|Amino Acid Sequence|Amino Acid Substitution|Cluster Analysis|Computational Biology|Databases, Genetic|Dipeptidases|Disease|Evolution, Molecular|Genetic Association Studies|Humans|Lod Score|Models, Genetic|Mutation|Phenotype|Proteins|Sequence Alignment', 'Journal Article', '10.1371/journal.pcbi.1000923', '20862353', 'Point mutations resulting in the substitution of a single amino acid can cause severe functional consequences, but can also be completely harmless. Understanding what determines the phenotypical impact is important both for planning targeted mutation experiments in the laboratory and for analyzing naturally occurring mutations found in patients. Common wisdom suggests using the extent of evolutionary conservation of a residue or a sequence motif as an indicator of its functional importance and thus vulnerability in case of mutation. In this work, we put forward the hypothesis that in addition to conservation, co-evolution of residues in a protein influences the likelihood of a residue to be functionally important and thus associated with disease. While the basic idea of a relation between co-evolution and functional sites has been explored before, we have conducted the first systematic and comprehensive analysis of point mutations causing disease in humans with respect to correlated mutations. We included 14,211 distinct positions with known disease-causing point mutations in 1,153 human proteins in our analysis. Our data show that (1) correlated positions are significantly more likely to be disease-associated than expected by chance, and that (2) this signal cannot be explained by conservation patterns of individual sequence positions. Although correlated residues have primarily been used to predict contact sites, our data are in agreement with previous observations that (3) many such correlations do not relate to physical contacts between amino acid residues. Access to our analysis results are provided at http://webclu.bio.wzw.tum.de/~pagel/supplements/correlated-positions/.'),
(84760, 2010, 'plos', 'Thermodynamics-based models of transcriptional regulation by enhancers: the roles of synergistic activation, cooperative binding and short-range repression', 'He, Xin|Samee, Md Abul Hassan|Blatti, Charles|Sinha, Saurabh', 'Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States of America.|Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States of America.|Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States of America.|Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States of America.', 'United States|United States|United States|United States', 109, 'Algorithms|Animals|Biological Evolution|Computational Biology|DNA|Drosophila melanogaster|Enhancer Elements, Genetic|Gene Expression Regulation|Models, Genetic|Software|Thermodynamics|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000935', '20862354', 'Quantitative models of cis-regulatory activity have the potential to improve our mechanistic understanding of transcriptional regulation. However, the few models available today have been based on simplistic assumptions about the sequences being modeled, or heuristic approximations of the underlying regulatory mechanisms. We have developed a thermodynamics-based model to predict gene expression driven by any DNA sequence, as a function of transcription factor concentrations and their DNA-binding specificities. It uses statistical thermodynamics theory to model not only protein-DNA interaction, but also the effect of DNA-bound activators and repressors on gene expression. In addition, the model incorporates mechanistic features such as synergistic effect of multiple activators, short range repression, and cooperativity in transcription factor-DNA binding, allowing us to systematically evaluate the significance of these features in the context of available expression data. Using this model on segmentation-related enhancers in Drosophila, we find that transcriptional synergy due to simultaneous action of multiple activators helps explain the data beyond what can be explained by cooperative DNA-binding alone. We find clear support for the phenomenon of short-range repression, where repressors do not directly interact with the basal transcriptional machinery. We also find that the binding sites contributing to an enhancers function may not be conserved during evolution, and a noticeable fraction of these undergo lineage-specific changes. Our implementation of the model, called GEMSTAT, is the first publicly available program for simultaneously modeling the regulatory activities of a given set of sequences.'),
(84761, 2010, 'plos', 'Optimal information transfer in the cortex through synchronization', 'Buehlmann, Andres|Deco, Gustavo', 'Computational Neuroscience, Universitat Pompeu Fabra, Barcelona, Spain. andres.buhlmann@upf.edu|Computational Neuroscience, Universitat Pompeu Fabra, Barcelona, Spain. andres.buhlmann@upf.edu', 'Spain|Spain', 91, 'Action Potentials|Algorithms|Animals|Cats|Cerebral Cortex|Cognition|Computational Biology|Cortical Synchronization|Databases, Factual|Entropy|Haplorhini|Models, Neurological|Neurons|Poisson Distribution|Statistics, Nonparametric', 'Journal Article', '10.1371/journal.pcbi.1000934', '20862355', 'In recent experimental work it has been shown that neuronal interactions are modulated by neuronal synchronization and that this modulation depends on phase shifts in neuronal oscillations. This result suggests that connections in a network can be shaped through synchronization. Here, we test and expand this hypothesis using a model network. We use transfer entropy, an information theoretical measure, to quantify the exchanged information. We show that transferred information depends on the phase relation of the signal, that the amount of exchanged information increases as a function of oscillations in the signal and that the speed of the information transfer increases as a function of synchronization. This implies that synchronization makes information transport more efficient. In summary, our results reinforce the hypothesis that synchronization modulates neuronal interactions and provide further evidence that gamma band synchronization has behavioral relevance.'),
(84762, 2010, 'plos', 'A Boolean model of the gene regulatory network underlying Mammalian cortical area development', 'Giacomantonio, Clare E|Goodhill, Geoffrey J', 'Queensland Brain Institute, The University of Queensland, St Lucia, Queensland, Australia.|Queensland Brain Institute, The University of Queensland, St Lucia, Queensland, Australia.', 'Australia|Australia', 54, 'Animals|COUP Transcription Factor I|Cerebral Cortex|Computational Biology|Eye Proteins|Fibroblast Growth Factor 8|Gene Expression Regulation, Developmental|Gene Regulatory Networks|Homeodomain Proteins|Mammals|Markov Chains|Models, Neurological|PAX6 Transcription Factor|Paired Box Transcription Factors|Repressor Proteins|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000936', '20862356', 'The cerebral cortex is divided into many functionally distinct areas. The emergence of these areas during neural development is dependent on the expression patterns of several genes. Along the anterior-posterior axis, gradients of Fgf8, Emx2, Pax6, Coup-tfi, and Sp8 play a particularly strong role in specifying areal identity. However, our understanding of the regulatory interactions between these genes that lead to their confinement to particular spatial patterns is currently qualitative and incomplete. We therefore used a computational model of the interactions between these five genes to determine which interactions, and combinations of interactions, occur in networks that reproduce the anterior-posterior expression patterns observed experimentally. The model treats expression levels as Boolean, reflecting the qualitative nature of the expression data currently available. We simulated gene expression patterns created by all possible networks containing the five genes of interest. We found that only of these networks were able to reproduce the experimentally observed expression patterns. These networks all lacked certain interactions and combinations of interactions including auto-regulation and inductive loops. Many higher order combinations of interactions also never appeared in networks that satisfied our criteria for good performance. While there was remarkable diversity in the structure of the networks that perform well, an analysis of the probability of each interaction gave an indication of which interactions are most likely to be present in the gene network regulating cortical area development. We found that in general, repressive interactions are much more likely than inductive ones, but that mutually repressive loops are not critical for correct network functioning. Overall, our model illuminates the design principles of the gene network regulating cortical area development, and makes novel predictions that can be tested experimentally.'),
(84763, 2010, 'plos', 'Is protein folding sub-diffusive?', 'Krivov, Sergei V', 'Institute of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom. s.krivov@leeds.ac.uk', 'United Kingdom', 0, 'Algorithms|Molecular Dynamics Simulation|Protein Folding|Proteins|Repressor Proteins|Thermodynamics|Viral Regulatory and Accessory Proteins', 'Journal Article', '10.1371/journal.pcbi.1000921', '20862361', 'Protein folding dynamics is often described as diffusion on a free energy surface considered as a function of one or few reaction coordinates. However, a growing number of experiments and models show that, when projected onto a reaction coordinate, protein dynamics is sub-diffusive. This raises the question as to whether the conventionally used diffusive description of the dynamics is adequate. Here, we numerically construct the optimum reaction coordinate for a long equilibrium folding trajectory of a Go model of a -repressor protein. The trajectory projected onto this coordinate exhibits diffusive dynamics, while the dynamics of the same trajectory projected onto a sub-optimal reaction coordinate is sub-diffusive. We show that the higher the (cut-based) free energy profile for the putative reaction coordinate, the more diffusive the dynamics become when projected on this coordinate. The results suggest that whether the projected dynamics is diffusive or sub-diffusive depends on the chosen reaction coordinate. Protein folding can be described as diffusion on the free energy surface as function of the optimum reaction coordinate. And conversely, the conventional reaction coordinates, even though they might be based on physical intuition, are often sub-optimal and, hence, show sub-diffusive dynamics.'),
(84764, 2010, 'plos', 'Similar impact of CD8+ T cell responses on early virus dynamics during SIV infections of rhesus macaques and sooty mangabeys', 'Kouyos, Roger D|Gordon, Shari N|Staprans, Silvija I|Silvestri, Guido|Regoes, Roland R', 'Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. roger.kouyos@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. roger.kouyos@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. roger.kouyos@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. roger.kouyos@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. roger.kouyos@env.ethz.ch', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 0, 'Animals|CD8-Positive T-Lymphocytes|Cercocebus atys|Killer Cells, Natural|Macaca mulatta|Models, Immunological|Simian Acquired Immunodeficiency Syndrome|Simian Immunodeficiency Virus|Viral Load|Virus Replication', 'Comparative Study', '10.1371/journal.pcbi.1000901', '20865048', 'Despite comparable levels of virus replication, simian immunodeficiency viruses (SIV) infection is non-pathogenic in natural hosts, such as sooty mangabeys (SM), whereas it is pathogenic in non-natural hosts, such as rhesus macaques (RM). Comparative studies of pathogenic and non-pathogenic SIV infection can thus shed light on the role of specific factors in SIV pathogenesis. Here, we determine the impact of target-cell limitation, CD8+ T cells, and Natural Killer (NK) cells on virus replication in the early SIV infection. To this end, we fit previously published data of experimental SIV infections in SMs and RMs with mathematical models incorporating these factors and assess to what extent the inclusion of individual factors determines the quality of the fits. We find that for both rhesus macaques and sooty mangabeys, target-cell limitation alone cannot explain the control of early virus replication, whereas including CD8+ T cells into the models significantly improves the fits. By contrast, including NK cells does only significantly improve the fits in SMs. These findings have important implications for our understanding of SIV pathogenesis as they suggest that the level of early CD8+ T cell responses is not the key difference between pathogenic and non-pathogenic SIV infection.'),
(84765, 2010, 'plos', 'A mechanistic view of the role of E3 in sumoylation', 'Tozluoxc4x9flu, Melda|Karaca, Ezgi|Nussinov, Ruth|Haliloxc4x9flu, Txc3xbcrkan', 'Polymer Research Center & Chemical Engineering Department, Bogazici University, Istanbul, Turkey.|Polymer Research Center & Chemical Engineering Department, Bogazici University, Istanbul, Turkey.|Polymer Research Center & Chemical Engineering Department, Bogazici University, Istanbul, Turkey.|Polymer Research Center & Chemical Engineering Department, Bogazici University, Istanbul, Turkey.', 'Turkey|Turkey|Turkey|Turkey', 0, 'Allosteric Regulation|Binding Sites|Humans|Molecular Chaperones|Molecular Conformation|Molecular Dynamics Simulation|Nuclear Pore Complex Proteins|Small Ubiquitin-Related Modifier Proteins|Sumoylation|Ubiquitin-Conjugating Enzymes|Ubiquitin-Protein Ligases', 'Journal Article', '10.1371/journal.pcbi.1000913', '20865051', 'Sumoylation, the covalent attachment of SUMO (Small Ubiquitin-Like Modifier) to proteins, differs from other Ubl (Ubiquitin-like) pathways. In sumoylation, E2 ligase Ubc9 can function without E3 enzymes, albeit with lower reaction efficiency. Here, we study the mechanism through which E3 ligase RanBP2 triggers target recognition and catalysis by E2 Ubc9. Two mechanisms were proposed for sumoylation. While in both the first step involves Ubc9 conjugation to SUMO, the subsequent sequence of events differs: in the first E2-SUMO forms a complex with the target and E3, followed by SUMO transfer to the target. In the second, Ubc9-SUMO binds to the target and facilitates SUMO transfer without E3. Using dynamic correlations obtained from explicit solvent molecular dynamic simulations we illustrate the key roles played by allostery in both mechanisms. Pre-existence of conformational states explains the experimental observations that sumoylation can occur without E3, even though at a reduced rate. Furthermore, we propose a mechanism for enhancement of sumoylation by E3. Analysis of the conformational ensembles of the complex of E2 conjugated to SUMO illustrates that the E2 enzyme is already largely pre-organized for target binding and catalysis, E3 binding shifts the equilibrium and enhances these pre-existing populations. We further observe that E3 binding regulates allosterically the key residues in E2, Ubc9 Asp100/Lys101 E2, for the target recognition.'),
(84766, 2010, 'plos', 'Reverse engineering of oxygen transport in the lung: adaptation to changing demands and resources through space-filling networks', 'Hou, Chen|Gheorghiu, Stefan|Huxley, Virginia H|Pfeifer, Peter', 'Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.', 'United States|United States|United States|United States', 0, 'Adaptation, Physiological|Cell Membrane Permeability|Diffusion|Exercise|Fractals|Humans|Lung|Models, Biological|Oxygen|Pulmonary Alveoli|Pulmonary Gas Exchange', 'Journal Article', '10.1371/journal.pcbi.1000902', '20865052', 'The space-filling fractal network in the human lung creates a remarkable distribution system for gas exchange. Landmark studies have illuminated how the fractal network guarantees minimum energy dissipation, slows air down with minimum hardware, maximizes the gas- exchange surface area, and creates respiratory flexibility between rest and exercise. In this paper, we investigate how the fractal architecture affects oxygen transport and exchange under varying physiological conditions, with respect to performance metrics not previously studied.We present a renormalization treatment of the diffusion-reaction equation which describes how oxygen concentrations drop in the airways as oxygen crosses the alveolar membrane system. The treatment predicts oxygen currents across the lung at different levels of exercise which agree with measured values within a few percent. The results exhibit wide-ranging adaptation to changing process parameters, including maximum oxygen uptake rate at minimum alveolar membrane permeability, the ability to rapidly switch from a low oxygen uptake rate at rest to high rates at exercise, and the ability to maintain a constant oxygen uptake rate in the event of a change in permeability or surface area. We show that alternative, less than space-filling architectures perform sub-optimally and that optimal performance of the space-filling architecture results from a competition between underexploration and overexploration of the surface by oxygen molecules.'),
(84767, 2010, 'plos', 'Modeling and dynamics of the inward-facing state of a Na+/Cl- dependent neurotransmitter transporter homologue', 'Shaikh, Saher Afshan|Tajkhorshid, Emad', 'Department of Biochemistry and Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Department of Biochemistry and Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.', 'United States|United States', 60, 'Amino Acid Transport Systems, Neutral|Binding Sites|Leucine|Models, Biological|Models, Molecular|Molecular Dynamics Simulation|Neurotransmitter Transport Proteins|Plasma Membrane Neurotransmitter Transport Proteins|Protein Structure, Secondary', 'Journal Article', '10.1371/journal.pcbi.1000905', '20865057', 'The leucine transporter (LeuT) has recently commanded exceptional attention due mainly to two distinctions, it provides the only crystal structures available for a protein homologous to the pharmacologically relevant neurotransmitter: sodium symporters (NSS), and, it exhibits a hallmark 5-TM inverted repeat (LeuT-fold), a fold recently discovered to also exist in several secondary transporter families, underscoring its general role in transporter function. Constructing the transport cycle of LeuT-fold transporters requires detailed structural and dynamic descriptions of the outward-facing (OF) and inward-facing (IF) states, as well as the intermediate states. To this end, we have modeled the structurally unknown IF state of LeuT, based on the known crystal structures of the OF state of LeuT and the IF state of vSGLT, a LeuT-fold transporter. The detailed methodology developed for the study combines structure-based alignment, threading, targeted MD and equilibrium MD, and can be applied to other proteins. The resulting IF-state models maintain the secondary structural features of LeuT. Water penetration and solvent accessibility calculations show that TM1, TM3, TM6 and TM8 line the substrate binding/unbinding pathway with TM10 and its pseudosymmetric partner, TM5, participating in the extracellular and intracellular halves of the lumen, respectively. We report conformational hotspots where notable changes in interactions occur between the IF and OF states. We observe Na2 exiting the LeuT-substrate- complex in the IF state, mainly due to TM1 bending. Inducing a transition in only one of the two pseudosymmetric domains, while allowing the second to respond dynamically, is found to be sufficient to induce the formation of the IF state. We also propose that TM2 and TM7 may be facilitators of TM1 and TM6 motion. Thus, this study not only presents a novel modeling methodology applied to obtain the IF state of LeuT, but also describes structural elements involved in a possibly general transport mechanism in transporters adopting the LeuT-fold.'),
(84768, 2010, 'plos', 'Frequency-dependent selection predicts patterns of radiations and biodiversity', 'Melián, Carlos J|Alonso, David|Vázquez, Diego P|Regetz, James|Allesina, Stefano', 'National Center for Ecological Analysis and Synthesis, University of California, Santa Barbara, Santa Barbara, California, United States of America. melian@nceas.ucsb.edu|National Center for Ecological Analysis and Synthesis, University of California, Santa Barbara, Santa Barbara, California, United States of America. melian@nceas.ucsb.edu|National Center for Ecological Analysis and Synthesis, University of California, Santa Barbara, Santa Barbara, California, United States of America. melian@nceas.ucsb.edu|National Center for Ecological Analysis and Synthesis, University of California, Santa Barbara, Santa Barbara, California, United States of America. melian@nceas.ucsb.edu|National Center for Ecological Analysis and Synthesis, University of California, Santa Barbara, Santa Barbara, California, United States of America. melian@nceas.ucsb.edu', 'United States|United States|United States|United States|United States', 15, 'Animals|Base Sequence|Biodiversity|Cichlids|Finches|Genetic Speciation|Models, Genetic|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000892', '20865126', 'Most empirical studies support a decline in speciation rates through time, although evidence for constant speciation rates also exists. Declining rates have been explained by invoking pre-existing niches, whereas constant rates have been attributed to non-adaptive processes such as sexual selection and mutation. Trends in speciation rate and the processes underlying it remain unclear, representing a critical information gap in understanding patterns of global diversity. Here we show that the temporal trend in the speciation rate can also be explained by frequency-dependent selection. We construct a frequency-dependent and DNA sequence-based model of speciation. We compare our model to empirical diversity patterns observed for cichlid fish and Darwins finches, two classic systems for which speciation rates and richness data exist. Negative frequency-dependent selection predicts well both the declining speciation rate found in cichlid fish and explains their species richness. For groups like the Darwins finches, in which speciation rates are constant and diversity is lower, speciation rate is better explained by a model without frequency-dependent selection. Our analysis shows that differences in diversity may be driven by incipient species abundance with frequency-dependent selection. Our results demonstrate that genetic-distance-based speciation and frequency-dependent selection are sufficient to explain the high diversity observed in natural systems and, importantly, predict decay through time in speciation rate in the absence of pre-existing niches.'),
(84769, 2010, 'plos', 'Evolution under fluctuating environments explains observed robustness in metabolic networks', 'Soyer, Orkun S|Pfeiffer, Thomas', 'Systems Biology Program, School of Engineering, Computing and Mathematics, University of Exeter, Exeter, United Kingdom. O.S.Soyer@exeter.ac.uk|Systems Biology Program, School of Engineering, Computing and Mathematics, University of Exeter, Exeter, United Kingdom. O.S.Soyer@exeter.ac.uk', 'United Kingdom|United Kingdom', 0, 'Biological Evolution|Biomass|Computer Simulation|Environment|Gene Deletion|Metabolic Networks and Pathways|Models, Biological|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000907', '20865149', 'A high level of robustness against gene deletion is observed in many organisms. However, it is still not clear which biochemical features underline this robustness and how these are acquired during evolution. One hypothesis, specific to metabolic networks, is that robustness emerges as a byproduct of selection for biomass production in different environments. To test this hypothesis we performed evolutionary simulations of metabolic networks under stable and fluctuating environments. We find that networks evolved under the latter scenario can better tolerate single gene deletion in specific environments. Such robustness is underlined by an increased number of independent fluxes and multifunctional enzymes in the evolved networks. Observed robustness in networks evolved under fluctuating environments was apparent, in the sense that it decreased significantly as we tested effects of gene deletions under all environments experienced during evolution. Furthermore, when we continued evolution of these networks under a stable environment, we found that any robustness they had acquired was completely lost. These findings provide evidence that evolution under fluctuating environments can account for the observed robustness in metabolic networks. Further, they suggest that organisms living under stable environments should display lower robustness in their metabolic networks, and that robustness should decrease upon switching to more stable environments.'),
(84770, 2010, 'plos', 'Computational prediction and experimental verification of new MAP kinase docking sites and substrates including Gli transcription factors', 'Whisenant, Thomas C|Ho, David T|Benz, Ryan W|Rogers, Jeffrey S|Kaake, Robyn M|Gordon, Elizabeth A|Huang, Lan|Baldi, Pierre|Bardwell, Lee', 'Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America.|Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America.|Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America.|Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America.|Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America.|Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America.|Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America.|Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America.|Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Algorithms|Artificial Intelligence|Binding Sites|Genome, Human|Humans|Knowledge Bases|Kruppel-Like Transcription Factors|Mitogen-Activated Protein Kinases|Nerve Tissue Proteins|Protein Binding|Substrate Specificity|Transcription Factors|Zinc Finger Protein GLI1|Zinc Finger Protein Gli3', 'Journal Article', '10.1371/journal.pcbi.1000908', '20865152', 'In order to fully understand protein kinase networks, new methods are needed to identify regulators and substrates of kinases, especially for weakly expressed proteins. Here we have developed a hybrid computational search algorithm that combines machine learning and expert knowledge to identify kinase docking sites, and used this algorithm to search the human genome for novel MAP kinase substrates and regulators focused on the JNK family of MAP kinases. Predictions were tested by peptide array followed by rigorous biochemical verification with in vitro binding and kinase assays on wild-type and mutant proteins. Using this procedure, we found new D-site class docking sites in previously known JNK substrates (hnRNP-K, PPM1J/PP2Czeta), as well as new JNK-interacting proteins (MLL4, NEIL1). Finally, we identified new D-site-dependent MAPK substrates, including the hedgehog-regulated transcription factors Gli1 and Gli3, suggesting that a direct connection between MAP kinase and hedgehog signaling may occur at the level of these key regulators. These results demonstrate that a genome-wide search for MAP kinase docking sites can be used to find new docking sites and substrates.'),
(84771, 2010, 'plos', 'Nonlinear gap junctions enable long-distance propagation of pulsating calcium waves in astrocyte networks', 'Goldberg, Mati|De Pittà, Maurizio|Volman, Vladislav|Berry, Hugues|Ben-Jacob, Eshel', 'School of Physics and Astronomy, Tel Aviv University, Ramat Aviv, Israel.|School of Physics and Astronomy, Tel Aviv University, Ramat Aviv, Israel.|School of Physics and Astronomy, Tel Aviv University, Ramat Aviv, Israel.|School of Physics and Astronomy, Tel Aviv University, Ramat Aviv, Israel.|School of Physics and Astronomy, Tel Aviv University, Ramat Aviv, Israel.', 'Israel|Israel|Israel|Israel|Israel', 0, 'Astrocytes|Brain|Calcium Signaling|Gap Junctions|Humans|Inositol 1,4,5-Trisphosphate|Models, Neurological|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.1000909', '20865153', 'A new paradigm has recently emerged in brain science whereby communications between glial cells and neuron-glia interactions should be considered together with neurons and their networks to understand higher brain functions. In particular, astrocytes, the main type of glial cells in the cortex, have been shown to communicate with neurons and with each other. They are thought to form a gap-junction-coupled syncytium supporting cell-cell communication via propagating Ca(2+) waves. An identified mode of propagation is based on cytoplasm-to-cytoplasm transport of inositol trisphosphate (IP(3)) through gap junctions that locally trigger Ca(2+) pulses via IP(3)-dependent Ca(2+)-induced Ca(2+) release. It is, however, currently unknown whether this intracellular route is able to support the propagation of long-distance regenerative Ca(2+) waves or is restricted to short-distance signaling. Furthermore, the influence of the intracellular signaling dynamics on intercellular propagation remains to be understood. In this work, we propose a model of the gap-junctional route for intercellular Ca(2+) wave propagation in astrocytes. Our model yields two major predictions. First, we show that long-distance regenerative signaling requires nonlinear coupling in the gap junctions. Second, we show that even with nonlinear gap junctions, long-distance regenerative signaling is favored when the internal Ca(2+) dynamics implements frequency modulation-encoding oscillations with pulsating dynamics, while amplitude modulation-encoding dynamics tends to restrict the propagation range. As a result, spatially heterogeneous molecular properties and/or weak couplings are shown to give rise to rich spatiotemporal dynamics that support complex propagation behaviors. These results shed new light on the mechanisms implicated in the propagation of Ca(2+) waves across astrocytes and the precise conditions under which glial cells may participate in information processing in the brain.'),
(84772, 2010, 'plos', 'Gene expression variability within and between human populations and implications toward disease susceptibility', 'Li, Jingjing|Liu, Yu|Kim, Taehyung|Min, Renqiang|Zhang, Zhaolei', 'Department of Molecular Genetics, University of Toronto, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.', 'Canada|Canada|Canada|Canada|Canada', 0, 'Chemokines|Female|Gene Expression Profiling|Genetic Predisposition to Disease|Genetic Variation|HIV Infections|HIV-1|Heterozygote|Humans|Male|Models, Genetic|Polymorphism, Single Nucleotide|Population|Untranslated Regions|Virus Internalization|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.1000910', '20865155', 'Variations in gene expression level might lead to phenotypic diversity across individuals or populations. Although many human genes are found to have differential mRNA levels between populations, the extent of gene expression that could vary within and between populations largely remains elusive. To investigate the dynamic range of gene expression, we analyzed the expression variability of xe2x88xbc18, 000 human genes across individuals within HapMap populations. Although xe2x88xbc20% of human genes show differentiated mRNA levels between populations, our results show that expression variability of most human genes in one population is not significantly deviant from another population, except for a small fraction that do show substantially higher expression variability in a particular population. By associating expression variability with sequence polymorphism, intriguingly, we found SNPs in the untranslated regions (5 and 3UTRs) of these variable genes show consistently elevated population heterozygosity. We performed differential expression analysis on a genome-wide scale, and found substantially reduced expression variability for a large number of genes, prohibiting them from being differentially expressed between populations. Functional analysis revealed that genes with the greatest within-population expression variability are significantly enriched for chemokine signaling in HIV-1 infection, and for HIV-interacting proteins that control viral entry, replication, and propagation. This observation combined with the finding that known human HIV host factors show substantially elevated expression variability, collectively suggest that gene expression variability might explain differential HIV susceptibility across individuals.'),
(84773, 2010, 'plos', 'Evidence of functional protein dynamics from X-ray crystallographic ensembles', 'Kohn, Jonathan E|Afonine, Pavel V|Ruscio, Jory Z|Adams, Paul D|Head-Gordon, Teresa', 'Department of Bioengineering, University of California, Berkeley, Berkeley, California, United States of America.|Department of Bioengineering, University of California, Berkeley, Berkeley, California, United States of America.|Department of Bioengineering, University of California, Berkeley, Berkeley, California, United States of America.|Department of Bioengineering, University of California, Berkeley, Berkeley, California, United States of America.|Department of Bioengineering, University of California, Berkeley, Berkeley, California, United States of America.', 'United States|United States|United States|United States|United States', 32, 'Animals|Crystallography, X-Ray|Models, Molecular|Molecular Dynamics Simulation|Muramidase|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1000911', '20865158', 'It is widely recognized that representing a protein as a single static conformation is inadequate to describe the dynamics essential to the performance of its biological function. We contrast the amino acid displacements below and above the protein dynamical transition temperature, T(D)xe2x88xbc215K, of hen egg white lysozyme using X-ray crystallography ensembles that are analyzed by molecular dynamics simulations as a function of temperature. We show that measuring structural variations across an ensemble of X-ray derived models captures the activation of conformational states that are of functional importance just above T(D), and they remain virtually identical to structural motions measured at 300K. Our results highlight the ability to observe functional structural variations across an ensemble of X-ray crystallographic data, and that residue fluctuations measured in MD simulations at room temperature are in quantitative agreement with the experimental observable.'),
(84774, 2010, 'plos', 'Linking changes in epithelial morphogenesis to cancer mutations using computational modeling', 'Rejniak, Katarzyna A|Wang, Shizhen E|Bryce, Nicole S|Chang, Hang|Parvin, Bahram|Jourquin, Jerome|Estrada, Lourdes|Gray, Joe W|Arteaga, Carlos L|Weaver, Alissa M|Quaranta, Vito|Anderson, Alexander R A', 'Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America. Kasia.Rejniak@moffitt.org|Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America. Kasia.Rejniak@moffitt.org|Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America. Kasia.Rejniak@moffitt.org|Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America. Kasia.Rejniak@moffitt.org|Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America. Kasia.Rejniak@moffitt.org|Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America. Kasia.Rejniak@moffitt.org|Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America. Kasia.Rejniak@moffitt.org|Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America. Kasia.Rejniak@moffitt.org|Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America. Kasia.Rejniak@moffitt.org|Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America. Kasia.Rejniak@moffitt.org|Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America. Kasia.Rejniak@moffitt.org|Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America. Kasia.Rejniak@moffitt.org', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Apoptosis|Breast Neoplasms|Cell Proliferation|Computer Simulation|Epithelium|Extracellular Matrix|Female|Humans|Mammary Glands, Human|Models, Biological|Morphogenesis|Mutation|Receptor, ErbB-2', 'Journal Article', '10.1371/journal.pcbi.1000900', '20865159', 'Most tumors arise from epithelial tissues, such as mammary glands and lobules, and their initiation is associated with the disruption of a finely defined epithelial architecture. Progression from intraductal to invasive tumors is related to genetic mutations that occur at a subcellular level but manifest themselves as functional and morphological changes at the cellular and tissue scales, respectively. Elevated proliferation and loss of epithelial polarization are the two most noticeable changes in cell phenotypes during this process. As a result, many three-dimensional cultures of tumorigenic clones show highly aberrant morphologies when compared to regular epithelial monolayers enclosing the hollow lumen (acini). In order to shed light on phenotypic changes associated with tumor cells, we applied the bio-mechanical IBCell model of normal epithelial morphogenesis quantitatively matched to data acquired from the non-tumorigenic human mammary cell line, MCF10A. We then used a high-throughput simulation study to reveal how modifications in model parameters influence changes in the simulated architecture. Three parameters have been considered in our study, which define cell sensitivity to proliferative, apoptotic and cell-ECM adhesive cues. By mapping experimental morphologies of four MCF10A-derived cell lines carrying different oncogenic mutations onto the model parameter space, we identified changes in cellular processes potentially underlying structural modifications of these mutants. As a case study, we focused on MCF10A cells expressing an oncogenic mutant HER2-YVMA to quantitatively assess changes in cell doubling time, cell apoptotic rate, and cell sensitivity to ECM accumulation when compared to the parental non-tumorigenic cell line. By mapping in vitro mutant morphologies onto in silico ones we have generated a means of linking the morphological and molecular scales via computational modeling. Thus, IBCell in combination with 3D acini cultures can form a computational/experimental platform for suggesting the relationship between the histopathology of neoplastic lesions and their underlying molecular defects.'),
(84775, 2010, 'plos', 'An introduction to biomolecular graphics', 'Mura, Cameron|McCrimmon, Colin M|Vertrees, Jason|Sawaya, Michael R', 'Department of Chemistry, University of Virginia, Charlottesville, Virginia, United States of America. cmura@virginia.edu|Department of Chemistry, University of Virginia, Charlottesville, Virginia, United States of America. cmura@virginia.edu|Department of Chemistry, University of Virginia, Charlottesville, Virginia, United States of America. cmura@virginia.edu|Department of Chemistry, University of Virginia, Charlottesville, Virginia, United States of America. cmura@virginia.edu', 'United States|United States|United States|United States', 25, 'Binding Sites|Computer Graphics|Ligands|Protein Conformation|Software', 'Journal Article', '10.1371/journal.pcbi.1000918', '20865174', '-'),
(84776, 2010, 'plos', 'Literature mining for the discovery of hidden connections between drugs, genes and diseases', 'Frijters, Raoul|van Vugt, Marianne|Smeets, Ruben|van Schaik, René|de Vlieg, Jacob|Alkema, Wynand', 'Computational Drug Discovery (CDD), Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.|Computational Drug Discovery (CDD), Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.|Computational Drug Discovery (CDD), Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.|Computational Drug Discovery (CDD), Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.|Computational Drug Discovery (CDD), Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.|Computational Drug Discovery (CDD), Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 103, 'Computational Biology|Data Mining|Disease|Drug Discovery|Genes|Humans|Leukocytes, Mononuclear|MEDLINE|Metabolic Networks and Pathways|Pattern Recognition, Automated|Pharmaceutical Preparations|ROC Curve|Reproducibility of Results|Signal Transduction|Software', 'Journal Article', '10.1371/journal.pcbi.1000943', '20885778', 'The scientific literature represents a rich source for retrieval of knowledge on associations between biomedical concepts such as genes, diseases and cellular processes. A commonly used method to establish relationships between biomedical concepts from literature is co-occurrence. Apart from its use in knowledge retrieval, the co-occurrence method is also well-suited to discover new, hidden relationships between biomedical concepts following a simple ABC-principle, in which A and C have no direct relationship, but are connected via shared B-intermediates. In this paper we describe CoPub Discovery, a tool that mines the literature for new relationships between biomedical concepts. Statistical analysis using ROC curves showed that CoPub Discovery performed well over a wide range of settings and keyword thesauri. We subsequently used CoPub Discovery to search for new relationships between genes, drugs, pathways and diseases. Several of the newly found relationships were validated using independent literature sources. In addition, new predicted relationships between compounds and cell proliferation were validated and confirmed experimentally in an in vitro cell proliferation assay. The results show that CoPub Discovery is able to identify novel associations between genes, drugs, pathways and diseases that have a high probability of being biologically valid. This makes CoPub Discovery a useful tool to unravel the mechanisms behind disease, to find novel drug targets, or to find novel applications for existing drugs.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84777, 2010, 'plos', 'Semantic similarity for automatic classification of chemical compounds', 'Ferreira, João D|Couto, Francisco M', 'LaSIGE, University of Lisbon, Lisbon, Portugal. joao.ferreira@lasige.di.fc.ul.pt|LaSIGE, University of Lisbon, Lisbon, Portugal. joao.ferreira@lasige.di.fc.ul.pt', 'Portugal|Portugal', 0, 'Algorithms|Artificial Intelligence|Blood-Brain Barrier|Chemical Phenomena|Classification|Computational Biology|Databases, Factual|Organic Chemicals|Pattern Recognition, Automated|Pharmaceutical Preparations|Reproducibility of Results|Software|Structure-Activity Relationship|Terminology as Topic', 'Journal Article', '10.1371/journal.pcbi.1000937', '20885779', 'With the increasing amount of data made available in the chemical field, there is a strong need for systems capable of comparing and classifying chemical compounds in an efficient and effective way. The best approaches existing today are based on the structure-activity relationship premise, which states that biological activity of a molecule is strongly related to its structural or physicochemical properties. This work presents a novel approach to the automatic classification of chemical compounds by integrating semantic similarity with existing structural comparison methods. Our approach was assessed based on the Matthews Correlation Coefficient for the prediction, and achieved values of 0.810 when used as a prediction of blood-brain barrier permeability, 0.694 for P-glycoprotein substrate, and 0.673 for estrogen receptor binding activity. These results expose a significant improvement over the currently existing methods, whose best performances were 0.628, 0.591, and 0.647 respectively. It was demonstrated that the integration of semantic similarity is a feasible and effective way to improve existing chemical compound classification systems. Among other possible uses, this tool helps the study of the evolution of metabolic pathways, the study of the correlation of metabolic networks with properties of those networks, or the improvement of ontologies that represent chemical information.'),
(84778, 2010, 'plos', 'Differentially expressed RNA from public microarray data identifies serum protein biomarkers for cross-organ transplant rejection and other conditions', 'Chen, Rong|Sigdel, Tara K|Li, Li|Kambham, Neeraja|Dudley, Joel T|Hsieh, Szu-Chuan|Klassen, R Bryan|Chen, Amery|Caohuu, Tuyen|Morgan, Alexander A|Valantine, Hannah A|Khush, Kiran K|Sarwal, Minnie M|Butte, Atul J', 'Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Biomarkers|Blood Proteins|Computational Biology|Data Mining|Databases, Genetic|Enzyme-Linked Immunosorbent Assay|Gene Expression Profiling|Graft Rejection|Heart Transplantation|Histocytochemistry|Humans|Kidney Glomerulus|Kidney Transplantation|Oligonucleotide Array Sequence Analysis|Proteinuria|RNA|ROC Curve|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000940', '20885780', 'Serum proteins are routinely used to diagnose diseases, but are hard to find due to low sensitivity in screening the serum proteome. Public repositories of microarray data, such as the Gene Expression Omnibus (GEO), contain RNA expression profiles for more than 16,000 biological conditions, covering more than 30% of United States mortality. We hypothesized that genes coding for serum- and urine-detectable proteins, and showing differential expression of RNA in disease-damaged tissues would make ideal diagnostic protein biomarkers for those diseases. We showed that predicted protein biomarkers are significantly enriched for known diagnostic protein biomarkers in 22 diseases, with enrichment significantly higher in diseases for which at least three datasets are available. We then used this strategy to search for new biomarkers indicating acute rejection (AR) across different types of transplanted solid organs. We integrated three biopsy-based microarray studies of AR from pediatric renal, adult renal and adult cardiac transplantation and identified 45 genes upregulated in all three. From this set, we chose 10 proteins for serum ELISA assays in 39 renal transplant patients, and discovered three that were significantly higher in AR. Interestingly, all three proteins were also significantly higher during AR in the 63 cardiac transplant recipients studied. Our best marker, serum PECAM1, identified renal AR with 89% sensitivity and 75% specificity, and also showed increased expression in AR by immunohistochemistry in renal, hepatic and cardiac transplant biopsies. Our results demonstrate that integrating gene expression microarray measurements from disease samples and even publicly-available data sets can be a powerful, fast, and cost-effective strategy for the discovery of new diagnostic serum protein biomarkers.'),
(84779, 2010, 'plos', 'Molecular dynamics simulations suggest that electrostatic funnel directs binding of Tamiflu to influenza N1 neuraminidases', 'Le, Ly|Lee, Eric H|Hardy, David J|Truong, Thanh N|Schulten, Klaus', 'Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Antiviral Agents|Binding Sites|Drug Resistance, Viral|Hydrogen Bonding|Influenza A Virus, H1N1 Subtype|Influenza A Virus, H5N1 Subtype|Molecular Dynamics Simulation|Neuraminidase|Oseltamivir|Point Mutation|Protein Binding|Static Electricity|Viral Proteins', 'Journal Article', '10.1371/journal.pcbi.1000939', '20885781', 'Oseltamivir (Tamiflu) is currently the frontline antiviral drug employed to fight the flu virus in infected individuals by inhibiting neuraminidase, a flu protein responsible for the release of newly synthesized virions. However, oseltamivir resistance has become a critical problem due to rapid mutation of the flu virus. Unfortunately, how mutations actually confer drug resistance is not well understood. In this study, we employ molecular dynamics (MD) and steered molecular dynamics (SMD) simulations, as well as graphics processing unit (GPU)-accelerated electrostatic mapping, to uncover the mechanism behind point mutation induced oseltamivir-resistance in both H5N1 avian and H1N1pdm swine flu N1-subtype neuraminidases. The simulations reveal an electrostatic binding funnel that plays a key role in directing oseltamivir into and out of its binding site on N1 neuraminidase. The binding pathway for oseltamivir suggests how mutations disrupt drug binding and how new drugs may circumvent the resistance mechanisms.'),
(84780, 2010, 'plos', 'Experimental and computational analysis of polyglutamine-mediated cytotoxicity', 'Tang, Matthew Y|Proctor, Carole J|Woulfe, John|Gray, Douglas A', 'Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.', 'Canada|Canada|Canada|Canada', 10, 'Cell Death|Cell Line, Tumor|Cell Survival|Computational Biology|Computer Simulation|Enzyme Inhibitors|Humans|Inclusion Bodies|Microscopy, Fluorescence|Microscopy, Video|Neurodegenerative Diseases|Peptides|Proteasome Endopeptidase Complex|Protein Folding|Reactive Oxygen Species|Stochastic Processes|Time-Lapse Imaging|p38 Mitogen-Activated Protein Kinases', 'Journal Article', '10.1371/journal.pcbi.1000944', '20885783', 'Expanded polyglutamine (polyQ) proteins are known to be the causative agents of a number of human neurodegenerative diseases but the molecular basis of their cytoxicity is still poorly understood. PolyQ tracts may impede the activity of the proteasome, and evidence from single cell imaging suggests that the sequestration of polyQ into inclusion bodies can reduce the proteasomal burden and promote cell survival, at least in the short term. The presence of misfolded protein also leads to activation of stress kinases such as p38MAPK, which can be cytotoxic. The relationships of these systems are not well understood. We have used fluorescent reporter systems imaged in living cells, and stochastic computer modeling to explore the relationships of polyQ, p38MAPK activation, generation of reactive oxygen species (ROS), proteasome inhibition, and inclusion body formation. In cells expressing a polyQ protein inclusion, body formation was preceded by proteasome inhibition but cytotoxicity was greatly reduced by administration of a p38MAPK inhibitor. Computer simulations suggested that without the generation of ROS, the proteasome inhibition and activation of p38MAPK would have significantly reduced toxicity. Our data suggest a vicious cycle of stress kinase activation and proteasome inhibition that is ultimately lethal to cells. There was close agreement between experimental data and the predictions of a stochastic computer model, supporting a central role for proteasome inhibition and p38MAPK activation in inclusion body formation and ROS-mediated cell death.'),
(84781, 2010, 'plos', 'Finding the dark matter in human and yeast protein network prediction and modelling', 'Ranea, Juan A G|Morilla, Ian|Lees, Jon G|Reid, Adam J|Yeats, Corin|Clegg, Andrew B|Sanchez-Jimenez, Francisca|Orengo, Christine', 'Research Department of Structural & Molecular Biology, University College London, London, United Kingdom.|Research Department of Structural & Molecular Biology, University College London, London, United Kingdom.|Research Department of Structural & Molecular Biology, University College London, London, United Kingdom.|Research Department of Structural & Molecular Biology, University College London, London, United Kingdom.|Research Department of Structural & Molecular Biology, University College London, London, United Kingdom.|Research Department of Structural & Molecular Biology, University College London, London, United Kingdom.|Research Department of Structural & Molecular Biology, University College London, London, United Kingdom.|Research Department of Structural & Molecular Biology, University College London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 16, 'Computational Biology|Databases, Protein|Fungal Proteins|Humans|Models, Molecular|Models, Statistical|Monte Carlo Method|Protein Interaction Mapping|Proteome|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1000945', '20885791', 'Accurate modelling of biological systems requires a deeper and more complete knowledge about the molecular components and their functional associations than we currently have. Traditionally, new knowledge on protein associations generated by experiments has played a central role in systems modelling, in contrast to generally less trusted bio-computational predictions. However, we will not achieve realistic modelling of complex molecular systems if the current experimental designs lead to biased screenings of real protein networks and leave large, functionally important areas poorly characterised. To assess the likelihood of this, we have built comprehensive network models of the yeast and human proteomes by using a meta-statistical integration of diverse computationally predicted protein association datasets. We have compared these predicted networks against combined experimental datasets from seven biological resources at different level of statistical significance. These eukaryotic predicted networks resemble all the topological and noise features of the experimentally inferred networks in both species, and we also show that this observation is not due to random behaviour. In addition, the topology of the predicted networks contains information on true protein associations, beyond the constitutive first order binary predictions. We also observe that most of the reliable predicted protein associations are experimentally uncharacterised in our models, constituting the hidden or dark matter of networks by analogy to astronomical systems. Some of this dark matter shows enrichment of particular functions and contains key functional elements of protein networks, such as hubs associated with important functional areas like the regulation of Ras protein signal transduction in human cells. Thus, characterising this large and functionally important dark matter, elusive to established experimental designs, may be crucial for modelling biological systems. In any case, these predictions provide a valuable guide to these experimentally elusive regions.'),
(84782, 2010, 'plos', 'Insights into the evolution and emergence of a novel infectious disease', 'Kubiak, Ruben J|Arinaminpathy, Nimalan|McLean, Angela R', 'Institute for Emerging Infections, James Martin 21st Century School, Department of Zoology, University of Oxford, Oxford, UK. ruben.kubiak@zoo.ox.ac.uk|Institute for Emerging Infections, James Martin 21st Century School, Department of Zoology, University of Oxford, Oxford, UK. ruben.kubiak@zoo.ox.ac.uk|Institute for Emerging Infections, James Martin 21st Century School, Department of Zoology, University of Oxford, Oxford, UK. ruben.kubiak@zoo.ox.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 13, 'Algorithms|Animals|Biological Evolution|Cities|Communicable Diseases, Emerging|Computational Biology|Computer Simulation|Demography|Host-Pathogen Interactions|Humans|Influenza A Virus, H5N1 Subtype|Models, Biological|Orthomyxoviridae Infections|Reproducibility of Results|Rural Population|Stochastic Processes|Transportation|Zoonoses', 'Journal Article', '10.1371/journal.pcbi.1000947', '20941384', 'Many zoonotic, novel infectious diseases in humans appear as sporadic infections with spatially and temporally restricted outbreaks, as seen with influenza A(H5N1). Adaptation is often a key factor for successfully establishing sustained human-to-human transmission. Here we use simple mathematical models to describe different adaptation scenarios with particular reference to spatial heterogeneity within the human population. We present analytical expressions for the probability of emergence per introduction, as well as the waiting time to a successful emergence event. Furthermore, we derive general analytical results for the statistical properties of emergence events, including the probability distribution of outbreak sizes. We compare our analytical results with a stochastic model, which has previously been studied computationally. Our results suggest that, for typical connection strengths between communities, spatial heterogeneity has only a weak effect on outbreak size distributions, and on the risk of emergence per introduction. For example, if Rxe2x82x80 = 1.4 or larger, any village connected to a large city by just ten commuters a day is, effectively, just a part of the city when considering the chances of emergence and the outbreak size distribution. We present empirical data on commuting patterns and show that the vast majority of communities for which such data are available are at least this well interconnected. For plausible parameter ranges, the effects of spatial heterogeneity are likely to be dominated by the evolutionary biology of host adaptation. We conclude by discussing implications for surveillance and control of emerging infections.'),
(84783, 2010, 'plos', 'Ten simple rules for editing Wikipedia', 'Logan, Darren W|Sandal, Massimo|Gardner, Paul P|Manske, Magnus|Bateman, Alex', 'Institute for Emerging Infections, James Martin 21st Century School, Department of Zoology, University of Oxford, Oxford, UK. ruben.kubiak@zoo.ox.ac.uk|Institute for Emerging Infections, James Martin 21st Century School, Department of Zoology, University of Oxford, Oxford, UK. ruben.kubiak@zoo.ox.ac.uk|Institute for Emerging Infections, James Martin 21st Century School, Department of Zoology, University of Oxford, Oxford, UK. ruben.kubiak@zoo.ox.ac.uk|Institute for Emerging Infections, James Martin 21st Century School, Department of Zoology, University of Oxford, Oxford, UK. ruben.kubiak@zoo.ox.ac.uk|Institute for Emerging Infections, James Martin 21st Century School, Department of Zoology, University of Oxford, Oxford, UK. ruben.kubiak@zoo.ox.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Editorial Policies|Humans|Information Services|Internet|Writing', 'Editorial', '10.1371/journal.pcbi.1000941', '20941386', '-'),
(84784, 2010, 'plos', 'Systems biology of coagulation initiation: kinetics of thrombin generation in resting and activated human blood', 'Chatterjee, Manash S|Denney, William S|Jing, Huiyan|Diamond, Scott L', 'Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, University of Pennsylvania. Philadelphia, Pennslyvania, United States of America.|Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, University of Pennsylvania. Philadelphia, Pennslyvania, United States of America.|Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, University of Pennsylvania. Philadelphia, Pennslyvania, United States of America.|Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, University of Pennsylvania. Philadelphia, Pennslyvania, United States of America.', 'United States|United States|United States|United States', 0, 'Blood Coagulation|Blood Coagulation Factors|Computer Simulation|Crotalid Venoms|Factor XIIa|Fibrinolytic Agents|Fluorescent Dyes|High-Throughput Screening Assays|Humans|Immunoassay|Lectins, C-Type|Metabolic Networks and Pathways|Plant Proteins|Platelet Activation|Reproducibility of Results|Systems Biology|Thrombin|Thromboplastin', 'Journal Article', '10.1371/journal.pcbi.1000950', '20941387', 'Blood function defines bleeding and clotting risks and dictates approaches for clinical intervention. Independent of adding exogenous tissue factor (TF), human blood treated in vitro with corn trypsin inhibitor (CTI, to block Factor XIIa) will generate thrombin after an initiation time (T(i)) of 1 to 2 hours (depending on donor), while activation of platelets with the GPVI-activator convulxin reduces T(i) to xe2x88xbc20 minutes. Since current kinetic models fail to generate thrombin in the absence of added TF, we implemented a Platelet-Plasma ODE model accounting for: the Hockin-Mann protease reaction network, thrombin-dependent display of platelet phosphatidylserine, VIIa function on activated platelets, XIIa and XIa generation and function, competitive thrombin substrates (fluorogenic detector and fibrinogen), and thrombin consumption during fibrin polymerization. The kinetic model consisting of 76 ordinary differential equations (76 species, 57 reactions, 105 kinetic parameters) predicted the clotting of resting and convulxin-activated human blood as well as predicted T(i) of human blood under 50 different initial conditions that titrated increasing levels of TF, Xa, Va, XIa, IXa, and VIIa. Experiments with combined anti-XI and anti-XII antibodies prevented thrombin production, demonstrating that a leak of XIIa past saturating amounts of CTI (and not blood-borne TF alone) was responsible for in vitro initiation without added TF. Clotting was not blocked by antibodies used individually against TF, VII/VIIa, P-selectin, GPIb, protein disulfide isomerase, cathepsin G, nor blocked by the ribosome inhibitor puromycin, the Clk1 kinase inhibitor Tg003, or inhibited VIIa (VIIai). This is the first model to predict the observed behavior of CTI-treated human blood, either resting or stimulated with platelet activators. CTI-treated human blood will clot in vitro due to the combined activity of XIIa and XIa, a process enhanced by platelet activators and which proceeds in the absence of any evidence for kinetically significant blood borne tissue factor.'),
(84785, 2010, 'plos', 'Quantitative analysis of immune response and erythropoiesis during rodent malarial infection', 'Miller, Martin R|Råberg, Lars|Read, Andrew F|Savill, Nicholas J', 'Centre for Infectious Diseases, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Infectious Diseases, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Infectious Diseases, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Infectious Diseases, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 23, 'Algorithms|Animals|Bayes Theorem|Erythrocytes|Erythropoiesis|Hemolysis|Host-Parasite Interactions|Malaria|Markov Chains|Merozoites|Mice|Mice, Inbred BALB C|Mice, Nude|Models, Biological|Monte Carlo Method|Parasitemia|Plasmodium chabaudi', 'Journal Article', '10.1371/journal.pcbi.1000946', '20941388', 'Malarial infection is associated with complex immune and erythropoietic responses in the host. A quantitative understanding of these processes is essential to help inform malaria therapy and for the design of effective vaccines. In this study, we use a statistical model-fitting approach to investigate the immune and erythropoietic responses in Plasmodium chabaudi infections of mice. Three mouse phenotypes (wildtype, T-cell-deficient nude mice, and nude mice reconstituted with T-cells taken from wildtype mice) were infected with one of two parasite clones (AS or AJ). Under a Bayesian framework, we use an adaptive population-based Markov chain Monte Carlo method and fit a set of dynamical models to observed data on parasite and red blood cell (RBC) densities. Model fits are compared using Bayes factors and parameter estimates obtained. We consider three independent immune mechanisms: clearance of parasitised RBCs (pRBC), clearance of unparasitised RBCs (uRBC), and clearance of parasites that burst from RBCs (merozoites). Our results suggest that the immune response of wildtype mice is associated with less destruction of uRBCs, compared to the immune response of nude mice. There is a greater degree of synchronisation between pRBC and uRBC clearance than between either mechanism and merozoite clearance. In all three mouse phenotypes, control of the peak of parasite density is associated with pRBC clearance. In wildtype mice and AS-infected nude mice, control of the peak is also associated with uRBC clearance. Our results suggest that uRBC clearance, rather than RBC infection, is the major determinant of RBC dynamics from approximately day 12 post-innoculation. During the first 2-3 weeks of blood-stage infection, immune-mediated clearance of pRBCs and uRBCs appears to have a much stronger effect than immune-mediated merozoite clearance. Upregulation of erythropoiesis is dependent on mouse phenotype and is greater in wildtype and reconstitited mice. Our study highlights the informative power of statistically rigorous model-fitting techniques in elucidating biological systems.'),
(84786, 2010, 'plos', 'HIV promoter integration site primarily modulates transcriptional burst size rather than frequency', 'Skupsky, Ron|Burnett, John C|Foley, Jonathan E|Schaffer, David V|Arkin, Adam P', 'California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, California, United States of America.|California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, California, United States of America.|California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, California, United States of America.|California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, California, United States of America.|California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, California, United States of America.', 'United States|United States|United States|United States|United States', 0, 'HEK293 Cells|HIV|HIV Long Terminal Repeat|Host-Pathogen Interactions|Humans|Jurkat Cells|Markov Chains|Models, Genetic|Particle Size|Promoter Regions, Genetic|Stochastic Processes|Transcription, Genetic|Virus Integration', 'Journal Article', '10.1371/journal.pcbi.1000952', '20941390', 'Mammalian gene expression patterns, and their variability across populations of cells, are regulated by factors specific to each gene in concert with its surrounding cellular and genomic environment. Lentiviruses such as HIV integrate their genomes into semi-random genomic locations in the cells they infect, and the resulting viral gene expression provides a natural system to dissect the contributions of genomic environment to transcriptional regulation. Previously, we showed that expression heterogeneity and its modulation by specific host factors at HIV integration sites are key determinants of infected-cell fate and a possible source of latent infections. Here, we assess the integration context dependence of expression heterogeneity from diverse single integrations of a HIV-promoter/GFP-reporter cassette in Jurkat T-cells. Systematically fitting a stochastic model of gene expression to our data reveals an underlying transcriptional dynamic, by which multiple transcripts are produced during short, infrequent bursts, that quantitatively accounts for the wide, highly skewed protein expression distributions observed in each of our clonal cell populations. Interestingly, we find that the size of transcriptional bursts is the primary systematic covariate over integration sites, varying from a few to tens of transcripts across integration sites, and correlating well with mean expression. In contrast, burst frequencies are scattered about a typical value of several per cell-division time and demonstrate little correlation with the clonal means. This pattern of modulation generates consistently noisy distributions over the sampled integration positions, with large expression variability relative to the mean maintained even for the most productive integrations, and could contribute to specifying heterogeneous, integration-site-dependent viral production patterns in HIV-infected cells. Genomic environment thus emerges as a significant control parameter for gene expression variation that may contribute to structuring mammalian genomes, as well as be exploited for survival by integrating viruses.'),
(84787, 2010, 'plos', 'Synchronization of firing in cortical fast-spiking interneurons at gamma frequencies: a phase-resetting analysis', 'Gouwens, Nathan W|Zeberg, Hugo|Tsumoto, Kunichika|Tateno, Takashi|Aihara, Kazuyuki|Robinson, Hugh P C', 'Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.|Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.|Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.|Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.|Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.|Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 29, 'Animals|Chi-Square Distribution|Computational Biology|Cortical Synchronization|Interneurons|Models, Neurological|Neocortex|Patch-Clamp Techniques|Rats|Rats, Wistar|Receptors, GABA|Synapses|Synaptic Potentials', 'Journal Article', '10.1371/journal.pcbi.1000951', '20941393', 'Fast-spiking (FS) cells in the neocortex are interconnected both by inhibitory chemical synapses and by electrical synapses, or gap-junctions. Synchronized firing of FS neurons is important in the generation of gamma oscillations, at frequencies between 30 and 80 Hz. To understand how these synaptic interactions control synchronization, artificial synaptic conductances were injected in FS cells, and the synaptic phase-resetting function (SPRF), describing how the compound synaptic input perturbs the phase of gamma-frequency spiking as a function of the phase at which it is applied, was measured. GABAergic and gap junctional conductances made distinct contributions to the SPRF, which had a surprisingly simple piecewise linear form, with a sharp midcycle break between phase delay and advance. Analysis of the SPRF showed how the intrinsic biophysical properties of FS neurons and their interconnections allow entrainment of firing over a wide gamma frequency band, whose upper and lower frequency limits are controlled by electrical synapses and GABAergic inhibition respectively.'),
(84788, 2010, 'plos', 'A computational framework for influenza antigenic cartography', 'Cai, Zhipeng|Zhang, Tong|Wan, Xiu-Feng', 'Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi, USA.|Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi, USA.|Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi, USA.', 'United States|United States|United States', 0, 'Algorithms|Animals|Antigens, Viral|Computational Biology|Databases, Factual|Ferrets|Hemagglutination Inhibition Tests|Humans|Immune Sera|Immunity, Herd|Influenza A Virus, H3N2 Subtype|Protein Interaction Mapping|Reproducibility of Results|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1000949', '20949097', 'Influenza viruses have been responsible for large losses of lives around the world and continue to present a great public health challenge. Antigenic characterization based on hemagglutination inhibition (HI) assay is one of the routine procedures for influenza vaccine strain selection. However, HI assay is only a crude experiment reflecting the antigenic correlations among testing antigens (viruses) and reference antisera (antibodies). Moreover, antigenic characterization is usually based on more than one HI dataset. The combination of multiple datasets results in an incomplete HI matrix with many unobserved entries. This paper proposes a new computational framework for constructing an influenza antigenic cartography from this incomplete matrix, which we refer to as Matrix Completion-Multidimensional Scaling (MC-MDS). In this approach, we first reconstruct the HI matrices with viruses and antibodies using low-rank matrix completion, and then generate the two-dimensional antigenic cartography using multidimensional scaling. Moreover, for influenza HI tables with herd immunity effect (such as those from Human influenza viruses), we propose a temporal model to reduce the inherent temporal bias of HI tables caused by herd immunity. By applying our method in HI datasets containing H3N2 influenza A viruses isolated from 1968 to 2003, we identified eleven clusters of antigenic variants, representing all major antigenic drift events in these 36 years. Our results showed that both the completed HI matrix and the antigenic cartography obtained via MC-MDS are useful in identifying influenza antigenic variants and thus can be used to facilitate influenza vaccine strain selection. The webserver is available at http://sysbio.cvm.msstate.edu/AntigenMap.'),
(84789, 2010, 'plos', 'Selection upon genome architecture: conservation of functional neighborhoods with changing genes', 'Al-Shahrour, Fátima|Minguez, Pablo|Marqués-Bonet, Tomás|Gazave, Elodie|Navarro, Arcadi|Dopazo, Joaquín', 'Department of Bioinformatics and Genomics, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.|Department of Bioinformatics and Genomics, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.|Department of Bioinformatics and Genomics, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.|Department of Bioinformatics and Genomics, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.|Department of Bioinformatics and Genomics, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.|Department of Bioinformatics and Genomics, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.', 'Spain|Spain|Spain|Spain|Spain|Spain', 41, 'Animals|Chickens|Chromosome Mapping|Gene Rearrangement|Genome|Genomics|Humans|Models, Genetic|Pan troglodytes|Phylogeny|Saccharomyces cerevisiae|Synteny|Zebrafish', 'Journal Article', '10.1371/journal.pcbi.1000953', '20949098', 'An increasing number of evidences show that genes are not distributed randomly across eukaryotic chromosomes, but rather in functional neighborhoods. Nevertheless, the driving force that originated and maintains such neighborhoods is still a matter of controversy. We present the first detailed multispecies cartography of genome regions enriched in genes with related functions and study the evolutionary implications of such clustering. Our results indicate that the chromosomes of higher eukaryotic genomes contain up to 12% of genes arranged in functional neighborhoods, with a high level of gene co-expression, which are consistently distributed in phylogenies. Unexpectedly, neighborhoods with homologous functions are formed by different (non-orthologous) genes in different species. Actually, instead of being conserved, functional neighborhoods present a higher degree of synteny breaks than the genome average. This scenario is compatible with the existence of selective pressures optimizing the coordinated transcription of blocks of functionally related genes. If these neighborhoods were broken by chromosomal rearrangements, selection would favor further rearrangements reconstructing other neighborhoods of similar function. The picture arising from this study is a dynamic genomic landscape with a high level of functional organization.'),
(84790, 2010, 'plos', 'Critical dynamics in the evolution of stochastic strategies for the iterated prisoners dilemma', 'Iliopoulos, Dimitris|Hintze, Arend|Adami, Christoph', 'Keck Graduate Institute for Applied Life Sciences, Claremont, California, USA.|Keck Graduate Institute for Applied Life Sciences, Claremont, California, USA.|Keck Graduate Institute for Applied Life Sciences, Claremont, California, USA.', 'United States|United States|United States', 20, 'Cell Physiological Phenomena|Computational Biology|Computer Simulation|Game Theory|Genes|Genetics, Population|Models, Genetic|Mutation|Principal Component Analysis|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1000948', '20949101', 'The observed cooperation on the level of genes, cells, tissues, and individuals has been the object of intense study by evolutionary biologists, mainly because cooperation often flourishes in biological systems in apparent contradiction to the selfish goal of survival inherent in Darwinian evolution. In order to resolve this paradox, evolutionary game theory has focused on the Prisoners Dilemma (PD), which incorporates the essence of this conflict. Here, we encode strategies for the iterated Prisoners Dilemma (IPD) in terms of conditional probabilities that represent the response of decision pathways given previous plays. We find that if these stochastic strategies are encoded as genes that undergo Darwinian evolution, the environmental conditions that the strategies are adapting to determine the fixed point of the evolutionary trajectory, which could be either cooperation or defection. A transition between cooperative and defective attractors occurs as a function of different parameters such as mutation rate, replacement rate, and memory, all of which affect a players ability to predict an opponents behavior. These results imply that in populations of players that can use previous decisions to plan future ones, cooperation depends critically on whether the players can rely on facing the same strategies that they have adapted to. Defection, on the other hand, is the optimal adaptive response in environments that change so quickly that the information gathered from previous plays cannot usefully be integrated for a response.'),
(84791, 2010, 'plos', 'Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies', 'Gnanakaran, S|Daniels, Marcus G|Bhattacharya, Tanmoy|Lapedes, Alan S|Sethi, Anurag|Li, Ming|Tang, Haili|Greene, Kelli|Gao, Hongmei|Haynes, Barton F|Cohen, Myron S|Shaw, George M|Seaman, Michael S|Kumar, Amit|Gao, Feng|Montefiori, David C|Korber, Bette', 'Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.', 'Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Me', 0, 'Algorithms|Amino Acid Sequence|Antibodies, Neutralizing|Artificial Intelligence|Cluster Analysis|Computational Biology|DNA Mutational Analysis|Epitope Mapping|Epitopes, T-Lymphocyte|HIV Envelope Protein gp120|HIV Envelope Protein gp41|HIV-1|Humans|Logistic Models|Models, Molecular|Mutation|Neutralization Tests|Phylogeny|Sequence Alignment', 'Journal Article', '10.1371/journal.pcbi.1000955', '20949103', 'A steady increase in knowledge of the molecular and antigenic structure of the gp120 and gp41 HIV-1 envelope glycoproteins (Env) is yielding important new insights for vaccine design, but it has been difficult to translate this information to an immunogen that elicits broadly neutralizing antibodies. To help bridge this gap, we used phylogenetically corrected statistical methods to identify amino acid signature patterns in Envs derived from people who have made potently neutralizing antibodies, with the hypothesis that these Envs may share common features that would be useful for incorporation in a vaccine immunogen. Before attempting this, essentially as a control, we explored the utility of our computational methods for defining signatures of complex neutralization phenotypes by analyzing Env sequences from 251 clonal viruses that were differentially sensitive to neutralization by the well-characterized gp120-specific monoclonal antibody, b12. We identified ten b12-neutralization signatures, including seven either in the b12-binding surface of gp120 or in the V2 region of gp120 that have been previously shown to impact b12 sensitivity. A simple algorithm based on the b12 signature pattern was predictive of b12 sensitivity/resistance in an additional blinded panel of 57 viruses. Upon obtaining these reassuring outcomes, we went on to apply these same computational methods to define signature patterns in Env from HIV-1 infected individuals who had potent, broadly neutralizing responses. We analyzed a checkerboard-style neutralization dataset with sera from 69 HIV-1-infected individuals tested against a panel of 25 different Envs. Distinct clusters of sera with high and low neutralization potencies were identified. Six signature positions in Env sequences obtained from the 69 samples were found to be strongly associated with either the high or low potency responses. Five sites were in the CD4-induced coreceptor binding site of gp120, suggesting an important role for this region in the elicitation of broadly neutralizing antibody responses against HIV-1.'),
(84792, 2010, 'plos', 'Wide-field motion integration in fly VS cells: insights from an inverse approach', 'Torben-Nielsen, Benjamin|Stiefel, Klaus M', 'Theoretical and Experimental Neurobiology Unit, Okinawa Institute of Science and Technology, Onna-Son, Okinawa, Japan. btorbennielsen@gmail.com|Theoretical and Experimental Neurobiology Unit, Okinawa Institute of Science and Technology, Onna-Son, Okinawa, Japan. btorbennielsen@gmail.com', 'Japan|Japan', 4, 'Algorithms|Animals|Computational Biology|Computer Simulation|Dendrites|Diptera|Electrophysiology|Ion Channels|Models, Neurological|Motion|Neurons|Visual Fields', 'Journal Article', '10.1371/journal.pcbi.1000932', '20957028', 'Fly lobula plate tangential cells are known to perform wide-field motion integration. It is assumed that the shape of these neurons, and in particular the shape of the subclass of VS cells, is responsible for this type of computation. We employed an inverse approach to investigate the morphology-function relationship underlying wide-field motion integration in VS cells. In the inverse approach detailed, model neurons are optimized to perform a predefined computation: here, wide-field motion integration. We embedded the model neurons to be optimized in a biologically plausible model of fly motion detection to provide realistic inputs, and subsequently optimized model neuron with and without active conductances (g(Na), g(K), g(K(Na))) along their dendrites to perform this computation. We found that both passive and active optimized model neurons perform well as wide-field motion integrators. In addition, all optimized morphologies share the same blueprint as real VS cells. In addition, we also found a recurring blueprint for the distribution of g(K) and g(Na) in the active models. Moreover, we demonstrate how this morphology and distribution of conductances contribute to wide-field motion integration. As such, by using the inverse approach we can predict the still unknown distribution of g(K) and g(Na) and their role in motion integration in VS cells.'),
(84793, 2010, 'plos', 'Drug off-target effects predicted using structural analysis in the context of a metabolic network model', 'Chang, Roger L|Xie, Li|Xie, Lei|Bourne, Philip E|Palsson, Bernhard Ø', 'Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Algorithms|Computational Biology|Drug Discovery|Gene Expression Profiling|Humans|Kidney|Kidney Diseases|Kidney Function Tests|Metabolic Networks and Pathways|Metabolomics|Models, Biological|Protein Binding|Proteome|Quinolines|ROC Curve', 'Journal Article', '10.1371/journal.pcbi.1000938', '20957118', 'Recent advances in structural bioinformatics have enabled the prediction of protein-drug off-targets based on their ligand binding sites. Concurrent developments in systems biology allow for prediction of the functional effects of system perturbations using large-scale network models. Integration of these two capabilities provides a framework for evaluating metabolic drug response phenotypes in silico. This combined approach was applied to investigate the hypertensive side effect of the cholesteryl ester transfer protein inhibitor torcetrapib in the context of human renal function. A metabolic kidney model was generated in which to simulate drug treatment. Causal drug off-targets were predicted that have previously been observed to impact renal function in gene-deficient patients and may play a role in the adverse side effects observed in clinical trials. Genetic risk factors for drug treatment were also predicted that correspond to both characterized and unknown renal metabolic disorders as well as cryptic genetic deficiencies that are not expected to exhibit a renal disorder phenotype except under drug treatment. This study represents a novel integration of structural and systems biology and a first step towards computational systems medicine. The methodology introduced herein has important implications for drug development and personalized medicine.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84794, 2010, 'plos', 'Non-centered spike-triggered covariance analysis reveals neurotrophin-3 as a developmental regulator of receptive field properties of ON-OFF retinal ganglion cells', 'Cantrell, Donald R|Cang, Jianhua|Troy, John B|Liu, Xiaorong', 'Interdepartmental Neuroscience Program, Northwestern University, Evanston, Illinois, USA.|Interdepartmental Neuroscience Program, Northwestern University, Evanston, Illinois, USA.|Interdepartmental Neuroscience Program, Northwestern University, Evanston, Illinois, USA.|Interdepartmental Neuroscience Program, Northwestern University, Evanston, Illinois, USA.', 'United States|United States|United States|United States', 28, 'Action Potentials|Analysis of Variance|Animals|Mice|Mice, Inbred C57BL|Mice, Transgenic|Nerve Growth Factors|Photic Stimulation|Principal Component Analysis|Retina|Retinal Ganglion Cells|Signal Transduction|Statistics, Nonparametric|Visual Fields', 'Journal Article', '10.1371/journal.pcbi.1000967', '20975932', 'The functional separation of ON and OFF pathways, one of the fundamental features of the visual system, starts in the retina. During postnatal development, some retinal ganglion cells (RGCs) whose dendrites arborize in both ON and OFF sublaminae of the inner plexiform layer transform into RGCs with dendrites that monostratify in either the ON or OFF sublamina, acquiring final dendritic morphology in a subtype-dependent manner. Little is known about how the receptive field (RF) properties of ON, OFF, and ON-OFF RGCs mature during this time because of the lack of a reliable and efficient method to classify RGCs into these subtypes. To address this deficiency, we developed an innovative variant of Spike Triggered Covariance (STC) analysis, which we term Spike Triggered Covariance - Non-Centered (STC-NC) analysis. Using a multi-electrode array (MEA), we recorded the responses of a large population of mouse RGCs to a Gaussian white noise stimulus. As expected, the Spike-Triggered Average (STA) fails to identify responses driven by symmetric static nonlinearities such as those that underlie ON-OFF center RGC behavior. The STC-NC technique, in contrast, provides an efficient means to identify ON-OFF responses and quantify their RF center sizes accurately. Using this new tool, we find that RGCs gradually develop sensitivity to focal stimulation after eye opening, that the percentage of ON-OFF center cells decreases with age, and that RF centers of ON and ON-OFF cells become smaller. Importantly, we demonstrate for the first time that neurotrophin-3 (NT-3) regulates the development of physiological properties of ON-OFF center RGCs. Overexpression of NT-3 leads to the precocious maturation of RGC responsiveness and accelerates the developmental decrease of RF center size in ON-OFF cells. In summary, our study introduces STC-NC analysis which successfully identifies subtype RGCs and demonstrates how RF development relates to a neurotrophic driver in the retina.'),
(84795, 2010, 'plos', 'Biosensor approach to psychopathology classification', 'Koshelev, Misha|Lohrenz, Terry|Vannucci, Marina|Montague, P Read', 'Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.|Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.|Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.|Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.', 'United States|United States|United States|United States', 16, 'Algorithms|Attention Deficit Disorder with Hyperactivity|Autistic Disorder|Bayes Theorem|Borderline Personality Disorder|Case-Control Studies|Cluster Analysis|Cognition|Computational Biology|Computer Simulation|Depressive Disorder, Major|Humans|Interpersonal Relations|Mental Disorders|Models, Biological|Psychology, Social|Reproducibility of Results|Role Playing|Social Behavior', 'Journal Article', '10.1371/journal.pcbi.1000966', '20975934', 'We used a multi-round, two-party exchange game in which a healthy subject played a subject diagnosed with a DSM-IV (Diagnostic and Statistics Manual-IV) disorder, and applied a Bayesian clustering approach to the behavior exhibited by the healthy subject. The goal was to characterize quantitatively the style of play elicited in the healthy subject (the proposer) by their DSM-diagnosed partner (the responder). The approach exploits the dynamics of the behavior elicited in the healthy proposer as a biosensor for cognitive features that characterize the psychopathology group at the other side of the interaction. Using a large cohort of subjects (n = 574), we found statistically significant clustering of proposers behavior overlapping with a range of DSM-IV disorders including autism spectrum disorder, borderline personality disorder, attention deficit hyperactivity disorder, and major depressive disorder. To further validate these results, we developed a computer agent to replace the human subject in the proposer role (the biosensor) and show that it can also detect these same four DSM-defined disorders. These results suggest that the highly developed social sensitivities that humans bring to a two-party social exchange can be exploited and automated to detect important psychopathologies, using an interpersonal behavioral probe not directly related to the defining diagnostic criteria.'),
(84796, 2010, 'plos', 'Non-bulk-like solvent behavior in the ribosome exit tunnel', 'Lucent, Del|Snow, Christopher D|Aitken, Colin Echeverría|Pande, Vijay S', 'Biophysics Program, Stanford University, Stanford, California, USA.|Biophysics Program, Stanford University, Stanford, California, USA.|Biophysics Program, Stanford University, Stanford, California, USA.|Biophysics Program, Stanford University, Stanford, California, USA.', 'United States|United States|United States|United States', 28, 'Archaeal Proteins|Computational Biology|Computer Simulation|Crystallography, X-Ray|Haloarcula marismortui|Molecular Dynamics Simulation|Protein Biosynthesis|Protein Folding|Ribosomes|Thermodynamics|Water', 'Journal Article', '10.1371/journal.pcbi.1000963', '20975935', 'As nascent proteins are synthesized by the ribosome, they depart via an exit tunnel running through the center of the large subunit. The exit tunnel likely plays an important part in various aspects of translation. Although water plays a key role in many bio-molecular processes, the nature of water confined to the exit tunnel has remained unknown. Furthermore, solvent in biological cavities has traditionally been characterized as either a continuous dielectric fluid, or a discrete tightly bound molecule. Using atomistic molecular dynamics simulations, we predict that the thermodynamic and kinetic properties of water confined within the ribosome exit tunnel are quite different from this simple two-state model. We find that the tunnel creates a complex microenvironment for the solvent resulting in perturbed rotational dynamics and heterogenous dielectric behavior. This gives rise to a very rugged solvation landscape and significantly retarded solvent diffusion. We discuss how this non-bulk-like solvent is likely to affect important biophysical processes such as sequence dependent stalling, co-translational folding, and antibiotic binding. We conclude with a discussion of the general applicability of these results to other biological cavities.'),
(84797, 2010, 'plos', 'Inherent high correlation of individual motility enhances population dispersal in a heterotrophic, planktonic protist', 'Menden-Deuer, Susanne', 'University of Rhode Island, Graduate School of Oceanography, Narragansett, Rhode Island, USA. smenden@gso.uri.edu', 'United States', 9, 'Analysis of Variance|Cell Movement|Computational Biology|Dinoflagellida|Image Processing, Computer-Assisted|Markov Chains|Microscopy, Video|Models, Biological|Plankton|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000942', '20975936', 'Quantitative linkages between individual organism movements and the resulting population distributions are fundamental to understanding a wide range of ecological processes, including rates of reproduction, consumption, and mortality, as well as the spread of diseases and invasions. Typically, quantitative data are collected on either movement behaviors or population distributions, rarely both. This study combines empirical observations and model simulations to gain a mechanistic understanding and predictive ability of the linkages between both individual movement behaviors and population distributions of a single-celled planktonic herbivore. In the laboratory, microscopic 3D movements and macroscopic population distributions were simultaneously quantified in a 1L tank, using automated video- and image-analysis routines. The vertical velocity component of cell movements was extracted from the empirical data and used to motivate a series of correlated random walk models that predicted population distributions. Validation of the model predictions with empirical data was essential to distinguish amongst a number of theoretically plausible model formulations. All model predictions captured the essence of the population redistribution (mean upward drift) but only models assuming long correlation times (minute), captured the variance in population distribution. Models assuming correlation times of 8 minutes predicted the least deviation from the empirical observations. Autocorrelation analysis of the empirical data failed to identify a de-correlation time in the up to 30-second-long swimming trajectories. These minute-scale estimates are considerably greater than previous estimates of second-scale correlation times. Considerable cell-to-cell variation and behavioral heterogeneity were critical to these results. Strongly correlated random walkers were predicted to have significantly greater dispersal distances and more rapid encounters with remote targets (e.g. resource patches, predators) than weakly correlated random walkers. The tendency to disperse rapidly in the absence of aggregative stimuli has important ramifications for the ecology and biogeography of planktonic organisms that perform this kind of random walk.'),
(84798, 2010, 'plos', 'Individualization as driving force of clustering phenomena in humans', 'Mäs, Michael|Flache, Andreas|Helbing, Dirk', 'Department of Sociology, Interuniversity Center for Social Science Theory and Methodology, University of Groningen, Groningen, The Netherlands. m.maes@rug.nl|Department of Sociology, Interuniversity Center for Social Science Theory and Methodology, University of Groningen, Groningen, The Netherlands. m.maes@rug.nl|Department of Sociology, Interuniversity Center for Social Science Theory and Methodology, University of Groningen, Groningen, The Netherlands. m.maes@rug.nl', 'Netherlands|Netherlands|Netherlands', 110, 'Algorithms|Animals|Anomie|Computational Biology|Computer Simulation|Cultural Diversity|Humans|Individuality|Mass Behavior|Models, Biological|Public Opinion', 'Journal Article', '10.1371/journal.pcbi.1000959', '20975937', 'One of the most intriguing dynamics in biological systems is the emergence of clustering, in the sense that individuals self-organize into separate agglomerations in physical or behavioral space. Several theories have been developed to explain clustering in, for instance, multi-cellular organisms, ant colonies, bee hives, flocks of birds, schools of fish, and animal herds. A persistent puzzle, however, is the clustering of opinions in human populations, particularly when opinions vary continuously, such as the degree to which citizens are in favor of or against a vaccination program. Existing continuous opinion formation models predict monoculture in the long run, unless subsets of the population are perfectly separated from each other. Yet, social diversity is a robust empirical phenomenon, although perfect separation is hardly possible in an increasingly connected world. Considering randomness has not overcome the theoretical shortcomings so far. Small perturbations of individual opinions trigger social influence cascades that inevitably lead to monoculture, while larger noise disrupts opinion clusters and results in rampant individualism without any social structure. Our solution to the puzzle builds on recent empirical research, combining the integrative tendencies of social influence with the disintegrative effects of individualization. A key element of the new computational model is an adaptive kind of noise. We conduct computer simulation experiments demonstrating that with this kind of noise a third phase besides individualism and monoculture becomes possible, characterized by the formation of metastable clusters with diversity between and consensus within clusters. When clusters are small, individualization tendencies are too weak to prohibit a fusion of clusters. When clusters grow too large, however, individualization increases in strength, which promotes their splitting. In summary, the new model can explain cultural clustering in human societies. Strikingly, model predictions are not only robust to noise-randomness is actually the central mechanism that sustains pluralism and clustering.'),
(84799, 2010, 'plos', 'Metabolic factors limiting performance in marathon runners', 'Rapoport, Benjamin I', 'Harvard Medical School, Boston, Massachusetts, USA. brapoport@post.harvard.edu', 'United States', 62, 'Athletic Performance|Blood Glucose|Carbohydrate Metabolism|Computational Biology|Exercise|Fats|Glycogen|Humans|Metabolism|Muscle, Skeletal|Oxygen|Physical Endurance|Running', 'Journal Article', '10.1371/journal.pcbi.1000960', '20975938', 'Each year in the past three decades has seen hundreds of thousands of runners register to run a major marathon. Of those who attempt to race over the marathon distance of 26 miles and 385 yards (42.195 kilometers), more than two-fifths experience severe and performance-limiting depletion of physiologic carbohydrate reserves (a phenomenon known as hitting the wall), and thousands drop out before reaching the finish lines (approximately 1-2% of those who start). Analyses of endurance physiology have often either used coarse approximations to suggest that human glycogen reserves are insufficient to fuel a marathon (making hitting the wall seem inevitable), or implied that maximal glycogen loading is required in order to complete a marathon without hitting the wall. The present computational study demonstrates that the energetic constraints on endurance runners are more subtle, and depend on several physiologic variables including the muscle mass distribution, liver and muscle glycogen densities, and running speed (exercise intensity as a fraction of aerobic capacity) of individual runners, in personalized but nevertheless quantifiable and predictable ways. The analytic approach presented here is used to estimate the distance at which runners will exhaust their glycogen stores as a function of running intensity. In so doing it also provides a basis for guidelines ensuring the safety and optimizing the performance of endurance runners, both by setting personally appropriate paces and by prescribing midrace fueling requirements for avoiding the wall. The present analysis also sheds physiologically principled light on important standards in marathon running that until now have remained empirically defined: The qualifying times for the Boston Marathon.'),
(84800, 2010, 'plos', 'Library of disordered patterns in 3D protein structures', 'Lobanov, Michail Yu|Furletova, Eugeniya I|Bogatyreva, Natalya S|Roytberg, Michail A|Galzitskaya, Oxana V', 'Institute of Protein Research, Russian Academy of Sciences, Pushchino, Russia.|Institute of Protein Research, Russian Academy of Sciences, Pushchino, Russia.|Institute of Protein Research, Russian Academy of Sciences, Pushchino, Russia.|Institute of Protein Research, Russian Academy of Sciences, Pushchino, Russia.|Institute of Protein Research, Russian Academy of Sciences, Pushchino, Russia.', '-|-|-|-|-', 45, 'Algorithms|Amino Acid Sequence|Bacterial Proteins|Computational Biology|Databases, Protein|Eukaryota|Molecular Sequence Data|Pattern Recognition, Automated|Protein Conformation|Proteins|Proteome|Sequence Alignment|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1000958', '20976197', 'Intrinsically disordered regions serve as molecular recognition elements, which play an important role in the control of many cellular processes and signaling pathways. It is useful to be able to predict positions of disordered regions in protein chains. The statistical analysis of disordered residues was done considering 34,464 unique protein chains taken from the PDB database. In this database, 4.95% of residues are disordered (i.e. invisible in X-ray structures). The statistics were obtained separately for the N- and C-termini as well as for the central part of the protein chain. It has been shown that frequencies of occurrence of disordered residues of 20 types at the termini of protein chains differ from the ones in the middle part of the protein chain. Our systematic analysis of disordered regions in PDB revealed 109 disordered patterns of different lengths. Each of them has disordered occurrences in at least five protein chains with identity less than 20%. The vast majority of all occurrences of each disordered pattern are disordered. This allows one to use the library of disordered patterns for predicting the status of a residue of a given protein to be ordered or disordered. We analyzed the occurrence of the selected patterns in three eukaryotic and three bacterial proteomes.'),
(84801, 2010, 'plos', 'Bistability in apoptosis by receptor clustering', 'Ho, Kenneth L|Harrington, Heather A', 'Courant Institute of Mathematical Sciences and Program in Computational Biology, New York University, New York, New York, USA. ho@courant.nyu.edu|Courant Institute of Mathematical Sciences and Program in Computational Biology, New York University, New York, New York, USA. ho@courant.nyu.edu', 'United States|United States', 26, 'Algorithms|Apoptosis|Fas Ligand Protein|Linear Models|Models, Biological|Protein Stability|Receptors, Death Domain', 'Journal Article', '10.1371/journal.pcbi.1000956', '20976242', 'Apoptosis is a highly regulated cell death mechanism involved in many physiological processes. A key component of extrinsically activated apoptosis is the death receptor Fas which, on binding to its cognate ligand FasL, oligomerize to form the death-inducing signaling complex. Motivated by recent experimental data, we propose a mathematical model of death ligand-receptor dynamics where FasL acts as a clustering agent for Fas, which form locally stable signaling platforms through proximity-induced receptor interactions. Significantly, the model exhibits hysteresis, providing an upstream mechanism for bistability and robustness. At low receptor concentrations, the bistability is contingent on the trimerism of FasL. Moreover, irreversible bistability, representing a committed cell death decision, emerges at high concentrations which may be achieved through receptor pre-association or localization onto membrane lipid rafts. Thus, our model provides a novel theory for these observed biological phenomena within the unified context of bistability. Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our model also suggests a mechanism by which cells may function as bistable life/death switches independently of any such dynamics in their downstream components. Our results highlight the role of death receptors in deciding cell fate and add to the signal processing capabilities attributed to receptor clustering.'),
(84802, 2010, 'plos', 'Evolution of a signaling nexus constrained by protein interfaces and conformational States', 'Temple, Brenda R S|Jones, Corbin D|Jones, Alan M', 'R. L. Juliano Structural Bioinformatics Core Facility, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. btemple@med.unc.edu|R. L. Juliano Structural Bioinformatics Core Facility, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. btemple@med.unc.edu|R. L. Juliano Structural Bioinformatics Core Facility, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. btemple@med.unc.edu', 'United States|United States|United States', 17, 'Adenylyl Cyclases|Amino Acid Sequence|Animals|Databases, Protein|Eukaryota|Evolution, Molecular|GTP-Binding Protein alpha Subunits|GTP-Binding Protein beta Subunits|Humans|Information Theory|Models, Genetic|Models, Molecular|Molecular Sequence Annotation|Molecular Sequence Data|Phylogeny|Protein Interaction Domains and Motifs|Protein Interaction Mapping|Sequence Alignment|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000962', '20976244', 'Heterotrimeric G proteins act as the physical nexus between numerous receptors that respond to extracellular signals and proteins that drive the cytoplasmic response. The Gxcexb1 subunit of the G protein, in particular, is highly constrained due to its many interactions with proteins that control or react to its conformational state. Various organisms contain differing sets of Gxcexb1-interacting proteins, clearly indicating that shifts in sequence and associated Gxcexb1 functionality were acquired over time. These numerous interactions constrained much of Gxcexb1 evolution, yet Gxcexb1 has diversified, through poorly understood processes, into several functionally specialized classes, each with a unique set of interacting proteins. Applying a synthetic sequence-based approach to mammalian Gxcexb1 subunits, we established a set of seventy-five evolutionarily important class-distinctive residues, sites where a single Gxcexb1 class is differentiated from the three other classes. We tested the hypothesis that shifts at these sites are important for class-specific functionality. Importantly, we mapped known and well-studied class-specific functionalities from all four mammalian classes to sixteen of our class-distinctive sites, validating the hypothesis. Our results show how unique functionality can evolve through the recruitment of residues that were ancestrally functional. We also studied acquisition of functionalities by following these evolutionarily important sites in non-mammalian organisms. Our results suggest that many class-distinctive sites were established early on in eukaryotic diversification and were critical for the establishment of new Gxcexb1 classes, whereas others arose in punctuated bursts throughout metazoan evolution. These Gxcexb1 class-distinctive residues are rational targets for future structural and functional studies.'),
(84803, 2010, 'plos', 'A covering method for detecting genetic associations between rare variants and common phenotypes', 'Bhatia, Gaurav|Bansal, Vikas|Harismendy, Olivier|Schork, Nicholas J|Topol, Eric J|Frazer, Kelly|Bafna, Vineet', 'Department of Computer Science and Engineering, University of California San Diego, La Jolla, California, USA. gbhatia@mit.edu|Department of Computer Science and Engineering, University of California San Diego, La Jolla, California, USA. gbhatia@mit.edu|Department of Computer Science and Engineering, University of California San Diego, La Jolla, California, USA. gbhatia@mit.edu|Department of Computer Science and Engineering, University of California San Diego, La Jolla, California, USA. gbhatia@mit.edu|Department of Computer Science and Engineering, University of California San Diego, La Jolla, California, USA. gbhatia@mit.edu|Department of Computer Science and Engineering, University of California San Diego, La Jolla, California, USA. gbhatia@mit.edu|Department of Computer Science and Engineering, University of California San Diego, La Jolla, California, USA. gbhatia@mit.edu', 'United States|United States|United States|United States|United States|United States|United States', 74, 'Algorithms|Amidohydrolases|Body Mass Index|Cannabinoid Receptor Modulators|Chi-Square Distribution|Cohort Studies|Computational Biology|Computer Simulation|Gene Frequency|Genetic Association Studies|Genetics, Population|Mutation|Obesity|Phenotype|Prostatic Secretory Proteins', 'Journal Article', '10.1371/journal.pcbi.1000954', '20976246', 'Genome wide association (GWA) studies, which test for association between common genetic markers and a disease phenotype, have shown varying degrees of success. While many factors could potentially confound GWA studies, we focus on the possibility that multiple, rare variants (RVs) may act in concert to influence disease etiology. Here, we describe an algorithm for RV analysis, RareCover. The algorithm combines a disparate collection of RVs with low effect and modest penetrance. Further, it does not require the rare variants be adjacent in location. Extensive simulations over a range of assumed penetrance and population attributable risk (PAR) values illustrate the power of our approach over other published methods, including the collapsing and weighted-collapsing strategies. To showcase the method, we apply RareCover to re-sequencing data from a cohort of 289 individuals at the extremes of Body Mass Index distribution (NCT00263042). Individual samples were re-sequenced at two genes, FAAH and MGLL, known to be involved in endocannabinoid metabolism (187Kbp for 148 obese and 150 controls). The RareCover analysis identifies exactly one significantly associated region in each gene, each about 5 Kbp in the upstream regulatory regions. The data suggests that the RVs help disrupt the expression of the two genes, leading to lowered metabolism of the corresponding cannabinoids. Overall, our results point to the power of including RVs in measuring genetic associations.'),
(84804, 2010, 'plos', 'An automated phenotype-driven approach (GeneForce) for refining metabolic and regulatory models', 'Barua, Dipak|Kim, Joonhoon|Reed, Jennifer L', 'Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.', 'United States|United States|United States', 38, 'Algorithms|Computational Biology|Escherichia coli|Gene Regulatory Networks|Metabolic Networks and Pathways|Models, Biological|Phenotype|Reproducibility of Results|Salmonella typhi', 'Journal Article', '10.1371/journal.pcbi.1000970', '21060853', 'Integrated constraint-based metabolic and regulatory models can accurately predict cellular growth phenotypes arising from genetic and environmental perturbations. Challenges in constructing such models involve the limited availability of information about transcription factor--gene target interactions and computational methods to quickly refine models based on additional datasets. In this study, we developed an algorithm, GeneForce, to identify incorrect regulatory rules and gene-protein-reaction associations in integrated metabolic and regulatory models. We applied the algorithm to refine integrated models of Escherichia coli and Salmonella typhimurium, and experimentally validated some of the algorithms suggested refinements. The adjusted E. coli model showed improved accuracy (xe2x88xbc80.0%) for predicting growth phenotypes for 50,557 cases (knockout mutants tested for growth in different environmental conditions). In addition to identifying needed model corrections, the algorithm was used to identify native E. coli genes that, if over-expressed, would allow E. coli to grow in new environments. We envision that this approach will enable the rapid development and assessment of genome-scale metabolic and regulatory network models for less characterized organisms, as such models can be constructed from genome annotations and cis-regulatory network predictions.'),
(84805, 2010, 'plos', 'Informing optimal environmental influenza interventions: how the host, agent, and environment alter dominant routes of transmission', 'Spicknall, Ian H|Koopman, James S|Nicas, Mark|Pujol, Josep M|Li, Sheng|Eisenberg, Joseph N S', 'Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America.', 'United States|United States|United States|United States|United States|United States', 0, 'Computational Biology|Computer Simulation|Environmental Exposure|Host-Pathogen Interactions|Humans|Influenza, Human|Models, Biological|Regression Analysis|Virus Shedding', 'Journal Article', '10.1371/journal.pcbi.1000969', '21060854', 'Influenza can be transmitted through respirable (small airborne particles), inspirable (intermediate size), direct-droplet-spray, and contact modes. How these modes are affected by features of the virus strain (infectivity, survivability, transferability, or shedding profiles), host population (behavior, susceptibility, or shedding profiles), and environment (host density, surface area to volume ratios, or host movement patterns) have only recently come under investigation. A discrete-event, continuous-time, stochastic transmission model was constructed to analyze the environmental processes through which a virus passes from one person to another via different transmission modes, and explore which factors increase or decrease different modes of transmission. With the exception of the inspiratory route, each route on its own can cause high transmission in isolation of other modes. Mode-specific transmission was highly sensitive to parameter values. For example, droplet and respirable transmission usually required high host density, while the contact route had no such requirement. Depending on the specific context, one or more modes may be sufficient to cause high transmission, while in other contexts no transmission may result. Because of this, when making intervention decisions that involve blocking environmental pathways, generic recommendations applied indiscriminately may be ineffective, instead intervention choice should be contextualized, depending on the specific features of people, virus strain, or venue in question.'),
(84806, 2010, 'plos', 'Endothelial cell capture of heparin-binding growth factors under flow', 'Zhao, Bing|Zhang, Changjiang|Forsten-Williams, Kimberly|Zhang, Jun|Fannon, Michael', 'Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, United States of America.|Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, United States of America.|Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, United States of America.|Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, United States of America.|Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, United States of America.', 'United States|United States|United States|United States|United States', 8, 'Animals|Bioreactors|Cattle|Cell Membrane|Cells, Cultured|Computational Biology|Computer Simulation|Endothelial Cells|Epidermal Growth Factor|Fibroblast Growth Factor 2|Heparan Sulfate Proteoglycans|Heparin Lyase|Models, Cardiovascular|Protein Binding|Proteoglycans|Receptors, Fibroblast Growth Factor|Rheology|Vascular Endothelial Growth Factor A', 'Journal Article', '10.1371/journal.pcbi.1000971', '21060855', 'Circulation is an important delivery method for both natural and synthetic molecules, but microenvironment interactions, regulated by endothelial cells and critical to the molecules fate, are difficult to interpret using traditional approaches. In this work, we analyzed and predicted growth factor capture under flow using computer modeling and a three-dimensional experimental approach that includes pertinent circulation characteristics such as pulsatile flow, competing binding interactions, and limited bioavailability. An understanding of the controlling features of this process was desired. The experimental module consisted of a bioreactor with synthetic endothelial-lined hollow fibers under flow. The physical design of the system was incorporated into the model parameters. The heparin-binding growth factor fibroblast growth factor-2 (FGF-2) was used for both the experiments and simulations. Our computational model was composed of three parts: (1) media flow equations, (2) mass transport equations and (3) cell surface reaction equations. The model is based on the flow and reactions within a single hollow fiber and was scaled linearly by the total number of fibers for comparison with experimental results. Our model predicted, and experiments confirmed, that removal of heparan sulfate (HS) from the system would result in a dramatic loss of binding by heparin-binding proteins, but not by proteins that do not bind heparin. The model further predicted a significant loss of bound protein at flow rates only slightly higher than average capillary flow rates, corroborated experimentally, suggesting that the probability of capture in a single pass at high flow rates is extremely low. Several other key parameters were investigated with the coupling between receptors and proteoglycans shown to have a critical impact on successful capture. The combined system offers opportunities to examine circulation capture in a straightforward quantitative manner that should prove advantageous for biologicals or drug delivery investigations.'),
(84807, 2010, 'plos', 'Numerical analysis of Ca2+ signaling in rat ventricular myocytes with realistic transverse-axial tubular geometry and inhibited sarcoplasmic reticulum', 'Cheng, Yuhui|Yu, Zeyun|Hoshijima, Masahiko|Holst, Michael J|McCulloch, Andrew D|McCammon, J Andrew|Michailova, Anushka P', 'Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 28, 'Adenosine Triphosphate|Algorithms|Animals|Calcium Signaling|Calmodulin|Cells, Cultured|Computational Biology|Computer Simulation|Imaging, Three-Dimensional|Models, Biological|Myocytes, Cardiac|Rats|Sarcoplasmic Reticulum|Software', 'Journal Article', '10.1371/journal.pcbi.1000972', '21060856', 'The t-tubules of mammalian ventricular myocytes are invaginations of the cell membrane that occur at each Z-line. These invaginations branch within the cell to form a complex network that allows rapid propagation of the electrical signal, and hence synchronous rise of intracellular calcium (Ca(2+)). To investigate how the t-tubule microanatomy and the distribution of membrane Ca(2+) flux affect cardiac excitation-contraction coupling we developed a 3-D continuum model of Ca(2+) signaling, buffering and diffusion in rat ventricular myocytes. The transverse-axial t-tubule geometry was derived from light microscopy structural data. To solve the nonlinear reaction-diffusion system we extended SMOL software tool (http://mccammon.ucsd.edu/smol/). The analysis suggests that the quantitative understanding of the Ca(2+) signaling requires more accurate knowledge of the t-tubule ultra-structure and Ca(2+) flux distribution along the sarcolemma. The results reveal the important role for mobile and stationary Ca(2+) buffers, including the Ca(2+) indicator dye. In agreement with experiment, in the presence of fluorescence dye and inhibited sarcoplasmic reticulum, the lack of detectible differences in the depolarization-evoked Ca(2+) transients was found when the Ca(2+) flux was heterogeneously distributed along the sarcolemma. In the absence of fluorescence dye, strongly non-uniform Ca(2+) signals are predicted. Even at modest elevation of Ca(2+), reached during Ca(2+) influx, large and steep Ca(2+) gradients are found in the narrow sub-sarcolemmal space. The model predicts that the branched t-tubule structure and changes in the normal Ca(2+) flux density along the cell membrane support initiation and propagation of Ca(2+) waves in rat myocytes.'),
(84808, 2010, 'plos', 'Role of lipids in spheroidal high density lipoproteins', 'Vuorela, Timo|Catte, Andrea|Niemelä, Perttu S|Hall, Anette|Hyvönen, Marja T|Marrink, Siewert-Jan|Karttunen, Mikko|Vattulainen, Ilpo', 'Department of Physics, Tampere University of Technology, Tampere, Finland.|Department of Physics, Tampere University of Technology, Tampere, Finland.|Department of Physics, Tampere University of Technology, Tampere, Finland.|Department of Physics, Tampere University of Technology, Tampere, Finland.|Department of Physics, Tampere University of Technology, Tampere, Finland.|Department of Physics, Tampere University of Technology, Tampere, Finland.|Department of Physics, Tampere University of Technology, Tampere, Finland.|Department of Physics, Tampere University of Technology, Tampere, Finland.', 'Finland|Finland|Finland|Finland|Finland|Finland|Finland|Finland', 65, 'Apolipoprotein A-I|Cholesterol|Cholesterol Esters|Computational Biology|Computer Simulation|Humans|Hydrophobic and Hydrophilic Interactions|Lipid Metabolism|Lipids|Lipoproteins, HDL|Molecular Dynamics Simulation|Nuclear Magnetic Resonance, Biomolecular|Phospholipids|Reproducibility of Results|Thermodynamics|Triglycerides', 'Journal Article', '10.1371/journal.pcbi.1000964', '21060857', 'We study the structure and dynamics of spherical high density lipoprotein (HDL) particles through coarse-grained multi-microsecond molecular dynamics simulations. We simulate both a lipid droplet without the apolipoprotein A-I (apoA-I) and the full HDL particle including two apoA-I molecules surrounding the lipid compartment. The present models are the first ones among computational studies where the size and lipid composition of HDL are realistic, corresponding to human serum HDL. We focus on the role of lipids in HDL structure and dynamics. Particular attention is paid to the assembly of lipids and the influence of lipid-protein interactions on HDL properties. We find that the properties of lipids depend significantly on their location in the particle (core, intermediate region, surface). Unlike the hydrophobic core, the intermediate and surface regions are characterized by prominent conformational lipid order. Yet, not only the conformations but also the dynamics of lipids are found to be distinctly different in the different regions of HDL, highlighting the importance of dynamics in considering the functionalization of HDL. The structure of the lipid droplet close to the HDL-water interface is altered by the presence of apoA-Is, with most prominent changes being observed for cholesterol and polar lipids. For cholesterol, slow trafficking between the surface layer and the regimes underneath is observed. The lipid-protein interactions are strongest for cholesterol, in particular its interaction with hydrophobic residues of apoA-I. Our results reveal that not only hydrophobicity but also conformational entropy of the molecules are the driving forces in the formation of HDL structure. The results provide the first detailed structural model for HDL and its dynamics with and without apoA-I, and indicate how the interplay and competition between entropy and detailed interactions may be used in nanoparticle and drug design through self-assembly.'),
(84809, 2010, 'plos', 'Networks of high mutual information define the structural proximity of catalytic sites: implications for catalytic residue identification', 'Marino Buslje, Cristina|Teppa, Elin|Di Doménico, Tomas|Delfino, José María|Nielsen, Morten', 'Fundación Instituto Leloir, Buenos Aires, Argentina. cmb@leloir.org.ar|Fundación Instituto Leloir, Buenos Aires, Argentina. cmb@leloir.org.ar|Fundación Instituto Leloir, Buenos Aires, Argentina. cmb@leloir.org.ar|Fundación Instituto Leloir, Buenos Aires, Argentina. cmb@leloir.org.ar|Fundación Instituto Leloir, Buenos Aires, Argentina. cmb@leloir.org.ar', 'Argentina|Argentina|Argentina|Argentina|Argentina', 51, 'Area Under Curve|Catalytic Domain|Computational Biology|Databases, Protein|Enzymes|Models, Molecular|Models, Statistical|Protein Conformation|Reproducibility of Results|Sequence Homology', 'Journal Article', '10.1371/journal.pcbi.1000978', '21079665', 'Identification of catalytic residues (CR) is essential for the characterization of enzyme function. CR are, in general, conserved and located in the functional site of a protein in order to attain their function. However, many non-catalytic residues are highly conserved and not all CR are conserved throughout a given protein family making identification of CR a challenging task. Here, we put forward the hypothesis that CR carry a particular signature defined by networks of close proximity residues with high mutual information (MI), and that this signature can be applied to distinguish functional from other non-functional conserved residues. Using a data set of 434 Pfam families included in the catalytic site atlas (CSA) database, we tested this hypothesis and demonstrated that MI can complement amino acid conservation scores to detect CR. The Kullback-Leibler (KL) conservation measurement was shown to significantly outperform both the Shannon entropy and maximal frequency measurements. Residues in the proximity of catalytic sites were shown to be rich in shared MI. A structural proximity MI average score (termed pMI) was demonstrated to be a strong predictor for CR, thus confirming the proposed hypothesis. A structural proximity conservation average score (termed pC) was also calculated and demonstrated to carry distinct information from pMI. A catalytic likeliness score (Cls), combining the KL, pC and pMI measures, was shown to lead to significantly improved prediction accuracy. At a specificity of 0.90, the Cls method was found to have a sensitivity of 0.816. In summary, we demonstrate that networks of residues with high MI provide a distinct signature on CR and propose that such a signature should be present in other classes of functional residues where the requirement to maintain a particular function places limitations on the diversification of the structural environment along the course of evolution.'),
(84810, 2010, 'plos', 'Monte Carlo analysis of neck linker extension in kinesin molecular motors', 'Kutys, Matthew L|Fricks, John|Hancock, William O', 'Department of Bioengineering, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Department of Bioengineering, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Department of Bioengineering, The Pennsylvania State University, University Park, Pennsylvania, United States of America.', 'United States|United States|United States', 22, 'Computational Biology|Elasticity|Friction|Kinesin|Molecular Dynamics Simulation|Monte Carlo Method|Thermodynamics|Tubulin', 'Journal Article', '10.1371/journal.pcbi.1000980', '21079666', 'Kinesin stepping is thought to involve both concerted conformational changes and diffusive movement, but the relative roles played by these two processes are not clear. The neck linker docking model is widely accepted in the field, but the remainder of the step--diffusion of the tethered head to the next binding site--is often assumed to occur rapidly with little mechanical resistance. Here, we investigate the effect of tethering by the neck linker on the diffusive movement of the kinesin head, and focus on the predicted behavior of motors with naturally or artificially extended neck linker domains. The kinesin chemomechanical cycle was modeled using a discrete-state Markov chain to describe chemical transitions. Brownian dynamics were used to model the tethered diffusion of the free head, incorporating resistive forces from the neck linker and a position-dependent microtubule binding rate. The Brownian dynamics and chemomechanical cycle were coupled to model processive runs consisting of many 8 nm steps. Three mechanical models of the neck linker were investigated: Constant Stiffness (a simple spring), Increasing Stiffness (analogous to a Worm-Like Chain), and Reflecting (negligible stiffness up to a limiting contour length). Motor velocities and run lengths from simulated paths were compared to experimental results from Kinesin-1 and a mutant containing an extended neck linker domain. When tethered by an increasingly stiff spring, the head is predicted to spend an unrealistically short amount of time within the binding zone, and extending the neck is predicted to increase both the velocity and processivity, contrary to experiments. These results suggest that the Worm-Like Chain is not an adequate model for the flexible neck linker domain. The model can be reconciled with experimental data if the neck linker is either much more compliant or much stiffer than generally assumed, or if weak kinesin-microtubule interactions stabilize the diffusing head near its binding site.'),
(84811, 2010, 'plos', 'Infectious disease modeling of social contagion in networks', 'Hill, Alison L|Rand, David G|Nowak, Martin A|Christakis, Nicholas A', 'Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. alhill@fas.harvard.edu|Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. alhill@fas.harvard.edu|Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. alhill@fas.harvard.edu|Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. alhill@fas.harvard.edu', 'United States|United States|United States|United States', 115, 'Computational Biology|Computer Simulation|Disease Transmission, Infectious|Humans|Models, Biological|Models, Psychological|Obesity|Regression Analysis|Social Behavior|Sociology, Medical', 'Journal Article', '10.1371/journal.pcbi.1000968', '21079667', 'Many behavioral phenomena have been found to spread interpersonally through social networks, in a manner similar to infectious diseases. An important difference between social contagion and traditional infectious diseases, however, is that behavioral phenomena can be acquired by non-social mechanisms as well as through social transmission. We introduce a novel theoretical framework for studying these phenomena (the SISa model) by adapting a classic disease model to include the possibility for automatic (or spontaneous) non-social infection. We provide an example of the use of this framework by examining the spread of obesity in the Framingham Heart Study Network. The interaction assumptions of the model are validated using longitudinal network transmission data. We find that the current rate of becoming obese is 2 per year and increases by 0.5 percentage points for each obese social contact. The rate of recovering from obesity is 4 per year, and does not depend on the number of non-obese contacts. The model predicts a long-term obesity prevalence of approximately 42, and can be used to evaluate the effect of different interventions on steady-state obesity. Model predictions quantitatively reproduce the actual historical time course for the prevalence of obesity. We find that since the 1970s, the rate of recovery from obesity has remained relatively constant, while the rates of both spontaneous infection and transmission have steadily increased over time. This suggests that the obesity epidemic may be driven by increasing rates of becoming obese, both spontaneously and transmissively, rather than by decreasing rates of losing weight. A key feature of the SISa model is its ability to characterize the relative importance of social transmission by quantitatively comparing rates of spontaneous versus contagious infection. It provides a theoretical framework for studying the interpersonal spread of any state that may also arise spontaneously, such as emotions, behaviors, health states, ideas or diseases with reservoirs.');
