INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85484, 2012, 'plos', 'Crossing overMarkov meets Mendel', 'Mneimneh, Saad', 'Department of Computer Science, Hunter College of CUNY, New York, NY, USA. saad@hunter.cuny.edu', 'United States', 1, 'Animals|Biological Evolution|Chromosomes|Computer Simulation|Genetic Variation|Heredity|Humans|Markov Chains|Models, Genetic|Models, Statistical', 'Journal Article', '10.1371/journal.pcbi.1002462', '22629235', 'Chromosomal crossover is a biological mechanism to combine parental traits. It is perhaps the first mechanism ever taught in any introductory biology class. The formulation of crossover, and resulting recombination, came about 100 years after Mendels famous experiments. To a great extent, this formulation is consistent with the basic genetic findings of Mendel. More importantly, it provides a mathematical insight for his two laws (and corrects them). From a mathematical perspective, and while it retains similarities, genetic recombination guarantees diversity so that we do not rapidly converge to the same being. It is this diversity that made the study of biology possible. In particular, the problem of genetic mapping and linkage-one of the first efforts towards a computational approach to biology-relies heavily on the mathematical foundation of crossover and recombination. Nevertheless, as students we often overlook the mathematics of these phenomena. Emphasizing the mathematical aspect of Mendels laws through crossover and recombination will prepare the students to make an early realization that biology, in addition to being experimental, IS a computational science. This can serve as a first step towards a broader curricular transformation in teaching biological sciences. I will show that a simple and modern treatment of Mendels laws using a Markov chain will make this step possible, and it will only require basic college-level probability and calculus. My personal teaching experience confirms that students WANT to know Markov chains because they hear about them from bioinformaticists all the time. This entire exposition is based on three homework problems that I designed for a course in computational biology. A typical reader is, therefore, an instructional staff member or a student in a computational field (e.g., computer science, mathematics, statistics, computational biology, bioinformatics). However, other students may easily follow by omitting the mathematically more elaborate parts. I kept those as separate sections in the exposition.'),
(85485, 2012, 'plos', 'Measuring Granger causality between cortical regions from voxelwise fMRI BOLD signals with LASSO', 'Tang, Wei|Bressler, Steven L|Sylvester, Chad M|Shulman, Gordon L|Corbetta, Maurizio', 'Center for Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, Florida, United States of America.|Center for Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, Florida, United States of America.|Center for Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, Florida, United States of America.|Center for Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, Florida, United States of America.|Center for Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, Florida, United States of America.', 'United States|United States|United States|United States|United States', 36, 'Algorithms|Animals|Brain|Brain Mapping|Computer Simulation|Humans|Magnetic Resonance Imaging|Models, Neurological|Models, Statistical|Nerve Net|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002513', '22654651', 'Functional brain network studies using the Blood Oxygen-Level Dependent (BOLD) signal from functional Magnetic Resonance Imaging (fMRI) are becoming increasingly prevalent in research on the neural basis of human cognition. An important problem in functional brain network analysis is to understand directed functional interactions between brain regions during cognitive performance. This problem has important implications for understanding top-down influences from frontal and parietal control regions to visual occipital cortex in visuospatial attention, the goal motivating the present study. A common approach to measuring directed functional interactions between two brain regions is to first create nodal signals by averaging the BOLD signals of all the voxels in each region, and to then measure directed functional interactions between the nodal signals. Another approach, that avoids averaging, is to measure directed functional interactions between all pairwise combinations of voxels in the two regions. Here we employ an alternative approach that avoids the drawbacks of both averaging and pairwise voxel measures. In this approach, we first use the Least Absolute Shrinkage Selection Operator (LASSO) to pre-select voxels for analysis, then compute a Multivariate Vector AutoRegressive (MVAR) model from the time series of the selected voxels, and finally compute summary Granger Causality (GC) statistics from the model to represent directed interregional interactions. We demonstrate the effectiveness of this approach on both simulated and empirical fMRI data. We also show that averaging regional BOLD activity to create a nodal signal may lead to biased GC estimation of directed interregional interactions. The approach presented here makes it feasible to compute GC between brain regions without the need for averaging. Our results suggest that in the analysis of functional brain networks, careful consideration must be given to the way that network nodes and edges are defined because those definitions may have important implications for the validity of the analysis.'),
(85486, 2012, 'plos', 'A two-dimensional model of the colonic crypt accounting for the role of the basement membrane and pericryptal fibroblast sheath', 'Dunn, Sara-Jane|Appleton, Paul L|Nelson, Scott A|Näthke, Inke S|Gavaghan, David J|Osborne, James M', 'Department of Computer Science, University of Oxford, Oxford, United Kingdom. sara-jane.dunn@microsoft.com|Department of Computer Science, University of Oxford, Oxford, United Kingdom. sara-jane.dunn@microsoft.com|Department of Computer Science, University of Oxford, Oxford, United Kingdom. sara-jane.dunn@microsoft.com|Department of Computer Science, University of Oxford, Oxford, United Kingdom. sara-jane.dunn@microsoft.com|Department of Computer Science, University of Oxford, Oxford, United Kingdom. sara-jane.dunn@microsoft.com|Department of Computer Science, University of Oxford, Oxford, United Kingdom. sara-jane.dunn@microsoft.com', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 28, 'Animals|Basement Membrane|Cell Communication|Colon|Computer Simulation|Fibroblasts|Humans|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002515', '22654652', 'The role of the basement membrane is vital in maintaining the integrity and structure of an epithelial layer, acting as both a mechanical support and forming the physical interface between epithelial cells and the surrounding connective tissue. The function of this membrane is explored here in the context of the epithelial monolayer that lines the colonic crypt, test-tube shaped invaginations that punctuate the lining of the intestine and coordinate a regular turnover of cells to replenish the epithelial layer every few days. To investigate the consequence of genetic mutations that perturb the system dynamics and can lead to colorectal cancer, it must be possible to track the emerging tissue level changes that arise in the crypt. To that end, a theoretical crypt model with a realistic, deformable geometry is required. A new discrete crypt model is presented, which focuses on the interaction between cell- and tissue-level behaviour, while incorporating key subcellular components. The model contains a novel description of the role of the surrounding tissue and musculature, based upon experimental observations of the tissue structure of the crypt, which are also reported. A two-dimensional (2D) cross-sectional geometry is considered, and the shape of the crypt is allowed to evolve and deform. Simulation results reveal how the shape of the crypt may contribute mechanically to the asymmetric division events typically associated with the stem cells at the base. The model predicts that epithelial cell migration may arise due to feedback between cell loss at the crypt collar and density-dependent cell division, an hypothesis which can be investigated in a wet lab. This work forms the basis for investigation of the deformation of the crypt structure that can occur due to proliferation of cells exhibiting mutant phenotypes, experiments that would not be possible in vivo or in vitro.'),
(85487, 2012, 'plos', 'Optimality of human contour integration', 'Ernst, Udo A|Mandon, Sunita|Schinkel-Bielefeld, Nadja|Neitzel, Simon D|Kreiter, Andreas K|Pawelzik, Klaus R', 'Department of Neurophysics, Institute for Theoretical Physics, University of Bremen, Bremen, Germany. udo@neuro.uni-bremen.de|Department of Neurophysics, Institute for Theoretical Physics, University of Bremen, Bremen, Germany. udo@neuro.uni-bremen.de|Department of Neurophysics, Institute for Theoretical Physics, University of Bremen, Bremen, Germany. udo@neuro.uni-bremen.de|Department of Neurophysics, Institute for Theoretical Physics, University of Bremen, Bremen, Germany. udo@neuro.uni-bremen.de|Department of Neurophysics, Institute for Theoretical Physics, University of Bremen, Bremen, Germany. udo@neuro.uni-bremen.de|Department of Neurophysics, Institute for Theoretical Physics, University of Bremen, Bremen, Germany. udo@neuro.uni-bremen.de', 'Germany|Germany|Germany|Germany|Germany|Germany', 21, 'Computer Simulation|Form Perception|Humans|Models, Neurological|Models, Statistical|Pattern Recognition, Physiological|Perceptual Masking', 'Journal Article', '10.1371/journal.pcbi.1002520', '22654653', 'For processing and segmenting visual scenes, the brain is required to combine a multitude of features and sensory channels. It is neither known if these complex tasks involve optimal integration of information, nor according to which objectives computations might be performed. Here, we investigate if optimal inference can explain contour integration in human subjects. We performed experiments where observers detected contours of curvilinearly aligned edge configurations embedded into randomly oriented distractors. The key feature of our framework is to use a generative process for creating the contours, for which it is possible to derive a class of ideal detection models. This allowed us to compare human detection for contours with different statistical properties to the corresponding ideal detection models for the same stimuli. We then subjected the detection models to realistic constraints and required them to reproduce human decisions for every stimulus as well as possible. By independently varying the four model parameters, we identify a single detection model which quantitatively captures all correlations of human decision behaviour for more than 2000 stimuli from 42 contour ensembles with greatly varying statistical properties. This model reveals specific interactions between edges closely matching independent findings from physiology and psychophysics. These interactions imply a statistics of contours for which edge stimuli are indeed optimally integrated by the visual system, with the objective of inferring the presence of contours in cluttered scenes. The recurrent algorithm of our model makes testable predictions about the temporal dynamics of neuronal populations engaged in contour integration, and it suggests a strong directionality of the underlying functional anatomy.'),
(85488, 2012, 'plos', 'Conformational spread in the flagellar motor switch: a model study', 'Ma, Qi|Nicolau, Dan V|Maini, Philip K|Berry, Richard M|Bai, Fan', 'Biodynamic Optical Imaging Center and Department of Life Sciences, Peking University, Beijing, China.|Biodynamic Optical Imaging Center and Department of Life Sciences, Peking University, Beijing, China.|Biodynamic Optical Imaging Center and Department of Life Sciences, Peking University, Beijing, China.|Biodynamic Optical Imaging Center and Department of Life Sciences, Peking University, Beijing, China.|Biodynamic Optical Imaging Center and Department of Life Sciences, Peking University, Beijing, China.', 'China|China|China|China|China', 13, 'Bacterial Proteins|Chemotaxis|Computer Simulation|Escherichia coli|Flagella|Membrane Proteins|Methyl-Accepting Chemotaxis Proteins|Models, Biological|Molecular Motor Proteins', 'Journal Article', '10.1371/journal.pcbi.1002523', '22654654', 'The reliable response to weak biological signals requires that they be amplified with fidelity. In E. coli, the flagellar motors that control swimming can switch direction in response to very small changes in the concentration of the signaling protein CheY-P, but how this works is not well understood. A recently proposed allosteric model based on cooperative conformational spread in a ring of identical protomers seems promising as it is able to qualitatively reproduce switching, locked state behavior and Hill coefficient values measured for the rotary motor. In this paper we undertook a comprehensive simulation study to analyze the behavior of this model in detail and made predictions on three experimentally observable quantities: switch time distribution, locked state interval distribution, Hill coefficient of the switch response. We parameterized the model using experimental measurements, finding excellent agreement with published data on motor behavior. Analysis of the simulated switching dynamics revealed a mechanism for chemotactic ultrasensitivity, in which cooperativity is indispensable for realizing both coherent switching and effective amplification. These results showed how cells can combine elements of analog and digital control to produce switches that are simultaneously sensitive and reliable.'),
(85489, 2012, 'plos', 'Identification of molecular pathologies sufficient to cause neuropathic excitability in primary somatosensory afferents using dynamical systems theory', 'Rho, Young-Ah|Prescott, Steven A', 'Department of Neurobiology and the Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Department of Neurobiology and the Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.', 'United States|United States', 17, 'Action Potentials|Animals|Biological Clocks|Computer Simulation|Humans|Models, Neurological|Nerve Net|Neural Pathways|Neuralgia|Neuronal Plasticity|Neurons, Afferent', 'Journal Article', '10.1371/journal.pcbi.1002524', '22654655', 'Pain caused by nerve injury (i.e. neuropathic pain) is associated with development of neuronal hyperexcitability at several points along the pain pathway. Within primary afferents, numerous injury-induced changes have been identified but it remains unclear which molecular changes are necessary and sufficient to explain cellular hyperexcitability. To investigate this, we built computational models that reproduce the switch from a normal spiking pattern characterized by a single spike at the onset of depolarization to a neuropathic one characterized by repetitive spiking throughout depolarization. Parameter changes that were sufficient to switch the spiking pattern also enabled membrane potential oscillations and bursting, suggesting that all three pathological changes are mechanistically linked. Dynamical analysis confirmed this prediction by showing that excitability changes co-develop when the nonlinear mechanism responsible for spike initiation switches from a quasi-separatrix-crossing to a subcritical Hopf bifurcation. This switch stems from biophysical changes that bias competition between oppositely directed fast- and slow-activating conductances operating at subthreshold potentials. Competition between activation and inactivation of a single conductance can be similarly biased with equivalent consequences for excitability. Bias can arise from a multitude of molecular changes occurring alone or in combination, in the latter case, changes can add or offset one another. Thus, our results identify pathological change in the nonlinear interaction between processes affecting spike initiation as the critical determinant of how simple injury-induced changes at the molecular level manifest complex excitability changes at the cellular level. We demonstrate that multiple distinct molecular changes are sufficient to produce neuropathic changes in excitability, however, given that nerve injury elicits numerous molecular changes that may be individually sufficient to alter spike initiation, our results argue that no single molecular change is necessary to produce neuropathic excitability. This deeper understanding of degenerate causal relationships has important implications for how we understand and treat neuropathic pain.'),
(85490, 2012, 'plos', 'Estimating the fitness cost of escape from HLA presentation in HIV-1 protease and reverse transcriptase', 'Mostowy, Rafal|Kouyos, Roger D|Hoof, Ilka|Hinkley, Trevor|Haddad, Mojgan|Whitcomb, Jeannette M|Petropoulos, Christos J|Kexc5x9fmir, Can|Bonhoeffer, Sebastian', 'Institute for Integrative Biology, ETH Zurich, Zurich, Switzerland. rafal.mostowy@gmail.com|Institute for Integrative Biology, ETH Zurich, Zurich, Switzerland. rafal.mostowy@gmail.com|Institute for Integrative Biology, ETH Zurich, Zurich, Switzerland. rafal.mostowy@gmail.com|Institute for Integrative Biology, ETH Zurich, Zurich, Switzerland. rafal.mostowy@gmail.com|Institute for Integrative Biology, ETH Zurich, Zurich, Switzerland. rafal.mostowy@gmail.com|Institute for Integrative Biology, ETH Zurich, Zurich, Switzerland. rafal.mostowy@gmail.com|Institute for Integrative Biology, ETH Zurich, Zurich, Switzerland. rafal.mostowy@gmail.com|Institute for Integrative Biology, ETH Zurich, Zurich, Switzerland. rafal.mostowy@gmail.com|Institute for Integrative Biology, ETH Zurich, Zurich, Switzerland. rafal.mostowy@gmail.com', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Swit', 10, 'Adaptation, Physiological|Computer Simulation|Genetic Fitness|HIV Protease|HIV Reverse Transcriptase|HIV-1|HLA Antigens|Models, Genetic|Mutation|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.1002525', '22654656', 'Human immunodeficiency virus (HIV-1) is, like most pathogens, under selective pressure to escape the immune system of its host. In particular, HIV-1 can avoid recognition by cytotoxic T lymphocytes (CTLs) by altering the binding affinity of viral peptides to human leukocyte antigen (HLA) molecules, the role of which is to present those peptides to the immune system. It is generally assumed that HLA escape mutations carry a replicative fitness cost, but these costs have not been quantified. In this study, we assess the replicative cost of mutations which are likely to escape presentation by HLA molecules in the region of HIV-1 protease and reverse transcriptase. Specifically, we combine computational approaches for prediction of in vitro replicative fitness and peptide binding affinity to HLA molecules. We find that mutations which impair binding to HLA-A molecules tend to have lower in vitro replicative fitness than mutations which do not impair binding to HLA-A molecules, suggesting that HLA-A escape mutations carry higher fitness costs than non-escape mutations. We argue that the association between fitness and HLA-A binding impairment is probably due to an intrinsic cost of escape from HLA-A molecules, and these costs are particularly strong for HLA-A alleles associated with efficient virus control. Counter-intuitively, we do not observe a significant effect in the case of HLA-B, but, as discussed, this does not argue against the relevance of HLA-B in virus control. Overall, this article points to the intriguing possibility that HLA-A molecules preferentially target more conserved regions of HIV-1, emphasizing the importance of HLA-A genes in the evolution of HIV-1 and RNA viruses in general.'),
(85491, 2012, 'plos', 'A computational investigation on the connection between dynamics properties of ribosomal proteins and ribosome assembly', 'Burton, Brittany|Zimmermann, Michael T|Jernigan, Robert L|Wang, Yongmei', 'Department of Chemistry, The University of Memphis, Memphis, Tennessee, United States of America.|Department of Chemistry, The University of Memphis, Memphis, Tennessee, United States of America.|Department of Chemistry, The University of Memphis, Memphis, Tennessee, United States of America.|Department of Chemistry, The University of Memphis, Memphis, Tennessee, United States of America.', 'United States|United States|United States|United States', 15, 'Binding Sites|Computer Simulation|Models, Chemical|Models, Molecular|Multiprotein Complexes|Protein Binding|Protein Conformation|Ribosomal Proteins|Ribosomes|Ultrasonography', 'Journal Article', '10.1371/journal.pcbi.1002530', '22654657', 'Assembly of the ribosome from its protein and RNA constituents has been studied extensively over the past 50 years, and experimental evidence suggests that prokaryotic ribosomal proteins undergo conformational changes during assembly. However, to date, no studies have attempted to elucidate these conformational changes. The present work utilizes computational methods to analyze protein dynamics and to investigate the linkage between dynamics and binding of these proteins during the assembly of the ribosome. Ribosomal proteins are known to be positively charged and we find the percentage of positive residues in r-proteins to be about twice that of the average protein: Lys+Arg is 18.7% for E. coli and 21.2% for T. thermophilus. Also, positive residues constitute a large proportion of RNA contacting residues: 39% for E. coli and 46% for T. thermophilus. This affirms the known importance of charge-charge interactions in the assembly of the ribosome. We studied the dynamics of three primary proteins from E. coli and T. thermophilus 30S subunits that bind early in the assembly (S15, S17, and S20) with atomic molecular dynamic simulations, followed by a study of all r-proteins using elastic network models. Molecular dynamics simulations show that solvent-exposed proteins (S15 and S17) tend to adopt more stable solution conformations than an RNA-embedded protein (S20). We also find protein residues that contact the 16S rRNA are generally more mobile in comparison with the other residues. This is because there is a larger proportion of contacting residues located in flexible loop regions. By the use of elastic network models, which are computationally more efficient, we show that this trend holds for most of the 30S r-proteins.'),
(85492, 2012, 'plos', 'Structural drift: the population dynamics of sequential learning', 'Crutchfield, James P|Whalen, Sean', 'Complexity Sciences Center, Physics Department, University of California Davis, Davis, California, United States of America. chaos@ucdavis.edu|Complexity Sciences Center, Physics Department, University of California Davis, Davis, California, United States of America. chaos@ucdavis.edu', 'United States|United States', 4, 'Artificial Intelligence|Biological Evolution|Causality|Communication|Computational Biology|Genetic Drift|Humans|Information Theory|Learning|Memory|Population Dynamics|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002510', '22685387', 'We introduce a theory of sequential causal inference in which learners in a chain estimate a structural model from their upstream teacher and then pass samples from the model to their downstream student. It extends the population dynamics of genetic drift, recasting Kimuras selectively neutral theory as a special case of a generalized drift process using structured populations with memory. We examine the diffusion and fixation properties of several drift processes and propose applications to learning, inference, and evolution. We also demonstrate how the organization of drift process space controls fidelity, facilitates innovations, and leads to information loss in sequential learning with and without memory.'),
(85493, 2012, 'plos', 'Standing genetic variation and the evolution of drug resistance in HIV', 'Pennings, Pleuni Simone', 'Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, United States of America. pennings@fas.harvard.edu', 'United States', 50, 'Anti-HIV Agents|Computational Biology|Computer Simulation|Drug Resistance, Viral|Evolution, Molecular|Female|Genes, Viral|Genetic Variation|HIV|HIV Infections|Humans|Infant, Newborn|Infectious Disease Transmission, Vertical|Models, Genetic|Mutation|Nevirapine|Pregnancy|Pregnancy Complications, Infectious|Treatment Failure|Viral Load', 'Journal Article', '10.1371/journal.pcbi.1002527', '22685388', 'Drug resistance remains a major problem for the treatment of HIV. Resistance can occur due to mutations that were present before treatment starts or due to mutations that occur during treatment. The relative importance of these two sources is unknown. Resistance can also be transmitted between patients, but this process is not considered in the current study. We study three different situations in which HIV drug resistance may evolve: starting triple-drug therapy, treatment with a single dose of nevirapine and interruption of treatment. For each of these three cases good data are available from literature, which allows us to estimate the probability that resistance evolves from standing genetic variation. Depending on the treatment we find probabilities of the evolution of drug resistance due to standing genetic variation between 0 and 39%. For patients who start triple-drug combination therapy, we find that drug resistance evolves from standing genetic variation in approximately 6% of the patients. We use a population-dynamic and population-genetic model to understand the observations and to estimate important evolutionary parameters under the assumption that treatment failure is caused by the fixation of a single drug resistance mutation. We find that both the effective population size of the virus before treatment, and the fitness of the resistant mutant during treatment, are key-arameters which determine the probability that resistance evolves from standing genetic variation. Importantly, clinical data indicate that both of these parameters can be manipulated by the kind of treatment that is used.'),
(85494, 2012, 'plos', 'Fine-tuning tomato agronomic properties by computational genome redesign', 'Carrera, Javier|Fernández Del Carmen, Asun|Fernández-Muñoz, Rafael|Rambla, Jose Luis|Pons, Clara|Jaramillo, Alfonso|Elena, Santiago F|Granell, Antonio', 'Instituto de Biologa Molecular y Celular de Plantas, Consejo Superior de Investigaciones Cientificas-UPV, Valencia, Spain. Javier.Carrera@synth-bio.org|Instituto de Biologa Molecular y Celular de Plantas, Consejo Superior de Investigaciones Cientificas-UPV, Valencia, Spain. Javier.Carrera@synth-bio.org|Instituto de Biologa Molecular y Celular de Plantas, Consejo Superior de Investigaciones Cientificas-UPV, Valencia, Spain. Javier.Carrera@synth-bio.org|Instituto de Biologa Molecular y Celular de Plantas, Consejo Superior de Investigaciones Cientificas-UPV, Valencia, Spain. Javier.Carrera@synth-bio.org|Instituto de Biologa Molecular y Celular de Plantas, Consejo Superior de Investigaciones Cientificas-UPV, Valencia, Spain. Javier.Carrera@synth-bio.org|Instituto de Biologa Molecular y Celular de Plantas, Consejo Superior de Investigaciones Cientificas-UPV, Valencia, Spain. Javier.Carrera@synth-bio.org|Instituto de Biologa Molecular y Celular de Plantas, Consejo Superior de Investigaciones Cientificas-UPV, Valencia, Spain. Javier.Carrera@synth-bio.org|Instituto de Biologa Molecular y Celular de Plantas, Consejo Superior de Investigaciones Cientificas-UPV, Valencia, Spain. Javier.Carrera@synth-bio.org', 'Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain', 6, 'Agriculture|Biotechnology|Computational Biology|Computer Simulation|Fruit|Gene Knockout Techniques|Genetic Engineering|Genome, Plant|Linear Models|Lycopersicon esculentum|Metabolome|Models, Genetic|Phenotype|Plants, Genetically Modified|Synthetic Biology|Transcriptome|Up-Regulation', 'Journal Article', '10.1371/journal.pcbi.1002528', '22685389', 'Considering cells as biofactories, we aimed to optimize its internal processes by using the same engineering principles that large industries are implementing nowadays: lean manufacturing. We have applied reverse engineering computational methods to transcriptomic, metabolomic and phenomic data obtained from a collection of tomato recombinant inbreed lines to formulate a kinetic and constraint-based model that efficiently describes the cellular metabolism from expression of a minimal core of genes. Based on predicted metabolic profiles, a close association with agronomic and organoleptic properties of the ripe fruit was revealed with high statistical confidence. Inspired in a synthetic biology approach, the model was used for exploring the landscape of all possible local transcriptional changes with the aim of engineering tomato fruits with fine-tuned biotechnological properties. The method was validated by the ability of the proposed genomes, engineered for modified desired agronomic traits, to recapitulate experimental correlations between associated metabolites.'),
(85495, 2012, 'plos', 'Structural and dynamic requirements for optimal activity of the essential bacterial enzyme dihydrodipicolinate synthase', 'Reboul, C F|Porebski, B T|Griffin, M D W|Dobson, R C J|Perugini, M A|Gerrard, J A|Buckle, A M', 'Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.', 'Australia|Australia|Australia|Australia|Australia|Australia|Australia', 14, 'Bacterial Proteins|Catalytic Domain|Computational Biology|Computer Simulation|Crystallography, X-Ray|Dimerization|Enzyme Stability|Escherichia coli|Escherichia coli Proteins|Hydro-Lyases|Methicillin-Resistant Staphylococcus aureus|Models, Molecular|Molecular Dynamics Simulation|Mutagenesis, Site-Directed|Protein Structure, Quaternary|Pyruvic Acid|Species Specificity|Substrate Specificity', 'Journal Article', '10.1371/journal.pcbi.1002537', '22685390', 'Dihydrodipicolinate synthase (DHDPS) is an essential enzyme involved in the lysine biosynthesis pathway. DHDPS from E. coli is a homotetramer consisting of a dimer of dimers, with the catalytic residues found at the tight-dimer interface. Crystallographic and biophysical evidence suggest that the dimers associate to stabilise the active site configuration, and mutation of a central dimer-dimer interface residue destabilises the tetramer, thus increasing the flexibility and reducing catalytic efficiency and substrate specificity. This has led to the hypothesis that the tetramer evolved to optimise the dynamics within the tight-dimer. In order to gain insights into DHDPS flexibility and its relationship to quaternary structure and function, we performed comparative Molecular Dynamics simulation studies of native tetrameric and dimeric forms of DHDPS from E. coli and also the native dimeric form from methicillin-resistant Staphylococcus aureus (MRSA). These reveal a striking contrast between the dynamics of tetrameric and dimeric forms. Whereas the E. coli DHDPS tetramer is relatively rigid, both the E. coli and MRSA DHDPS dimers display high flexibility, resulting in monomer reorientation within the dimer and increased flexibility at the tight-dimer interface. The mutant E. coli DHDPS dimer exhibits disorder within its active site with deformation of critical catalytic residues and removal of key hydrogen bonds that render it inactive, whereas the similarly flexible MRSA DHDPS dimer maintains its catalytic geometry and is thus fully functional. Our data support the hypothesis that in both bacterial species optimal activity is achieved by fine tuning protein dynamics in different ways: E. coli DHDPS buttresses together two dimers, whereas MRSA dampens the motion using an extended tight-dimer interface.'),
(85496, 2012, 'plos', 'Integrative approach to pain genetics identifies pain sensitivity loci across diseases', 'Ruau, David|Dudley, Joel T|Chen, Rong|Phillips, Nicholas G|Swan, Gary E|Lazzeroni, Laura C|Clark, J David|Butte, Atul J|Angst, Martin S', 'Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America. druau@stanford.edu|Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America. druau@stanford.edu|Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America. druau@stanford.edu|Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America. druau@stanford.edu|Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America. druau@stanford.edu|Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America. druau@stanford.edu|Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America. druau@stanford.edu|Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America. druau@stanford.edu|Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America. druau@stanford.edu', 'United States|United States|United States|United States|United States|United States|United States|Un', 10, 'Cohort Studies|Cold Temperature|Computational Biology|Databases, Genetic|Disease|Female|Gene Expression Profiling|Genome-Wide Association Study|Humans|Integrative Medicine|LIM Domain Proteins|Male|Models, Genetic|Neurocalcin|Pain|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002538', '22685391', 'Identifying human genes relevant for the processing of pain requires difficult-to-conduct and expensive large-scale clinical trials. Here, we examine a novel integrative paradigm for data-driven discovery of pain gene candidates, taking advantage of the vast amount of existing disease-related clinical literature and gene expression microarray data stored in large international repositories. First, thousands of diseases were ranked according to a disease-specific pain index (DSPI), derived from Medical Subject Heading (MESH) annotations in MEDLINE. Second, gene expression profiles of 121 of these human diseases were obtained from public sources. Third, genes with expression variation significantly correlated with DSPI across diseases were selected as candidate pain genes. Finally, selected candidate pain genes were genotyped in an independent human cohort and prospectively evaluated for significant association between variants and measures of pain sensitivity. The strongest signal was with rs4512126 (5q32, ABLIM3, Pxe2x80x8a=xe2x80x8a1.3xc3x9710xe2x81xbbxc2xb9xe2x81xb0) for the sensitivity to cold pressor pain in males, but not in females. Significant associations were also observed with rs12548828, rs7826700 and rs1075791 on 8q22.2 within NCALD (Pxe2x80x8a=xe2x80x8a1.7xc3x9710xe2x81xbbxe2x81xb4, 1.8xc3x9710xe2x81xbbxe2x81xb4, and 2.2xc3x9710xe2x81xbbxe2x81xb4 respectively). Our results demonstrate the utility of a novel paradigm that integrates publicly available disease-specific gene expression data with clinical data curated from MEDLINE to facilitate the discovery of pain-relevant genes. This data-derived list of pain gene candidates enables additional focused and efficient biological studies validating additional candidates.'),
(85497, 2012, 'plos', 'A maximum entropy test for evaluating higher-order correlations in spike counts', 'Onken, Arno|Dragoi, Valentin|Obermayer, Klaus', 'Technische Universität Berlin, Berlin, Germany. arno.onken@unige.ch|Technische Universität Berlin, Berlin, Germany. arno.onken@unige.ch|Technische Universität Berlin, Berlin, Germany. arno.onken@unige.ch', 'Germany|Germany|Germany', 2, 'Action Potentials|Animals|Cats|Computational Biology|Computer Simulation|Evoked Potentials, Visual|Likelihood Functions|Models, Neurological|Monte Carlo Method|Neurons|Photic Stimulation|Visual Cortex', 'Comparative Study', '10.1371/journal.pcbi.1002539', '22685392', 'Evaluating the importance of higher-order correlations of neural spike counts has been notoriously hard. A large number of samples are typically required in order to estimate higher-order correlations and resulting information theoretic quantities. In typical electrophysiology data sets with many experimental conditions, however, the number of samples in each condition is rather small. Here we describe a method that allows to quantify evidence for higher-order correlations in exactly these cases. We construct a family of reference distributions: maximum entropy distributions, which are constrained only by marginals and by linear correlations as quantified by the Pearson correlation coefficient. We devise a Monte Carlo goodness-of-fit test, which tests--for a given divergence measure of interest--whether the experimental data lead to the rejection of the null hypothesis that it was generated by one of the reference distributions. Applying our test to artificial data shows that the effects of higher-order correlations on these divergence measures can be detected even when the number of samples is small. Subsequently, we apply our method to spike count data which were recorded with multielectrode arrays from the primary visual cortex of anesthetized cat during an adaptation experiment. Using mutual information as a divergence measure we find that there are spike count bin sizes at which the maximum entropy hypothesis can be rejected for a substantial number of neuronal pairs. These results demonstrate that higher-order correlations can matter when estimating information theoretic quantities in V1. They also show that our test is able to detect their presence in typical in-vivo data sets, where the number of samples is too small to estimate higher-order correlations directly.'),
(85498, 2012, 'plos', 'A platform-independent method for detecting errors in metagenomic sequencing data: DRISEE', 'Keegan, Kevin P|Trimble, William L|Wilkening, Jared|Wilke, Andreas|Harrison, Travis|DSouza, Mark|Meyer, Folker', 'Argonne National Laboratory, Argonne, Illinois, United States of America. kkeegan@anl.gov|Argonne National Laboratory, Argonne, Illinois, United States of America. kkeegan@anl.gov|Argonne National Laboratory, Argonne, Illinois, United States of America. kkeegan@anl.gov|Argonne National Laboratory, Argonne, Illinois, United States of America. kkeegan@anl.gov|Argonne National Laboratory, Argonne, Illinois, United States of America. kkeegan@anl.gov|Argonne National Laboratory, Argonne, Illinois, United States of America. kkeegan@anl.gov|Argonne National Laboratory, Argonne, Illinois, United States of America. kkeegan@anl.gov', 'United States|United States|United States|United States|United States|United States|United States', 40, 'Computational Biology|Data Interpretation, Statistical|Genomics|High-Throughput Nucleotide Sequencing|Humans|Metagenomics|Sequence Analysis', 'Comparative Study', '10.1371/journal.pcbi.1002541', '22685393', 'We provide a novel method, DRISEE (duplicate read inferred sequencing error estimation), to assess sequencing quality (alternatively referred to as noise or error) within and/or between sequencing samples. DRISEE provides positional error estimates that can be used to inform read trimming within a sample. It also provides global (whole sample) error estimates that can be used to identify samples with high or varying levels of sequencing error that may confound downstream analyses, particularly in the case of studies that utilize data from multiple sequencing samples. For shotgun metagenomic data, we believe that DRISEE provides estimates of sequencing error that are more accurate and less constrained by technical limitations than existing methods that rely on reference genomes or the use of scores (e.g. Phred). Here, DRISEE is applied to (non amplicon) data sets from both the 454 and Illumina platforms. The DRISEE error estimate is obtained by analyzing sets of artifactual duplicate reads (ADRs), a known by-product of both sequencing platforms. We present DRISEE as an open-source, platform-independent method to assess sequencing error in shotgun metagenomic data, and utilize it to discover previously uncharacterized error in de novo sequence data from the 454 and Illumina sequencing platforms.'),
(85499, 2012, 'plos', 'Sarcomeric pattern formation by actin cluster coalescence', 'Friedrich, Benjamin M|Fischer-Friedrich, Elisabeth|Gov, Nir S|Safran, Samuel A', 'Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot, Israel. ben@pks.mpg.de|Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot, Israel. ben@pks.mpg.de|Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot, Israel. ben@pks.mpg.de|Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot, Israel. ben@pks.mpg.de', 'Israel|Israel|Israel|Israel', 22, 'Actins|Computational Biology|Computer Simulation|Models, Biological|Muscle Contraction|Muscle Fibers, Skeletal|Myosins|Sarcomeres', 'Journal Article', '10.1371/journal.pcbi.1002544', '22685394', 'Contractile function of striated muscle cells depends crucially on the almost crystalline order of actin and myosin filaments in myofibrils, but the physical mechanisms that lead to myofibril assembly remains ill-defined. Passive diffusive sorting of actin filaments into sarcomeric order is kinetically impossible, suggesting a pivotal role of active processes in sarcomeric pattern formation. Using a one-dimensional computational model of an initially unstriated actin bundle, we show that actin filament treadmilling in the presence of processive plus-end crosslinking provides a simple and robust mechanism for the polarity sorting of actin filaments as well as for the correct localization of myosin filaments. We propose that the coalescence of crosslinked actin clusters could be key for sarcomeric pattern formation. In our simulations, sarcomere spacing is set by filament length prompting tight length control already at early stages of pattern formation. The proposed mechanism could be generic and apply both to premyofibrils and nascent myofibrils in developing muscle cells as well as possibly to striated stress-fibers in non-muscle cells.'),
(85500, 2012, 'plos', 'Minimum free energy path of ligand-induced transition in adenylate kinase', 'Matsunaga, Yasuhiro|Fujisaki, Hiroshi|Terada, Tohru|Furuta, Tadaomi|Moritsugu, Kei|Kidera, Akinori', 'Computational Science Research Program, RIKEN, Wako, Japan. ymatsunaga@riken.jp|Computational Science Research Program, RIKEN, Wako, Japan. ymatsunaga@riken.jp|Computational Science Research Program, RIKEN, Wako, Japan. ymatsunaga@riken.jp|Computational Science Research Program, RIKEN, Wako, Japan. ymatsunaga@riken.jp|Computational Science Research Program, RIKEN, Wako, Japan. ymatsunaga@riken.jp|Computational Science Research Program, RIKEN, Wako, Japan. ymatsunaga@riken.jp', 'Japan|Japan|Japan|Japan|Japan|Japan', 55, 'Adenosine Monophosphate|Adenosine Triphosphate|Adenylate Kinase|Computational Biology|Computer Simulation|Entropy|Escherichia coli|Escherichia coli Proteins|Ligands|Models, Molecular|Molecular Dynamics Simulation|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1002555', '22685395', 'Large-scale conformational changes in proteins involve barrier-crossing transitions on the complex free energy surfaces of high-dimensional space. Such rare events cannot be efficiently captured by conventional molecular dynamics simulations. Here we show that, by combining the on-the-fly string method and the multi-state Bennett acceptance ratio (MBAR) method, the free energy profile of a conformational transition pathway in Escherichia coli adenylate kinase can be characterized in a high-dimensional space. The minimum free energy paths of the conformational transitions in adenylate kinase were explored by the on-the-fly string method in 20-dimensional space spanned by the 20 largest-amplitude principal modes, and the free energy and various kinds of average physical quantities along the pathways were successfully evaluated by the MBAR method. The influence of ligand binding on the pathways was characterized in terms of rigid-body motions of the lid-shaped ATP-binding domain (LID) and the AMP-binding (AMPbd) domains. It was found that the LID domain was able to partially close without the ligand, while the closure of the AMPbd domain required the ligand binding. The transition state ensemble of the ligand bound form was identified as those structures characterized by highly specific binding of the ligand to the AMPbd domain, and was validated by unrestrained MD simulations. It was also found that complete closure of the LID domain required the dehydration of solvents around the P-loop. These findings suggest that the interplay of the two different types of domain motion is an essential feature in the conformational transition of the enzyme.'),
(85501, 2012, 'plos', 'Termination of Caxc2xb2+ release for clustered IPxe2x82x83R channels', 'Rxc3xbcdiger, Sten|Jung, Peter|Shuai, Jian-Wei', 'Institut fxc3xbcr Physik, Humboldt-Universitxc3xa4t zu Berlin, Berlin, Germany. sten.ruediger@physik.hu-berlin.de|Institut fxc3xbcr Physik, Humboldt-Universitxc3xa4t zu Berlin, Berlin, Germany. sten.ruediger@physik.hu-berlin.de|Institut fxc3xbcr Physik, Humboldt-Universitxc3xa4t zu Berlin, Berlin, Germany. sten.ruediger@physik.hu-berlin.de', 'Germany|Germany|Germany', 19, 'Calcium|Calcium Signaling|Computer Simulation|Feedback, Physiological|Inositol 1,4,5-Trisphosphate Receptors|Ion Channel Gating|Membrane Microdomains|Models, Biological|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002485', '22693433', 'In many cell types, release of calcium ions is controlled by inositol 1,4,5-trisphosphate (IPxe2x82x83) receptor channels. Elevations in Caxc2xb2xe2x81xba concentration after intracellular release through IPxe2x82x83 receptors (IPxe2x82x83R) can either propagate in the form of waves spreading through the entire cell or produce spatially localized puffs. The appearance of waves and puffs is thought to implicate random initial openings of one or a few channels and subsequent activation of neighboring channels because of an autocatalytic feedback. It is much less clear, however, what determines the further time course of release, particularly since the lifetime is very different for waves (several seconds) and puffs (around 100 ms). Here we study the lifetime of Caxc2xb2xe2x81xba signals and their dependence on residual Caxc2xb2xe2x81xba microdomains. Our general idea is that Caxc2xb2xe2x81xba microdomains are dynamical and mediate the effect of other physiological processes. Specifically, we focus on the mechanism by which Caxc2xb2xe2x81xba binding proteins (buffers) alter the lifetime of Caxc2xb2xe2x81xba signals. We use stochastic simulations of channel gating coupled to a coarse-grained description for the Caxc2xb2xe2x81xba concentration. To describe the Caxc2xb2xe2x81xba concentration in a phenomenological way, we here introduce a differential equation, which reflects the buffer characteristics by a few effective parameters. This non-stationary model for microdomains gives deep insight into the dynamical differences between puffs and waves. It provides a novel explanation for the different lifetimes of puffs and waves and suggests that puffs are terminated by Caxc2xb2xe2x81xba inhibition while IPxe2x82x83 unbinding is responsible for termination of waves. Thus our analysis hints at an additional role of IP3 and shows how cells can make use of the full complexity in IPxe2x82x83R gating behavior to achieve different signals.'),
(85502, 2012, 'plos', 'Simulation of molecular data under diverse evolutionary scenarios', 'Arenas, Miguel', 'Computational and Molecular Population Genetics Lab-CMPG, Institute of Ecology and Evolution, University of Bern, Bern, Switzerland. miguel.arenasbusto@iee.unibe.ch', 'Switzerland', 35, 'Computational Biology|Computer Simulation|Europe|Evolution, Molecular|Humans|Models, Genetic|Recombination, Genetic|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002495', '22693434', '-');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85503, 2012, 'plos', 'Accessible high-throughput virtual screening molecular docking software for students and educators', 'Jacob, Reed B|Andersen, Tim|McDougal, Owen M', 'Boise State University, Boise, Idaho, United States of America.|Boise State University, Boise, Idaho, United States of America.|Boise State University, Boise, Idaho, United States of America.', 'United States|United States|United States', 44, 'Computational Biology|High-Throughput Screening Assays|Humans|Models, Biological|Models, Chemical|Models, Molecular|Software|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1002499', '22693435', 'We survey low cost high-throughput virtual screening (HTVS) computer programs for instructors who wish to demonstrate molecular docking in their courses. Since HTVS programs are a useful adjunct to the time consuming and expensive wet bench experiments necessary to discover new drug therapies, the topic of molecular docking is core to the instruction of biochemistry and molecular biology. The availability of HTVS programs coupled with decreasing costs and advances in computer hardware have made computational approaches to drug discovery possible at institutional and non-profit budgets. This paper focuses on HTVS programs with graphical user interfaces (GUIs) that use either DOCK or AutoDock for the prediction of DockoMatic, PyRx, DockingServer, and MOLA since their utility has been proven by the research community, they are free or affordable, and the programs operate on a range of computer platforms.'),
(85504, 2012, 'plos', 'Entrainment of the mammalian cell cycle by the circadian clock: modeling two coupled cellular rhythms', 'Gxc3xa9rard, Claude|Goldbeter, Albert', 'Facultxc3xa9 des Sciences, Universitxc3xa9 Libre de Bruxelles-ULB, Campus Plaine, CP 231, Brussels, Belgium.|Facultxc3xa9 des Sciences, Universitxc3xa9 Libre de Bruxelles-ULB, Campus Plaine, CP 231, Brussels, Belgium.', 'Belgium|Belgium', 0, 'Animals|Cell Cycle|Cell Cycle Proteins|Circadian Clocks|Cyclin-Dependent Kinases|DNA Replication|Intracellular Signaling Peptides and Proteins|Mammals|Models, Biological|Nuclear Proteins|Protein-Tyrosine Kinases', 'Journal Article', '10.1371/journal.pcbi.1002516', '22693436', 'The cell division cycle and the circadian clock represent two major cellular rhythms. These two periodic processes are coupled in multiple ways, given that several molecular components of the cell cycle network are controlled in a circadian manner. For example, in the network of cyclin-dependent kinases (Cdks) that governs progression along the successive phases of the cell cycle, the synthesis of the kinase Wee1, which inhibits the G2/M transition, is enhanced by the complex CLOCK-BMAL1 that plays a central role in the circadian clock network. Another component of the latter network, REV-ERBxcexb1, inhibits the synthesis of the Cdk inhibitor p21. Moreover, the synthesis of the oncogene c-Myc, which promotes G1 cyclin synthesis, is repressed by CLOCK-BMAL1. Using detailed computational models for the two networks we investigate the conditions in which the mammalian cell cycle can be entrained by the circadian clock. We show that the cell cycle can be brought to oscillate at a period of 24 h or 48 h when its autonomous period prior to coupling is in an appropriate range. The model indicates that the combination of multiple modes of coupling does not necessarily facilitate entrainment of the cell cycle by the circadian clock. Entrainment can also occur as a result of circadian variations in the level of a growth factor controlling entry into G1. Outside the range of entrainment, the coupling to the circadian clock may lead to disconnected oscillations in the cell cycle and the circadian system, or to complex oscillatory dynamics of the cell cycle in the form of endoreplication, complex periodic oscillations or chaos. The model predicts that the transition from entrainment to 24 h or 48 h might occur when the strength of coupling to the circadian clock or the level of growth factor decrease below critical values.'),
(85505, 2012, 'plos', 'Exploring massive, genome scale datasets with the GenometriCorr package', 'Favorov, Alexander|Mularoni, Loris|Cope, Leslie M|Medvedeva, Yulia|Mironov, Andrey A|Makeev, Vsevolod J|Wheelan, Sarah J', 'Department of Oncology, Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. favorov@sensi.org|Department of Oncology, Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. favorov@sensi.org|Department of Oncology, Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. favorov@sensi.org|Department of Oncology, Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. favorov@sensi.org|Department of Oncology, Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. favorov@sensi.org|Department of Oncology, Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. favorov@sensi.org|Department of Oncology, Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. favorov@sensi.org', 'United States|United States|United States|United States|United States|United States|United States', 79, 'Animals|Chromosomes|Databases, Genetic|Epigenomics|Genetic Loci|Genome|Genomics|Humans|Information Storage and Retrieval|Internet|Models, Genetic|Models, Statistical|RNA, Transfer|Software|Statistics, Nonparametric|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1002529', '22693437', 'We have created a statistically grounded tool for determining the correlation of genomewide data with other datasets or known biological features, intended to guide biological exploration of high-dimensional datasets, rather than providing immediate answers. The software enables several biologically motivated approaches to these data and here we describe the rationale and implementation for each approach. Our models and statistics are implemented in an R package that efficiently calculates the spatial correlation between two sets of genomic intervals (data and/or annotated features), for use as a metric of functional interaction. The software handles any type of pointwise or interval data and instead of running analyses with predefined metrics, it computes the significance and direction of several types of spatial association, this is intended to suggest potentially relevant relationships between the datasets.'),
(85506, 2012, 'plos', 'General anesthetics predicted to block the GLIC pore with micromolar affinity', 'LeBard, David N|Hxc3xa9nin, Jxc3xa9rxc3xb4me|Eckenhoff, Roderic G|Klein, Michael L|Brannigan, Grace', 'Department of Chemistry and Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania, United States of America.|Department of Chemistry and Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania, United States of America.|Department of Chemistry and Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania, United States of America.|Department of Chemistry and Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania, United States of America.|Department of Chemistry and Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania, United States of America.', 'United States|United States|United States|United States|United States', 51, 'Allosteric Site|Anesthetics, General|Bacterial Proteins|Binding Sites|Computer Simulation|Cysteine Loop Ligand-Gated Ion Channel Receptors|Models, Molecular|Protein Conformation|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002532', '22693438', 'Although general anesthetics are known to modulate the activity of ligand-gated ion channels in the Cys-loop superfamily, there is at present neither consensus on the underlying mechanisms, nor predictive models of this modulation. Viable models need to offer quantitative assessment of the relative importance of several identified anesthetic binding sites. However, to date, precise affinity data for individual sites has been challenging to obtain by biophysical means. Here, the likely role of pore block inhibition by the general anesthetics isoflurane and propofol of the prokaryotic pentameric channel GLIC is investigated by molecular simulations. Microscopic affinities are calculated for both single and double occupancy binding of isoflurane and propofol to the GLIC pore. Computations are carried out for an open-pore conformation in which the pore is restrained to crystallographic radius, and a closed-pore conformation that results from unrestrained molecular dynamics equilibration of the structure. The GLIC pore is predicted to be blocked at the micromolar concentrations for which inhibition by isofluorane and propofol is observed experimentally. Calculated affinities suggest that pore block by propofol occurs at signifcantly lower concentrations than those for which inhibition is observed: we argue that this discrepancy may result from binding of propofol to an allosteric site recently identified by X-ray crystallography, which may cause a competing gain-of-function effect. Affinities of isoflurane and propofol to the allosteric site are also calculated, and shown to be 3 mM for isoflurane and 10 xcexbcM for propofol, both anesthetics have a lower affinity for the allosteric site than for the unoccupied pore.'),
(85507, 2012, 'plos', 'Quality of computationally inferred gene ontology annotations', 'Skunca, Nives|Altenhoff, Adrian|Dessimoz, Christophe', 'Ruxc4x91er Boxc5xa1kovixc4x87 Institute, Division of Electronics, Zagreb, Croatia.|Ruxc4x91er Boxc5xa1kovixc4x87 Institute, Division of Electronics, Zagreb, Croatia.|Ruxc4x91er Boxc5xa1kovixc4x87 Institute, Division of Electronics, Zagreb, Croatia.', 'Croatia|Croatia|Croatia', 0, 'Computational Biology|Database Management Systems|Databases, Genetic|Molecular Sequence Annotation|Reproducibility of Results|Vocabulary, Controlled', 'Journal Article', '10.1371/journal.pcbi.1002533', '22693439', 'Gene Ontology (GO) has established itself as the undisputed standard for protein function annotation. Most annotations are inferred electronically, i.e. without individual curator supervision, but they are widely considered unreliable. At the same time, we crucially depend on those automated annotations, as most newly sequenced genomes are non-model organisms. Here, we introduce a methodology to systematically and quantitatively evaluate electronic annotations. By exploiting changes in successive releases of the UniProt Gene Ontology Annotation database, we assessed the quality of electronic annotations in terms of specificity, reliability, and coverage. Overall, we not only found that electronic annotations have significantly improved in recent years, but also that their reliability now rivals that of annotations inferred by curators when they use evidence other than experiments from primary literature. This work provides the means to identify the subset of electronic annotations that can be relied upon-an important outcome given that >98% of all annotations are inferred without direct curation.'),
(85508, 2012, 'plos', 'Thermodynamic basis for the emergence of genomes during prebiotic evolution', 'Woo, Hyung-June|Vijaya Satya, Ravi|Reifman, Jaques', 'DoD Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, United States Army Medical Research and Materiel Command, Fort Detrick, Maryland, United States of America.|DoD Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, United States Army Medical Research and Materiel Command, Fort Detrick, Maryland, United States of America.|DoD Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, United States Army Medical Research and Materiel Command, Fort Detrick, Maryland, United States of America.', 'United States|United States|United States', 0, 'DNA-Directed DNA Polymerase|Evolution, Molecular|Genome|Models, Genetic|Origin of Life|RNA|RNA, Catalytic|Stochastic Processes|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002534', '22693440', 'The RNA world hypothesis views modern organisms as descendants of RNA molecules. The earliest RNA molecules must have been random sequences, from which the first genomes that coded for polymerase ribozymes emerged. The quasispecies theory by Eigen predicts the existence of an error threshold limiting genomic stability during such transitions, but does not address the spontaneity of changes. Following a recent theoretical approach, we applied the quasispecies theory combined with kinetic/thermodynamic descriptions of RNA replication to analyze the collective behavior of RNA replicators based on known experimental kinetics data. We find that, with increasing fidelity (relative rate of base-extension for Watson-Crick versus mismatched base pairs), replications without enzymes, with ribozymes, and with protein-based polymerases are above, near, and below a critical point, respectively. The prebiotic evolution therefore must have crossed this critical region. Over large regions of the phase diagram, fitness increases with increasing fidelity, biasing random drifts in sequence space toward crystallization. This region encloses the experimental nonenzymatic fidelity value, favoring evolutions toward polymerase sequences with ever higher fidelity, despite error rates above the error catastrophe threshold. Our work shows that experimentally characterized kinetics and thermodynamics of RNA replication allow us to determine the physicochemical conditions required for the spontaneous crystallization of biological information. Our findings also suggest that among many potential oligomers capable of templated replication, RNAs may have evolved to form prebiotic genomes due to the value of their nonenzymatic fidelity.'),
(85509, 2012, 'plos', 'The CanOE strategy: integrating genomic and metabolic contexts across multiple prokaryote genomes to find candidate genes for orphan enzymes', 'Smith, Adam Alexander Thil|Belda, Eugeni|Viari, Alain|Medigue, Claudine|Vallenet, David', 'CEA DSV IG, Genoscope, Evry, France. aatsmith@orange.fr|CEA DSV IG, Genoscope, Evry, France. aatsmith@orange.fr|CEA DSV IG, Genoscope, Evry, France. aatsmith@orange.fr|CEA DSV IG, Genoscope, Evry, France. aatsmith@orange.fr|CEA DSV IG, Genoscope, Evry, France. aatsmith@orange.fr', 'France|France|France|France|France', 0, 'Archaeal Proteins|Bacterial Proteins|Databases, Genetic|Enzymes|Genome, Archaeal|Genome, Bacterial|Genomics|Metabolome|Metabolomics|Models, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002540', '22693442', 'Of all biochemically characterized metabolic reactions formalized by the IUBMB, over one out of four have yet to be associated with a nucleic or protein sequence, i.e. are sequence-orphan enzymatic activities. Few bioinformatics annotation tools are able to propose candidate genes for such activities by exploiting context-dependent rather than sequence-dependent data, and none are readily accessible and propose result integration across multiple genomes. Here, we present CanOE (Candidate genes for Orphan Enzymes), a four-step bioinformatics strategy that proposes ranked candidate genes for sequence-orphan enzymatic activities (or orphan enzymes for short). The first step locates genomic metabolons, i.e. groups of co-localized genes coding proteins catalyzing reactions linked by shared metabolites, in one genome at a time. These metabolons can be particularly helpful for aiding bioanalysts to visualize relevant metabolic data. In the second step, they are used to generate candidate associations between un-annotated genes and gene-less reactions. The third step integrates these gene-reaction associations over several genomes using gene families, and summarizes the strength of family-reaction associations by several scores. In the final step, these scores are used to rank members of gene families which are proposed for metabolic reactions. These associations are of particular interest when the metabolic reaction is a sequence-orphan enzymatic activity. Our strategy found over 60,000 genomic metabolons in more than 1,000 prokaryote organisms from the MicroScope platform, generating candidate genes for many metabolic reactions, of which more than 70 distinct orphan reactions. A computational validation of the approach is discussed. Finally, we present a case study on the anaerobic allantoin degradation pathway in Escherichia coli K-12.'),
(85510, 2012, 'plos', 'Structure and age jointly influence rates of protein evolution', 'Toll-Riera, Macarena|Bostick, David|Albà, M Mar|Plotkin, Joshua B', 'Evolutionary Genomics Group, Fundació Institut Municipal dInvestigació Mèdica-FIMIM, Universitat Pompeu Fabra-UPF, Barcelona, Spain.|Evolutionary Genomics Group, Fundació Institut Municipal dInvestigació Mèdica-FIMIM, Universitat Pompeu Fabra-UPF, Barcelona, Spain.|Evolutionary Genomics Group, Fundació Institut Municipal dInvestigació Mèdica-FIMIM, Universitat Pompeu Fabra-UPF, Barcelona, Spain.|Evolutionary Genomics Group, Fundació Institut Municipal dInvestigació Mèdica-FIMIM, Universitat Pompeu Fabra-UPF, Barcelona, Spain.', 'Spain|Spain|Spain|Spain', 0, 'Animals|Binding Sites|Computational Biology|Eukaryota|Evolution, Molecular|Humans|Mice|Protein Conformation|Protein Stability|Proteins|Solvents', 'Journal Article', '10.1371/journal.pcbi.1002542', '22693443', 'What factors determine a proteins rate of evolution are actively debated. Especially unclear is the relative role of intrinsic factors of present-day proteins versus historical factors such as protein age. Here we study the interplay of structural properties and evolutionary age, as determinants of protein evolutionary rate. We use a large set of one-to-one orthologs between human and mouse proteins, with mapped PDB structures. We report that previously observed structural correlations also hold within each age group - including relationships between solvent accessibility, designabililty, and evolutionary rates. However, age also plays a crucial role: age modulates the relationship between solvent accessibility and rate. Additionally, younger proteins, despite being less designable, tend to evolve faster than older proteins. We show that previously reported relationships between age and rate cannot be explained by structural biases among age groups. Finally, we introduce a knowledge-based potential function to study the stability of proteins through large-scale computation. We find that older proteins are more stable for their native structure, and more robust to mutations, than younger ones. Our results underscore that several determinants, both intrinsic and historical, can interact to determine rates of protein evolution.'),
(85511, 2012, 'plos', 'Metabolic reconstruction for metagenomic data and its application to the human microbiome', 'Abubucker, Sahar|Segata, Nicola|Goll, Johannes|Schubert, Alyxandria M|Izard, Jacques|Cantarel, Brandi L|Rodriguez-Mueller, Beltran|Zucker, Jeremy|Thiagarajan, Mathangi|Henrissat, Bernard|White, Owen|Kelley, Scott T|Methé, Barbara|Schloss, Patrick D|Gevers, Dirk|Mitreva, Makedonka|Huttenhower, Curtis', 'The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.|The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.|The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.|The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.|The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.|The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.|The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.|The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.|The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.|The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.|The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.|The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.|The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.|The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.|The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.|The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.|The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 573, 'Computational Biology|Digestive System|Female|Genetics, Microbial|Glycosaminoglycans|Humans|Hydrogen-Ion Concentration|Metabolic Networks and Pathways|Metabolome|Metagenome|Multigene Family|Vagina', 'Journal Article', '10.1371/journal.pcbi.1002358', '22719234', 'Microbial communities carry out the majority of the biochemical activity on the planet, and they play integral roles in processes including metabolism and immune homeostasis in the human microbiome. Shotgun sequencing of such communities metagenomes provides information complementary to organismal abundances from taxonomic markers, but the resulting data typically comprise short reads from hundreds of different organisms and are at best challenging to assemble comparably to single-organism genomes. Here, we describe an alternative approach to infer the functional and metabolic potential of a microbial community metagenome. We determined the gene families and pathways present or absent within a community, as well as their relative abundances, directly from short sequence reads. We validated this methodology using a collection of synthetic metagenomes, recovering the presence and abundance both of large pathways and of small functional modules with high accuracy. We subsequently applied this method, HUMAnN, to the microbial communities of 649 metagenomes drawn from seven primary body sites on 102 individuals as part of the Human Microbiome Project (HMP). This provided a means to compare functional diversity and organismal ecology in the human microbiome, and we determined a core of 24 ubiquitously present modules. Core pathways were often implemented by different enzyme families within different body sites, and 168 functional modules and 196 metabolic pathways varied in metagenomic abundance specifically to one or more niches within the microbiome. These included glycosaminoglycan degradation in the gut, as well as phosphate and amino acid transport linked to host phenotype (vaginal pH) in the posterior fornix. An implementation of our methodology is available at http://huttenhower.sph.harvard.edu/humann. This provides a means to accurately and efficiently characterize microbial metabolic pathways and functional modules directly from high-throughput sequencing reads, enabling the determination of community roles in the HMP cohort and in future metagenomic studies.'),
(85512, 2012, 'plos', 'The role of non-native interactions in the folding of knotted proteins', 'Skrbixc4x87, Tatjana|Micheletti, Cristian|Faccioli, Pietro', 'ECT*- European Centre for Theoretical Studies in Nuclear Physics and Related Areas, Villazzano (Trento), Italy.|ECT*- European Centre for Theoretical Studies in Nuclear Physics and Related Areas, Villazzano (Trento), Italy.|ECT*- European Centre for Theoretical Studies in Nuclear Physics and Related Areas, Villazzano (Trento), Italy.', 'Italy|Italy|Italy', 0, 'Carboxyl and Carbamoyl Transferases|Computational Biology|Computer Simulation|Kinetics|Models, Molecular|Monte Carlo Method|Ornithine Carbamoyltransferase|Protein Conformation|Protein Folding|Static Electricity|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002504', '22719235', 'Stochastic simulations of coarse-grained protein models are used to investigate the propensity to form knots in early stages of protein folding. The study is carried out comparatively for two homologous carbamoyltransferases, a natively-knotted N-acetylornithine carbamoyltransferase (AOTCase) and an unknotted ornithine carbamoyltransferase (OTCase). In addition, two different sets of pairwise amino acid interactions are considered: one promoting exclusively native interactions, and the other additionally including non-native quasi-chemical and electrostatic interactions. With the former model neither protein shows a propensity to form knots. With the additional non-native interactions, knotting propensity remains negligible for the natively-unknotted OTCase while for AOTCase it is much enhanced. Analysis of the trajectories suggests that the different entanglement of the two transcarbamylases follows from the tendency of the C-terminal to point away from (for OTCase) or approach and eventually thread (for AOTCase) other regions of partly-folded protein. The analysis of the OTCase/AOTCase pair clarifies that natively-knotted proteins can spontaneously knot during early folding stages and that non-native sequence-dependent interactions are important for promoting and disfavouring early knotting events.'),
(85513, 2012, 'plos', 'Visualization and analysis of 3D microscopic images', 'Long, Fuhui|Zhou, Jianlong|Peng, Hanchuan', 'Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America.|Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America.|Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America.', 'United States|United States|United States', 41, 'Animals|Brain|Caenorhabditis elegans|Computational Biology|Computer Simulation|Drosophila melanogaster|Gene Expression Profiling|Imaging, Three-Dimensional|Microscopy', 'Journal Article', '10.1371/journal.pcbi.1002519', '22719236', 'In a wide range of biological studies, it is highly desirable to visualize and analyze three-dimensional (3D) microscopic images. In this primer, we first introduce several major methods for visualizing typical 3D images and related multi-scale, multi-time-point, multi-color data sets. Then, we discuss three key categories of image analysis tasks, namely segmentation, registration, and annotation. We demonstrate how to pipeline these visualization and analysis modules using examples of profiling the single-cell gene-expression of C. elegans and constructing a map of stereotyped neurite tracts in a fruit fly brain.'),
(85514, 2012, 'plos', 'Fast coding of orientation in primary visual cortex', 'Shriki, Oren|Kohn, Adam|Shamir, Maoz', 'Department of Physiology and Neurobiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel. shrikio@mail.nih.gov|Department of Physiology and Neurobiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel. shrikio@mail.nih.gov|Department of Physiology and Neurobiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel. shrikio@mail.nih.gov', 'Israel|Israel|Israel', 0, 'Action Potentials|Animals|Computational Biology|Evoked Potentials, Visual|Humans|Macaca fascicularis|Models, Neurological|Neurons|Orientation|Photic Stimulation|Time Factors|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1002536', '22719237', 'Understanding how populations of neurons encode sensory information is a major goal of systems neuroscience. Attempts to answer this question have focused on responses measured over several hundred milliseconds, a duration much longer than that frequently used by animals to make decisions about the environment. How reliably sensory information is encoded on briefer time scales, and how best to extract this information, is unknown. Although it has been proposed that neuronal response latency provides a major cue for fast decisions in the visual system, this hypothesis has not been tested systematically and in a quantitative manner. Here we use a simple race to threshold readout mechanism to quantify the information content of spike time latency of primary visual (V1) cortical cells to stimulus orientation. We find that many V1 cells show pronounced tuning of their spike latency to stimulus orientation and that almost as much information can be extracted from spike latencies as from firing rates measured over much longer durations. To extract this information, stimulus onset must be estimated accurately. We show that the responses of cells with weak tuning of spike latency can provide a reliable onset detector. We find that spike latency information can be pooled from a large neuronal population, provided that the decision threshold is scaled linearly with the population size, yielding a processing time of the order of a few tens of milliseconds. Our results provide a novel mechanism for extracting information from neuronal populations over the very brief time scales in which behavioral judgments must sometimes be made.'),
(85515, 2012, 'plos', 'Spine calcium transients induced by synaptically-evoked action potentials can predict synapse location and establish synaptic democracy', 'Sterratt, David C|Groen, Martine R|Meredith, Rhiannon M|van Ooyen, Arjen', 'Institute for Adaptive and Neural Computation, School of Informatics, University of Edinburgh, Edinburgh, Scotland, United Kingdom.|Institute for Adaptive and Neural Computation, School of Informatics, University of Edinburgh, Edinburgh, Scotland, United Kingdom.|Institute for Adaptive and Neural Computation, School of Informatics, University of Edinburgh, Edinburgh, Scotland, United Kingdom.|Institute for Adaptive and Neural Computation, School of Informatics, University of Edinburgh, Edinburgh, Scotland, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Animals|CA1 Region, Hippocampal|Calcium Signaling|Computational Biology|Computer Simulation|Dendrites|Evoked Potentials|Male|Models, Neurological|Rats|Rats, Wistar|Receptors, N-Methyl-D-Aspartate|Synapses|alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid', 'Journal Article', '10.1371/journal.pcbi.1002545', '22719238', 'CA1 pyramidal neurons receive hundreds of synaptic inputs at different distances from the soma. Distance-dependent synaptic scaling enables distal and proximal synapses to influence the somatic membrane equally, a phenomenon called synaptic democracy. How this is established is unclear. The backpropagating action potential (BAP) is hypothesised to provide distance-dependent information to synapses, allowing synaptic strengths to scale accordingly. Experimental measurements show that a BAP evoked by current injection at the soma causes calcium currents in the apical shaft whose amplitudes decay with distance from the soma. However, in vivo action potentials are not induced by somatic current injection but by synaptic inputs along the dendrites, which creates a different excitable state of the dendrites. Due to technical limitations, it is not possible to study experimentally whether distance information can also be provided by synaptically-evoked BAPs. Therefore we adapted a realistic morphological and electrophysiological model to measure BAP-induced voltage and calcium signals in spines after Schaffer collateral synapse stimulation. We show that peak calcium concentration is highly correlated with soma-synapse distance under a number of physiologically-realistic suprathreshold stimulation regimes and for a range of dendritic morphologies. Peak calcium levels also predicted the attenuation of the EPSP across the dendritic tree. Furthermore, we show that peak calcium can be used to set up a synaptic democracy in a homeostatic manner, whereby synapses regulate their synaptic strength on the basis of the difference between peak calcium and a uniform target value. We conclude that information derived from synaptically-generated BAPs can indicate synapse location and can subsequently be utilised to implement a synaptic democracy.'),
(85516, 2012, 'plos', 'Complex spatial dynamics of oncolytic viruses in vitro: mathematical and experimental approaches', 'Wodarz, Dominik|Hofacre, Andrew|Lau, John W|Sun, Zhiying|Fan, Hung|Komarova, Natalia L', 'Department of Ecology and Evolutionary Biology, University of California, Irvine, California, United States of America. dwodarz@uci.edu|Department of Ecology and Evolutionary Biology, University of California, Irvine, California, United States of America. dwodarz@uci.edu|Department of Ecology and Evolutionary Biology, University of California, Irvine, California, United States of America. dwodarz@uci.edu|Department of Ecology and Evolutionary Biology, University of California, Irvine, California, United States of America. dwodarz@uci.edu|Department of Ecology and Evolutionary Biology, University of California, Irvine, California, United States of America. dwodarz@uci.edu|Department of Ecology and Evolutionary Biology, University of California, Irvine, California, United States of America. dwodarz@uci.edu', 'United States|United States|United States|United States|United States|United States', 33, 'Adenoviruses, Human|Computational Biology|Computer Simulation|Genetic Engineering|Green Fluorescent Proteins|HEK293 Cells|Humans|Models, Biological|Neoplasms|Oncolytic Virotherapy|Oncolytic Viruses|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.1002547', '22719239', 'Oncolytic viruses replicate selectively in tumor cells and can serve as targeted treatment agents. While promising results have been observed in clinical trials, consistent success of therapy remains elusive. The dynamics of virus spread through tumor cell populations has been studied both experimentally and computationally. However, a basic understanding of the principles underlying virus spread in spatially structured target cell populations has yet to be obtained. This paper studies such dynamics, using a newly constructed recombinant adenovirus type-5 (Ad5) that expresses enhanced jellyfish green fluorescent protein (EGFP), AdEGFPuci, and grows on human 293 embryonic kidney epithelial cells, allowing us to track cell numbers and spatial patterns over time. The cells are arranged in a two-dimensional setting and allow virus spread to occur only to target cells within the local neighborhood. Despite the simplicity of the setup, complex dynamics are observed. Experiments gave rise to three spatial patterns that we call hollow ring structure, filled ring structure, and disperse pattern. An agent-based, stochastic computational model is used to simulate and interpret the experiments. The model can reproduce the experimentally observed patterns, and identifies key parameters that determine which pattern of virus growth arises. The model is further used to study the long-term outcome of the dynamics for the different growth patterns, and to investigate conditions under which the virus population eliminates the target cells. We find that both the filled ring structure and disperse pattern of initial expansion are indicative of treatment failure, where target cells persist in the long run. The hollow ring structure is associated with either target cell extinction or low-level persistence, both of which can be viewed as treatment success. Interestingly, it is found that equilibrium properties of ordinary differential equations describing the dynamics in local neighborhoods in the agent-based model can predict the outcome of the spatial virus-cell dynamics, which has important practical implications. This analysis provides a first step towards understanding spatial oncolytic virus dynamics, upon which more detailed investigations and further complexity can be built.'),
(85517, 2012, 'plos', 'Location-dependent effects of inhibition on local spiking in pyramidal neuron dendrites', 'Jadi, Monika|Polsky, Alon|Schiller, Jackie|Mel, Bartlett W', 'Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America. jadi@salk.edu|Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America. jadi@salk.edu|Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America. jadi@salk.edu|Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America. jadi@salk.edu', 'United States|United States|United States|United States', 0, 'Action Potentials|Animals|Calcium Signaling|Computational Biology|Computer Simulation|Dendrites|Excitatory Postsynaptic Potentials|In Vitro Techniques|Male|Models, Neurological|N-Methylaspartate|Pyramidal Cells|Rats|Rats, Wistar|Somatosensory Cortex|alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid|gamma-Aminobutyric Acid', 'Journal Article', '10.1371/journal.pcbi.1002550', '22719240', 'Cortical computations are critically dependent on interactions between pyramidal neurons (PNs) and a menagerie of inhibitory interneuron types. A key feature distinguishing interneuron types is the spatial distribution of their synaptic contacts onto PNs, but the location-dependent effects of inhibition are mostly unknown, especially under conditions involving active dendritic responses. We studied the effect of somatic vs. dendritic inhibition on local spike generation in basal dendrites of layer 5 PNs both in neocortical slices and in simple and detailed compartmental models, with equivalent results: somatic inhibition divisively suppressed the amplitude of dendritic spikes recorded at the soma while minimally affecting dendritic spike thresholds. In contrast, distal dendritic inhibition raised dendritic spike thresholds while minimally affecting their amplitudes. On-the-path dendritic inhibition modulated both the gain and threshold of dendritic spikes depending on its distance from the spike initiation zone. Our findings suggest that cortical circuits could assign different mixtures of gain vs. threshold inhibition to different neural pathways, and thus tailor their local computations, by managing their relative activation of soma- vs. dendrite-targeting interneurons.'),
(85518, 2012, 'plos', 'The impact of phenotypic switching on glioblastoma growth and invasion', 'Gerlee, Philip|Nelander, Sven', 'Sahlgrenska Cancer Center, Institute of Medicine, Göteborg, Sweden. philip.gerlee@gu.se|Sahlgrenska Cancer Center, Institute of Medicine, Göteborg, Sweden. philip.gerlee@gu.se', 'Sweden|Sweden', 44, 'Apoptosis|Brain Neoplasms|Cell Movement|Cell Proliferation|Computational Biology|Computer Simulation|Disease Progression|Glioblastoma|Humans|Models, Biological|Neoplasm Invasiveness|Phenotype|Prognosis|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002556', '22719241', 'The brain tumour glioblastoma is characterised by diffuse and infiltrative growth into surrounding brain tissue. At the macroscopic level, the progression speed of a glioblastoma tumour is determined by two key factors: the cell proliferation rate and the cell migration speed. At the microscopic level, however, proliferation and migration appear to be mutually exclusive phenotypes, as indicated by recent in vivo imaging data. Here, we develop a mathematical model to analyse how the phenotypic switching between proliferative and migratory states of individual cells affects the macroscopic growth of the tumour. For this, we propose an individual-based stochastic model in which glioblastoma cells are either in a proliferative state, where they are stationary and divide, or in motile state in which they are subject to random motion. From the model we derive a continuum approximation in the form of two coupled reaction-diffusion equations, which exhibit travelling wave solutions whose speed of invasion depends on the model parameters. We propose a simple analytical method to predict progression rate from the cell-specific parameters and demonstrate that optimal glioblastoma growth depends on a non-trivial trade-off between the phenotypic switching rates. By linking cellular properties to an in vivo outcome, the model should be applicable to designing relevant cell screens for glioblastoma and cytometry-based patient prognostics.'),
(85519, 2012, 'plos', 'Probing the mutational interplay between primary and promiscuous protein functions: a computational-experimental approach', 'Garcia-Seisdedos, Hector|Ibarra-Molero, Beatriz|Sanchez-Ruiz, Jose M', 'Facultad de Ciencias, Departamento de Quimica Fisica, Universidad de Granada, Granada, Spain.|Facultad de Ciencias, Departamento de Quimica Fisica, Universidad de Granada, Granada, Spain.|Facultad de Ciencias, Departamento de Quimica Fisica, Universidad de Granada, Granada, Spain.', 'Spain|Spain|Spain', 10, 'Computational Biology|Computer Simulation|Directed Molecular Evolution|Escherichia coli Proteins|Evolution, Molecular|Least-Squares Analysis|Models, Biological|Models, Molecular|Mutation|Protein Conformation|Protein Folding|Protein Structure, Tertiary|Proteins|Thioredoxins', 'Journal Article', '10.1371/journal.pcbi.1002558', '22719242', 'Protein promiscuity is of considerable interest due its role in adaptive metabolic plasticity, its fundamental connection with molecular evolution and also because of its biotechnological applications. Current views on the relation between primary and promiscuous protein activities stem largely from laboratory evolution experiments aimed at increasing promiscuous activity levels. Here, on the other hand, we attempt to assess the main features of the simultaneous modulation of the primary and promiscuous functions during the course of natural evolution. The computational/experimental approach we propose for this task involves the following steps: a function-targeted, statistical coupling analysis of evolutionary data is used to determine a set of positions likely linked to the recruitment of a promiscuous activity for a new function, a combinatorial library of mutations on this set of positions is prepared and screened for both, the primary and the promiscuous activities, a partial-least-squares reconstruction of the full combinatorial space is carried out, finally, an approximation to the Pareto set of variants with optimal primary/promiscuous activities is derived. Application of the approach to the emergence of folding catalysis in thioredoxin scaffolds reveals an unanticipated scenario: diverse patterns of primary/promiscuous activity modulation are possible, including a moderate (but likely significant in a biological context) simultaneous enhancement of both activities. We show that this scenario can be most simply explained on the basis of the conformational diversity hypothesis, although alternative interpretations cannot be ruled out. Overall, the results reported may help clarify the mechanisms of the evolution of new functions. From a different viewpoint, the partial-least-squares-reconstruction/Pareto-set-prediction approach we have introduced provides the computational basis for an efficient directed-evolution protocol aimed at the simultaneous enhancement of several protein features and should therefore open new possibilities in the engineering of multi-functional enzymes.'),
(85520, 2012, 'plos', 'Computing with neural synchrony', 'Brette, Romain', 'Laboratoire Psychologie de la Perception, CNRS and Université Paris Descartes, Sorbonne Paris Cité, Paris, France. romain.brette@ens.fr', 'France', 0, 'Action Potentials|Animals|Auditory Perception|Computational Biology|Computer Simulation|Humans|Models, Neurological|Nerve Net|Neuronal Plasticity|Perception|Smell|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1002561', '22719243', 'Neurons communicate primarily with spikes, but most theories of neural computation are based on firing rates. Yet, many experimental observations suggest that the temporal coordination of spikes plays a role in sensory processing. Among potential spike-based codes, synchrony appears as a good candidate because neural firing and plasticity are sensitive to fine input correlations. However, it is unclear what role synchrony may play in neural computation, and what functional advantage it may provide. With a theoretical approach, I show that the computational interest of neural synchrony appears when neurons have heterogeneous properties. In this context, the relationship between stimuli and neural synchrony is captured by the concept of synchrony receptive field, the set of stimuli which induce synchronous responses in a group of neurons. In a heterogeneous neural population, it appears that synchrony patterns represent structure or sensory invariants in stimuli, which can then be detected by postsynaptic neurons. The required neural circuitry can spontaneously emerge with spike-timing-dependent plasticity. Using examples in different sensory modalities, I show that this allows simple neural circuits to extract relevant information from realistic sensory stimuli, for example to identify a fluctuating odor in the presence of distractors. This theory of synchrony-based computation shows that relative spike timing may indeed have computational relevance, and suggests new types of neural network models for sensory processing with appealing computational properties.'),
(85521, 2012, 'plos', 'Charge profile analysis reveals that activation of pro-apoptotic regulators Bax and Bak relies on charge transfer mediated allosteric regulation', 'Ionescu, Crina-Maria|Svobodovxc3xa1 Vaxc5x99ekovxc3xa1, Radka|Prehn, Jochen H M|Huber, Heinrich J|Koxc4x8da, Jaroslav', 'CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic.|CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic.|CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic.|CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic.|CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic.', '-|-|-|-|-', 0, 'Allosteric Regulation|Amino Acid Sequence|Apoptosis|Computational Biology|Computer Simulation|Humans|Models, Biological|Models, Molecular|Molecular Sequence Data|Protein Conformation|Protein Interaction Domains and Motifs|Sequence Homology, Amino Acid|Static Electricity|bcl-2 Homologous Antagonist-Killer Protein|bcl-2-Associated X Protein', 'Journal Article', '10.1371/journal.pcbi.1002565', '22719244', 'The pro-apoptotic proteins Bax and Bak are essential for executing programmed cell death (apoptosis), yet the mechanism of their activation is not properly understood at the structural level. For the first time in cell death research, we calculated intra-protein charge transfer in order to study the structural alterations and their functional consequences during Bax activation. Using an electronegativity equalization model, we investigated the changes in the Bax charge profile upon activation by a functional peptide of its natural activator protein, Bim. We found that charge reorganizations upon activator binding mediate the exposure of the functional sites of Bax, rendering Bax active. The affinity of the Bax C-domain for its binding groove is decreased due to the Arg94-mediated abrogation of the Ser184-Asp98 interaction. We further identified a network of charge reorganizations that confirms previous speculations of allosteric sensing, whereby the activation information is conveyed from the activation site, through the hydrophobic core of Bax, to the well-distanced functional sites of Bax. The network was mediated by a hub of three residues on helix 5 of the hydrophobic core of Bax. Sequence and structural alignment revealed that this hub was conserved in the Bak amino acid sequence, and in the 3D structure of folded Bak. Our results suggest that allostery mediated by charge transfer is responsible for the activation of both Bax and Bak, and that this might be a prototypical mechanism for a fast activation of proteins during signal transduction. Our method can be applied to any protein or protein complex in order to map the progress of allosteric changes through the proteins structure.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85522, 2012, 'plos', 'Modelling cell polarization driven by synthetic spatially graded Rac activation', 'Holmes, William R|Lin, Benjamin|Levchenko, Andre|Edelstein-Keshet, Leah', 'Department of Mathematics, University of British Columbia, Vancouver, British Columbia, Canada. wrholmes@math.ubc.ca|Department of Mathematics, University of British Columbia, Vancouver, British Columbia, Canada. wrholmes@math.ubc.ca|Department of Mathematics, University of British Columbia, Vancouver, British Columbia, Canada. wrholmes@math.ubc.ca|Department of Mathematics, University of British Columbia, Vancouver, British Columbia, Canada. wrholmes@math.ubc.ca', 'Canada|Canada|Canada|Canada', 33, 'Cell Membrane|Cell Polarity|Cell Shape|Computational Biology|Computer Simulation|Cytosol|Enzyme Activation|Feedback, Physiological|HeLa Cells|Humans|Models, Biological|Phosphatidylinositols|Receptor Cross-Talk|cdc42 GTP-Binding Protein|rac GTP-Binding Proteins|rho GTP-Binding Proteins', 'Journal Article', '10.1371/journal.pcbi.1002366', '22737059', 'The small GTPase Rac is known to be an important regulator of cell polarization, cytoskeletal reorganization, and motility of mammalian cells. In recent microfluidic experiments, HeLa cells endowed with appropriate constructs were subjected to gradients of the small molecule rapamycin leading to synthetic membrane recruitment of a Rac activator and direct graded activation of membrane-associated Rac. Rac activation could thus be triggered independent of upstream signaling mechanisms otherwise responsible for transducing activating gradient signals. The response of the cells to such stimulation depended on exceeding a threshold of activated Rac. Here we develop a minimal reaction-diffusion model for the GTPase network alone and for GTPase-phosphoinositide crosstalk that is consistent with experimental observations for the polarization of the cells. The modeling suggests that mutual inhibition is a more likely mode of cell polarization than positive feedback of Rac onto its own activation. We use a new analytical tool, Local Perturbation Analysis, to approximate the partial differential equations by ordinary differential equations for local and global variables. This method helps to analyze the parameter space and behaviour of the proposed models. The models and experiments suggest that (1) spatially uniform stimulation serves to sensitize a cell to applied gradients. (2) Feedback between phosphoinositides and Rho GTPases sensitizes a cell. (3) Cell lengthening/flattening accompanying polarization can increase the sensitivity of a cell and stabilize an otherwise unstable polarization.'),
(85523, 2012, 'plos', 'Potassium starvation in yeast: mechanisms of homeostasis revealed by mathematical modeling', 'Kahm, Matthias|Navarrete, Clara|Llopis-Torregrosa, Vicent|Herrera, Rito|Barreto, Lina|Yenush, Lynne|Ariño, Joaquin|Ramos, Jose|Kschischo, Maik', 'Department of Mathematics and Technology, RheinAhrCampus, University of Applied Sciences, Koblenz, Remagen, Germany.|Department of Mathematics and Technology, RheinAhrCampus, University of Applied Sciences, Koblenz, Remagen, Germany.|Department of Mathematics and Technology, RheinAhrCampus, University of Applied Sciences, Koblenz, Remagen, Germany.|Department of Mathematics and Technology, RheinAhrCampus, University of Applied Sciences, Koblenz, Remagen, Germany.|Department of Mathematics and Technology, RheinAhrCampus, University of Applied Sciences, Koblenz, Remagen, Germany.|Department of Mathematics and Technology, RheinAhrCampus, University of Applied Sciences, Koblenz, Remagen, Germany.|Department of Mathematics and Technology, RheinAhrCampus, University of Applied Sciences, Koblenz, Remagen, Germany.|Department of Mathematics and Technology, RheinAhrCampus, University of Applied Sciences, Koblenz, Remagen, Germany.|Department of Mathematics and Technology, RheinAhrCampus, University of Applied Sciences, Koblenz, Remagen, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany', 0, 'Algorithms|Cation Transport Proteins|Cell Membrane|Computational Biology|Computer Simulation|Genes, Fungal|Homeostasis|Ion Transport|Models, Biological|Mutation|Potassium|Proton-Translocating ATPases|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Sodium-Hydrogen Exchangers', 'Journal Article', '10.1371/journal.pcbi.1002548', '22737060', 'The intrinsic ability of cells to adapt to a wide range of environmental conditions is a fundamental process required for survival. Potassium is the most abundant cation in living cells and is required for essential cellular processes, including the regulation of cell volume, pH and protein synthesis. Yeast cells can grow from low micromolar to molar potassium concentrations and utilize sophisticated control mechanisms to keep the internal potassium concentration in a viable range. We developed a mathematical model for Saccharomyces cerevisiae to explore the complex interplay between biophysical forces and molecular regulation facilitating potassium homeostasis. By using a novel inference method (the reverse tracking algorithm) we predicted and then verified experimentally that the main regulators under conditions of potassium starvation are proton fluxes responding to changes of potassium concentrations. In contrast to the prevailing view, we show that regulation of the main potassium transport systems (Trk1,2 and Nha1) in the plasma membrane is not sufficient to achieve homeostasis.'),
(85524, 2012, 'plos', 'Protein scaffolds can enhance the bistability of multisite phosphorylation systems', 'Chan, Carlo|Liu, Xinfeng|Wang, Liming|Bardwell, Lee|Nie, Qing|Enciso, Germán', 'Department of Mathematics, Center for Mathematical and Complex Biological Systems, Center for Complex Biological Systems, University of California, Irvine, California, USA.|Department of Mathematics, Center for Mathematical and Complex Biological Systems, Center for Complex Biological Systems, University of California, Irvine, California, USA.|Department of Mathematics, Center for Mathematical and Complex Biological Systems, Center for Complex Biological Systems, University of California, Irvine, California, USA.|Department of Mathematics, Center for Mathematical and Complex Biological Systems, Center for Complex Biological Systems, University of California, Irvine, California, USA.|Department of Mathematics, Center for Mathematical and Complex Biological Systems, Center for Complex Biological Systems, University of California, Irvine, California, USA.|Department of Mathematics, Center for Mathematical and Complex Biological Systems, Center for Complex Biological Systems, University of California, Irvine, California, USA.', 'United States|United States|United States|United States|United States|United States', 24, 'Binding Sites|Computational Biology|Computer Simulation|Kinetics|Linear Models|Models, Biological|Phosphorylation|Protein Kinases|Protein Processing, Post-Translational|Protein Stability|Proteins', 'Journal Article', '10.1371/journal.pcbi.1002551', '22737061', 'The phosphorylation of a substrate at multiple sites is a common protein modification that can give rise to important structural and electrostatic changes. Scaffold proteins can enhance protein phosphorylation by facilitating an interaction between a protein kinase enzyme and its target substrate. In this work we consider a simple mathematical model of a scaffold protein and show that under specific conditions, the presence of the scaffold can substantially raise the likelihood that the resulting system will exhibit bistable behavior. This phenomenon is especially pronounced when the enzymatic reactions have sufficiently large K(M), compared to the concentration of the target substrate. We also find for a closely related model that bistable systems tend to have a specific kinetic conformation. Using deficiency theory and other methods, we provide a number of necessary conditions for bistability, such as the presence of multiple phosphorylation sites and the dependence of the scaffold binding/unbinding rates on the number of phosphorylated sites.'),
(85525, 2012, 'plos', 'Short term synaptic depression imposes a frequency dependent filter on synaptic information transfer', 'Rosenbaum, Robert|Rubin, Jonathan|Doiron, Brent', 'Mathematics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. robertr@pitt.edu|Mathematics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. robertr@pitt.edu|Mathematics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. robertr@pitt.edu', 'United States|United States|United States', 0, 'Action Potentials|Animals|Computational Biology|Computer Simulation|Models, Neurological|Neuronal Plasticity|Neurotransmitter Agents|Stochastic Processes|Synapses|Synaptic Transmission|Synaptic Vesicles', 'Journal Article', '10.1371/journal.pcbi.1002557', '22737062', 'Depletion of synaptic neurotransmitter vesicles induces a form of short term depression in synapses throughout the nervous system. This plasticity affects how synapses filter presynaptic spike trains. The filtering properties of short term depression are often studied using a deterministic synapse model that predicts the mean synaptic response to a presynaptic spike train, but ignores variability introduced by the probabilistic nature of vesicle release and stochasticity in synaptic recovery time. We show that this additional variability has important consequences for the synaptic filtering of presynaptic information. In particular, a synapse model with stochastic vesicle dynamics suppresses information encoded at lower frequencies more than information encoded at higher frequencies, while a model that ignores this stochasticity transfers information encoded at any frequency equally well. This distinction between the two models persists even when large numbers of synaptic contacts are considered. Our study provides strong evidence that the stochastic nature neurotransmitter vesicle dynamics must be considered when analyzing the information flow across a synapse.'),
(85526, 2012, 'plos', 'Multiple genetic interaction experiments provide complementary information useful for gene function prediction', 'Michaut, Magali|Bader, Gary D', 'The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.', 'Canada|Canada', 13, 'Computational Biology|Computer Simulation|Epistasis, Genetic|Gene Regulatory Networks|Genome, Fungal|Models, Genetic|Mutation|Phenotype|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1002559', '22737063', 'Genetic interactions help map biological processes and their functional relationships. A genetic interaction is defined as a deviation from the expected phenotype when combining multiple genetic mutations. In Saccharomyces cerevisiae, most genetic interactions are measured under a single phenotype - growth rate in standard laboratory conditions. Recently genetic interactions have been collected under different phenotypic readouts and experimental conditions. How different are these networks and what can we learn from their differences? We conducted a systematic analysis of quantitative genetic interaction networks in yeast performed under different experimental conditions. We find that networks obtained using different phenotypic readouts, in different conditions and from different laboratories overlap less than expected and provide significant unique information. To exploit this information, we develop a novel method to combine individual genetic interaction data sets and show that the resulting network improves gene function prediction performance, demonstrating that individual networks provide complementary information. Our results support the notion that using diverse phenotypic readouts and experimental conditions will substantially increase the amount of gene function information produced by genetic interaction screens.'),
(85527, 2012, 'plos', 'Complementarity of spike- and rate-based dynamics of neural systems', 'Wilson, M T|Robinson, P A|ONeill, B|Steyn-Ross, D A', 'School of Engineering, University of Waikato, Hamilton, New Zealand. mtwilson@waikato.ac.nz|School of Engineering, University of Waikato, Hamilton, New Zealand. mtwilson@waikato.ac.nz|School of Engineering, University of Waikato, Hamilton, New Zealand. mtwilson@waikato.ac.nz|School of Engineering, University of Waikato, Hamilton, New Zealand. mtwilson@waikato.ac.nz', 'New Zealand|New Zealand|New Zealand|New Zealand', 10, 'Action Potentials|Animals|Computational Biology|Computer Simulation|Humans|Models, Neurological|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.1002560', '22737064', 'Relationships between spiking-neuron and rate-based approaches to the dynamics of neural assemblies are explored by analyzing a model system that can be treated by both methods, with the rate-based method further averaged over multiple neurons to give a neural-field approach. The system consists of a chain of neurons, each with simple spiking dynamics that has a known rate-based equivalent. The neurons are linked by propagating activity that is described in terms of a spatial interaction strength with temporal delays that reflect distances between neurons, feedback via a separate delay loop is also included because such loops also exist in real brains. These interactions are described using a spatiotemporal coupling function that can carry either spikes or rates to provide coupling between neurons. Numerical simulation of corresponding spike- and rate-based methods with these compatible couplings then allows direct comparison between the dynamics arising from these approaches. The rate-based dynamics can reproduce two different forms of oscillation that are present in the spike-based model: spiking rates of individual neurons and network-induced modulations of spiking rate that occur if network interactions are sufficiently strong. Depending on conditions either mode of oscillation can dominate the spike-based dynamics and in some situations, particularly when the ratio of the frequencies of these two modes is integer or half-integer, the two can both be present and interact with each other.'),
(85528, 2012, 'plos', 'A scalable algorithm to explore the Gibbs energy landscape of genome-scale metabolic networks', 'De Martino, Daniele|Figliuzzi, Matteo|De Martino, Andrea|Marinari, Enzo', 'Dipartimento di Fisica, Sapienza Università di Roma, Roma, Italy.|Dipartimento di Fisica, Sapienza Università di Roma, Roma, Italy.|Dipartimento di Fisica, Sapienza Università di Roma, Roma, Italy.|Dipartimento di Fisica, Sapienza Università di Roma, Roma, Italy.', 'Italy|Italy|Italy|Italy', 0, 'Algorithms|Computational Biology|Computer Simulation|Erythrocytes|Escherichia coli|Genome|Genome, Human|Humans|Metabolic Networks and Pathways|Models, Biological|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002562', '22737065', 'The integration of various types of genomic data into predictive models of biological networks is one of the main challenges currently faced by computational biology. Constraint-based models in particular play a key role in the attempt to obtain a quantitative understanding of cellular metabolism at genome scale. In essence, their goal is to frame the metabolic capabilities of an organism based on minimal assumptions that describe the steady states of the underlying reaction network via suitable stoichiometric constraints, specifically mass balance and energy balance (i.e. thermodynamic feasibility). The implementation of these requirements to generate viable configurations of reaction fluxes and/or to test given flux profiles for thermodynamic feasibility can however prove to be computationally intensive. We propose here a fast and scalable stoichiometry-based method to explore the Gibbs energy landscape of a biochemical network at steady state. The method is applied to the problem of reconstructing the Gibbs energy landscape underlying metabolic activity in the human red blood cell, and to that of identifying and removing thermodynamically infeasible reaction cycles in the Escherichia coli metabolic network (iAF1260). In the former case, we produce consistent predictions for chemical potentials (or log-concentrations) of intracellular metabolites, in the latter, we identify a restricted set of loops (23 in total) in the periplasmic and cytoplasmic core as the origin of thermodynamic infeasibility in a large sample (10(6)) of flux configurations generated randomly and compatibly with the prior information available on reaction reversibility.'),
(85529, 2012, 'plos', 'MC EMiNEM maps the interaction landscape of the Mediator', 'Niederberger, Theresa|Etzold, Stefanie|Lidschreiber, Michael|Maier, Kerstin C|Martin, Dietmar E|Fröhlich, Holger|Cramer, Patrick|Tresch, Achim', 'Gene Center Munich and Center for integrated Protein Science CiPSM, Department of Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany.|Gene Center Munich and Center for integrated Protein Science CiPSM, Department of Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany.|Gene Center Munich and Center for integrated Protein Science CiPSM, Department of Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany.|Gene Center Munich and Center for integrated Protein Science CiPSM, Department of Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany.|Gene Center Munich and Center for integrated Protein Science CiPSM, Department of Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany.|Gene Center Munich and Center for integrated Protein Science CiPSM, Department of Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany.|Gene Center Munich and Center for integrated Protein Science CiPSM, Department of Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany.|Gene Center Munich and Center for integrated Protein Science CiPSM, Department of Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany', 15, 'Algorithms|Bayes Theorem|Computational Biology|Computer Simulation|Gene Expression Profiling|Mediator Complex|Models, Biological|Models, Statistical|Monte Carlo Method|Protein Interaction Mapping|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins', 'Journal Article', '10.1371/journal.pcbi.1002568', '22737066', 'The Mediator is a highly conserved, large multiprotein complex that is involved essentially in the regulation of eukaryotic mRNA transcription. It acts as a general transcription factor by integrating regulatory signals from gene-specific activators or repressors to the RNA Polymerase II. The internal network of interactions between Mediator subunits that conveys these signals is largely unknown. Here, we introduce MC EMiNEM, a novel method for the retrieval of functional dependencies between proteins that have pleiotropic effects on mRNA transcription. MC EMiNEM is based on Nested Effects Models (NEMs), a class of probabilistic graphical models that extends the idea of hierarchical clustering. It combines mode-hopping Monte Carlo (MC) sampling with an Expectation-Maximization (EM) algorithm for NEMs to increase sensitivity compared to existing methods. A meta-analysis of four Mediator perturbation studies in Saccharomyces cerevisiae, three of which are unpublished, provides new insight into the Mediator signaling network. In addition to the known modular organization of the Mediator subunits, MC EMiNEM reveals a hierarchical ordering of its internal information flow, which is putatively transmitted through structural changes within the complex. We identify the N-terminus of Med7 as a peripheral entity, entailing only local structural changes upon perturbation, while the C-terminus of Med7 and Med19 appear to play a central role. MC EMiNEM associates Mediator subunits to most directly affected genes, which, in conjunction with gene set enrichment analysis, allows us to construct an interaction map of Mediator subunits and transcription factors.'),
(85530, 2012, 'plos', 'Use it and improve it or lose it: interactions between arm function and use in humans post-stroke', 'Hidaka, Yukikazu|Han, Cheol E|Wolf, Steven L|Winstein, Carolee J|Schweighofer, Nicolas', 'Computer Science, University of Southern California, Los Angeles, California, USA.|Computer Science, University of Southern California, Los Angeles, California, USA.|Computer Science, University of Southern California, Los Angeles, California, USA.|Computer Science, University of Southern California, Los Angeles, California, USA.|Computer Science, University of Southern California, Los Angeles, California, USA.', 'United States|United States|United States|United States|United States', 0, 'Activities of Daily Living|Bayes Theorem|Exercise Therapy|Humans|Longitudinal Studies|Models, Biological|Motor Skills|Randomized Controlled Trials as Topic|Regression Analysis|Stroke|Stroke Rehabilitation|Upper Extremity', 'Journal Article', '10.1371/journal.pcbi.1002343', '22761551', 'Use it and improve it, or lose it is one of the axioms of motor therapy after stroke. There is, however, little understanding of the interactions between arm function and use in humans post-stroke. Here, we explored putative non-linear interactions between upper extremity function and use by developing a first-order dynamical model of stroke recovery with longitudinal data from participants receiving constraint induced movement therapy (CIMT) in the EXCITE clinical trial. Using a Bayesian regression framework, we systematically compared this model with competitive models that included, or not, interactions between function and use. Model comparisons showed that the model with the predicted interactions between arm function and use was the best fitting model. Furthermore, by comparing the model parameters before and after CIMT intervention in participants receiving the intervention one year after randomization, we found that therapy increased the parameter that controls the effect of arm function on arm use. Increase in this parameter, which can be thought of as the confidence to use the arm for a given level of function, lead to increase in spontaneous use after therapy compared to before therapy.'),
(85531, 2012, 'plos', 'Equation-free analysis of two-component system signalling model reveals the emergence of co-existing phenotypes in the absence of multistationarity', 'Hoyle, Rebecca B|Avitabile, Daniele|Kierzek, Andrzej M', 'Department of Mathematics, University of Surrey, Guildford, United Kingdom. r.hoyle@surrey.ac.uk|Department of Mathematics, University of Surrey, Guildford, United Kingdom. r.hoyle@surrey.ac.uk|Department of Mathematics, University of Surrey, Guildford, United Kingdom. r.hoyle@surrey.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 7, 'Algorithms|Bacteria|Bacterial Proteins|Computational Biology|Computer Simulation|Escherichia coli|Kinetics|Models, Biological|Phenotype|Signal Transduction|Stochastic Processes|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002396', '22761552', 'Phenotypic differences of genetically identical cells under the same environmental conditions have been attributed to the inherent stochasticity of biochemical processes. Various mechanisms have been suggested, including the existence of alternative steady states in regulatory networks that are reached by means of stochastic fluctuations, long transient excursions from a stable state to an unstable excited state, and the switching on and off of a reaction network according to the availability of a constituent chemical species. Here we analyse a detailed stochastic kinetic model of two-component system signalling in bacteria, and show that alternative phenotypes emerge in the absence of these features. We perform a bifurcation analysis of deterministic reaction rate equations derived from the model, and find that they cannot reproduce the whole range of qualitative responses to external signals demonstrated by direct stochastic simulations. In particular, the mixed mode, where stochastic switching and a graded response are seen simultaneously, is absent. However, probabilistic and equation-free analyses of the stochastic model that calculate stationary states for the mean of an ensemble of stochastic trajectories reveal that slow transcription of either response regulator or histidine kinase leads to the coexistence of an approximate basal solution and a graded response that combine to produce the mixed mode, thus establishing its essential stochastic nature. The same techniques also show that stochasticity results in the observation of an all-or-none bistable response over a much wider range of external signals than would be expected on deterministic grounds. Thus we demonstrate the application of numerical equation-free methods to a detailed biochemical reaction network model, and show that it can provide new insight into the role of stochasticity in the emergence of phenotypic diversity.'),
(85532, 2012, 'plos', 'Viral perturbations of host networks reflect disease etiology', 'Gulbahce, Natali|Yan, Han|Dricot, Amélie|Padi, Megha|Byrdsong, Danielle|Franchi, Rachel|Lee, Deok-Sun|Rozenblatt-Rosen, Orit|Mar, Jessica C|Calderwood, Michael A|Baldwin, Amy|Zhao, Bo|Santhanam, Balaji|Braun, Pascal|Simonis, Nicolas|Huh, Kyung-Won|Hellner, Karin|Grace, Miranda|Chen, Alyce|Rubio, Renee|Marto, Jarrod A|Christakis, Nicholas A|Kieff, Elliott|Roth, Frederick P|Roecklein-Canfield, Jennifer|Decaprio, James A|Cusick, Michael E|Quackenbush, John|Hill, David E|Münger, Karl|Vidal, Marc|Barabási, Albert-László', 'Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.|Center for Complex Networks Research-CCNR and Department of Physics, Northeastern University, Boston, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Computational Biology|Disease|Fanconi Anemia|Genetic Predisposition to Disease|Herpesvirus 4, Human|Host-Pathogen Interactions|Human papillomavirus 16|Humans|Models, Biological|Protein Interaction Maps|Viral Proteins|Virus Diseases', 'Journal Article', '10.1371/journal.pcbi.1002531', '22761553', 'Many human diseases, arising from mutations of disease susceptibility genes (genetic diseases), are also associated with viral infections (virally implicated diseases), either in a directly causal manner or by indirect associations. Here we examine whether viral perturbations of host interactome may underlie such virally implicated disease relationships. Using as models two different human viruses, Epstein-Barr virus (EBV) and human papillomavirus (HPV), we find that host targets of viral proteins reside in network proximity to products of disease susceptibility genes. Expression changes in virally implicated disease tissues and comorbidity patterns cluster significantly in the network vicinity of viral targets. The topological proximity found between cellular targets of viral proteins and disease genes was exploited to uncover a novel pathway linking HPV to Fanconi anemia.'),
(85533, 2012, 'plos', 'What can systems theory of networks offer to biology?', 'Rajapakse, Indika|Groudine, Mark|Mesbahi, Mehran', 'Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. irajapak@fhcrc.org|Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. irajapak@fhcrc.org|Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. irajapak@fhcrc.org', 'United States|United States|United States', 16, 'Cell Differentiation|Computational Biology|Humans|Models, Biological|Signal Transduction|Systems Theory', 'Journal Article', '10.1371/journal.pcbi.1002543', '22761554', '-'),
(85534, 2012, 'plos', 'Prosthetic avian vocal organ controlled by a freely behaving bird based on a low dimensional model of the biomechanical periphery', 'Arneodo, Ezequiel M|Perl, Yonatan Sanz|Goller, Franz|Mindlin, Gabriel B', 'Laboratorio de Sistemas Dinámicos, Departamento de Física, FCEyN, Universidad de Buenos Aires, Buenos Aires, Argentina. zeke@df.uba.ar|Laboratorio de Sistemas Dinámicos, Departamento de Física, FCEyN, Universidad de Buenos Aires, Buenos Aires, Argentina. zeke@df.uba.ar|Laboratorio de Sistemas Dinámicos, Departamento de Física, FCEyN, Universidad de Buenos Aires, Buenos Aires, Argentina. zeke@df.uba.ar|Laboratorio de Sistemas Dinámicos, Departamento de Física, FCEyN, Universidad de Buenos Aires, Buenos Aires, Argentina. zeke@df.uba.ar', 'Argentina|Argentina|Argentina|Argentina', 8, 'Animal Structures|Animals|Behavior, Animal|Biomechanical Phenomena|Bioprosthesis|Computational Biology|Finches|Humans|Models, Biological|Nonlinear Dynamics|Signal Processing, Computer-Assisted|Vocalization, Animal', 'Journal Article', '10.1371/journal.pcbi.1002546', '22761555', 'Because of the parallels found with human language production and acquisition, birdsong is an ideal animal model to study general mechanisms underlying complex, learned motor behavior. The rich and diverse vocalizations of songbirds emerge as a result of the interaction between a pattern generator in the brain and a highly nontrivial nonlinear periphery. Much of the complexity of this vocal behavior has been understood by studying the physics of the avian vocal organ, particularly the syrinx. A mathematical model describing the complex periphery as a nonlinear dynamical system leads to the conclusion that nontrivial behavior emerges even when the organ is commanded by simple motor instructions: smooth paths in a low dimensional parameter space. An analysis of the model provides insight into which parameters are responsible for generating a rich variety of diverse vocalizations, and what the physiological meaning of these parameters is. By recording the physiological motor instructions elicited by a spontaneously singing muted bird and computing the model on a Digital Signal Processor in real-time, we produce realistic synthetic vocalizations that replace the birds own auditory feedback. In this way, we build a bio-prosthetic avian vocal organ driven by a freely behaving bird via its physiologically coded motor commands. Since it is based on a low-dimensional nonlinear mathematical model of the peripheral effector, the emulation of the motor behavior requires light computation, in such a way that our bio-prosthetic device can be implemented on a portable platform.'),
(85535, 2012, 'plos', 'Simple epidemiological dynamics explain phylogenetic clustering of HIV from patients with recent infection', 'Volz, Erik M|Koopman, James S|Ward, Melissa J|Brown, Andrew Leigh|Frost, Simon D W', 'Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America. erikvolz@umich.edu|Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America. erikvolz@umich.edu|Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America. erikvolz@umich.edu|Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America. erikvolz@umich.edu|Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America. erikvolz@umich.edu', 'United States|United States|United States|United States|United States', 0, 'Cluster Analysis|Computational Biology|Computer Simulation|Epidemics|Epidemiologic Factors|Genes, pol|HIV Infections|HIV-1|Homosexuality, Male|Humans|Male|Michigan|Models, Biological|Phylogeny|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1002552', '22761556', 'Phylogenies of highly genetically variable viruses such as HIV-1 are potentially informative of epidemiological dynamics. Several studies have demonstrated the presence of clusters of highly related HIV-1 sequences, particularly among recently HIV-infected individuals, which have been used to argue for a high transmission rate during acute infection. Using a large set of HIV-1 subtype B pol sequences collected from men who have sex with men, we demonstrate that virus from recent infections tend to be phylogenetically clustered at a greater rate than virus from patients with chronic infection (excess clustering) and also tend to cluster with other recent HIV infections rather than chronic, established infections (excess co-clustering), consistent with previous reports. To determine the role that a higher infectivity during acute infection may play in excess clustering and co-clustering, we developed a simple model of HIV infection that incorporates an early period of intensified transmission, and explicitly considers the dynamics of phylogenetic clusters alongside the dynamics of acute and chronic infected cases. We explored the potential for clustering statistics to be used for inference of acute stage transmission rates and found that no single statistic explains very much variance in parameters controlling acute stage transmission rates. We demonstrate that high transmission rates during the acute stage is not the main cause of excess clustering of virus from patients with early/acute infection compared to chronic infection, which may simply reflect the shorter time since transmission in acute infection. Higher transmission during acute infection can result in excess co-clustering of sequences, while the extent of clustering observed is most sensitive to the fraction of infections sampled.'),
(85536, 2012, 'plos', 'Modeling boundary vector cell firing given optic flow as a cue', 'Raudies, Florian|Hasselmo, Michael E', 'Center for Computational Neuroscience and Neural Technology-CompNet, Boston University, Boston, Massachusetts, United States of America. fraudies@bu.edu|Center for Computational Neuroscience and Neural Technology-CompNet, Boston University, Boston, Massachusetts, United States of America. fraudies@bu.edu', 'United States|United States', 17, 'Animals|Computational Biology|Computer Simulation|Entorhinal Cortex|Evoked Potentials, Visual|Models, Neurological|Photic Stimulation|Rats|Visual Pathways', 'Journal Article', '10.1371/journal.pcbi.1002553', '22761557', 'Boundary vector cells in entorhinal cortex fire when a rat is in locations at a specific distance from walls of an environment. This firing may originate from memory of the barrier location combined with path integration, or the firing may depend upon the apparent visual input image stream. The modeling work presented here investigates the role of optic flow, the apparent change of patterns of light on the retina, as input for boundary vector cell firing. Analytical spherical flow is used by a template model to segment walls from the ground, to estimate self-motion and the distance and allocentric direction of walls, and to detect drop-offs. Distance estimates of walls in an empty circular or rectangular box have a mean error of less than or equal to two centimeters. Integrating these estimates into a visually driven boundary vector cell model leads to the firing patterns characteristic for boundary vector cells. This suggests that optic flow can influence the firing of boundary vector cells.'),
(85537, 2012, 'plos', 'Posterior association networks and functional modules inferred from rich phenotypes of gene perturbations', 'Wang, Xin|Castro, Mauro A|Mulder, Klaas W|Markowetz, Florian', 'Cancer Research UK Cambridge Research Institute, Cambridge, Cambridgeshire, United Kingdom.|Cancer Research UK Cambridge Research Institute, Cambridge, Cambridgeshire, United Kingdom.|Cancer Research UK Cambridge Research Institute, Cambridge, Cambridgeshire, United Kingdom.|Cancer Research UK Cambridge Research Institute, Cambridge, Cambridgeshire, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 14, 'Adult Stem Cells|Bayes Theorem|Cell Line, Tumor|Cell Proliferation|Computational Biology|Computer Simulation|Epistasis, Genetic|Gene Regulatory Networks|Genetic Association Studies|Humans|Models, Biological|Protein Interaction Mapping|RNA Interference|Sarcoma, Ewing', 'Journal Article', '10.1371/journal.pcbi.1002566', '22761558', 'Combinatorial gene perturbations provide rich information for a systematic exploration of genetic interactions. Despite successful applications to bacteria and yeast, the scalability of this approach remains a major challenge for higher organisms such as humans. Here, we report a novel experimental and computational framework to efficiently address this challenge by limiting the search space for important genetic interactions. We propose to integrate rich phenotypes of multiple single gene perturbations to robustly predict functional modules, which can subsequently be subjected to further experimental investigations such as combinatorial gene silencing. We present posterior association networks (PANs) to predict functional interactions between genes estimated using a Bayesian mixture modelling approach. The major advantage of this approach over conventional hypothesis tests is that prior knowledge can be incorporated to enhance predictive power. We demonstrate in a simulation study and on biological data, that integrating complementary information greatly improves prediction accuracy. To search for significant modules, we perform hierarchical clustering with multiscale bootstrap resampling. We demonstrate the power of the proposed methodologies in applications to Ewings sarcoma and human adult stem cells using publicly available and custom generated data, respectively. In the former application, we identify a gene module including many confirmed and highly promising therapeutic targets. Genes in the module are also significantly overrepresented in signalling pathways that are known to be critical for proliferation of Ewings sarcoma cells. In the latter application, we predict a functional network of chromatin factors controlling epidermal stem cell fate. Further examinations using ChIP-seq, ChIP-qPCR and RT-qPCR reveal that the basis of their genetic interactions may arise from transcriptional cross regulation. A Bioconductor package implementing PAN is freely available online at http://bioconductor.org/packages/release/bioc/html/PANR.html.'),
(85538, 2012, 'plos', 'ProteinHistorian: tools for the comparative analysis of eukaryote protein origin', 'Capra, John A|Williams, Alexander G|Pollard, Katherine S', 'J. David Gladstone Institutes, University of California, San Francisco, California, United States of America. tony.capra@gladstone.ucsf.edu|J. David Gladstone Institutes, University of California, San Francisco, California, United States of America. tony.capra@gladstone.ucsf.edu|J. David Gladstone Institutes, University of California, San Francisco, California, United States of America. tony.capra@gladstone.ucsf.edu', 'United States|United States|United States', 45, 'Algorithms|Animals|Computational Biology|Computer Simulation|Databases, Protein|Evolution, Molecular|Gene Expression|Humans|Models, Genetic|Phylogeny|Proteins|Software|Species Specificity|Time Factors', 'Comparative Study', '10.1371/journal.pcbi.1002567', '22761559', 'The evolutionary history of a protein reflects the functional history of its ancestors. Recent phylogenetic studies identified distinct evolutionary signatures that characterize proteins involved in cancer, Mendelian disease, and different ontogenic stages. Despite the potential to yield insight into the cellular functions and interactions of proteins, such comparative phylogenetic analyses are rarely performed, because they require custom algorithms. We developed ProteinHistorian to make tools for performing analyses of protein origins widely available. Given a list of proteins of interest, ProteinHistorian estimates the phylogenetic age of each protein, quantifies enrichment for proteins of specific ages, and compares variation in protein age with other protein attributes. ProteinHistorian allows flexibility in the definition of protein age by including several algorithms for estimating ages from different databases of evolutionary relationships. We illustrate the use of ProteinHistorian with three example analyses. First, we demonstrate that proteins with high expression in human, compared to chimpanzee and rhesus macaque, are significantly younger than those with human-specific low expression. Next, we show that human proteins with annotated regulatory functions are significantly younger than proteins with catalytic functions. Finally, we compare protein length and age in many eukaryotic species and, as expected from previous studies, find a positive, though often weak, correlation between protein age and length. ProteinHistorian is available through a web server with an intuitive interface and as a set of command line tools, this allows biologists and bioinformaticians alike to integrate these approaches into their analysis pipelines. ProteinHistorians modular, extensible design facilitates the integration of new datasets and algorithms. The ProteinHistorian web server, source code, and pre-computed ages for 32 eukaryotic genomes are freely available under the GNU public license at http://lighthouse.ucsf.edu/ProteinHistorian/.'),
(85539, 2012, 'plos', 'A report of the Curriculum Task Force of the ISCB Education Committee', 'Welch, Lonnie R|Schwartz, Russell|Lewitter, Fran', 'School of Electrical Engineering and Computer Science, Ohio University, Athens, Ohio, United States of America. welch@ohio.edu|School of Electrical Engineering and Computer Science, Ohio University, Athens, Ohio, United States of America. welch@ohio.edu|School of Electrical Engineering and Computer Science, Ohio University, Athens, Ohio, United States of America. welch@ohio.edu', 'United States|United States|United States', 0, 'Advisory Committees|Computational Biology|Curriculum|Data Collection|Internationality|Societies, Scientific', 'Journal Article', '10.1371/journal.pcbi.1002570', '22761560', '-'),
(85540, 2012, 'plos', 'Virtual patients and sensitivity analysis of the Guyton model of blood pressure regulation: towards individualized models of whole-body physiology', 'Moss, Robert|Grosse, Thibault|Marchant, Ivanny|Lassau, Nathalie|Gueyffier, François|Thomas, S Randall', 'IR4M UMR8081 CNRS, Université Paris-Sud, Orsay, France.|IR4M UMR8081 CNRS, Université Paris-Sud, Orsay, France.|IR4M UMR8081 CNRS, Université Paris-Sud, Orsay, France.|IR4M UMR8081 CNRS, Université Paris-Sud, Orsay, France.|IR4M UMR8081 CNRS, Université Paris-Sud, Orsay, France.|IR4M UMR8081 CNRS, Université Paris-Sud, Orsay, France.', 'France|France|France|France|France|France', 19, 'Blood Pressure|Cardiac Output|Computational Biology|Computer Simulation|Humans|Hypertension|Models, Cardiovascular|Monte Carlo Method|Precision Medicine|Reproducibility of Results|Urination|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1002571', '22761561', 'Mathematical models that integrate multi-scale physiological data can offer insight into physiological and pathophysiological function, and may eventually assist in individualized predictive medicine. We present a methodology for performing systematic analyses of multi-parameter interactions in such complex, multi-scale models. Human physiology models are often based on or inspired by Arthur Guytons whole-body circulatory regulation model. Despite the significance of this model, it has not been the subject of a systematic and comprehensive sensitivity study. Therefore, we use this model as a case study for our methodology. Our analysis of the Guyton model reveals how the multitude of model parameters combine to affect the model dynamics, and how interesting combinations of parameters may be identified. It also includes a virtual population from which virtual individuals can be chosen, on the basis of exhibiting conditions similar to those of a real-world patient. This lays the groundwork for using the Guyton model for in silico exploration of pathophysiological states and treatment strategies. The results presented here illustrate several potential uses for the entire dataset of sensitivity results and the virtual individuals that we have generated, which are included in the supplementary material. More generally, the presented methodology is applicable to modern, more complex multi-scale physiological models.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85541, 2012, 'plos', 'Bringing molecules back into molecular evolution', 'Wilke, Claus O', 'Institute of Cell and Molecular Biology, The University of Texas at Austin, Austin, Texas, United States of America. wilke@austin.utexas.edu', 'United States', 0, 'Biophysical Phenomena|Computational Biology|Computer Simulation|Evolution, Molecular|Models, Genetic|Models, Molecular|Proteins', 'Journal Article', '10.1371/journal.pcbi.1002572', '22761562', 'Much molecular-evolution research is concerned with sequence analysis. Yet these sequences represent real, three-dimensional molecules with complex structure and function. Here I highlight a growing trend in the field to incorporate molecular structure and function into computational molecular-evolution work. I consider three focus areas: reconstruction and analysis of past evolutionary events, such as phylogenetic inference or methods to infer selection pressures, development of toy models and simulations to identify fundamental principles of molecular evolution, and atom-level, highly realistic computational modeling of molecular structure and function aimed at making predictions about possible future evolutionary events.'),
(85542, 2012, 'plos', 'A model-based Bayesian estimation of the rate of evolution of VNTR loci in Mycobacterium tuberculosis', 'Aandahl, R Zachariah|Reyes, Josephine F|Sisson, Scott A|Tanaka, Mark M', 'School of Mathematics and Statistics, University of New South Wales, Sydney, New South Wales, Australia.|School of Mathematics and Statistics, University of New South Wales, Sydney, New South Wales, Australia.|School of Mathematics and Statistics, University of New South Wales, Sydney, New South Wales, Australia.|School of Mathematics and Statistics, University of New South Wales, Sydney, New South Wales, Australia.', 'Australia|Australia|Australia|Australia', 0, 'Bayes Theorem|Computational Biology|Computer Simulation|DNA, Bacterial|Databases, Nucleic Acid|Evolution, Molecular|Humans|Linear Models|Minisatellite Repeats|Models, Genetic|Mutation|Mycobacterium tuberculosis|Tuberculosis, Pulmonary', 'Comparative Study', '10.1371/journal.pcbi.1002573', '22761563', 'Variable numbers of tandem repeats (VNTR) typing is widely used for studying the bacterial cause of tuberculosis. Knowledge of the rate of mutation of VNTR loci facilitates the study of the evolution and epidemiology of Mycobacterium tuberculosis. Previous studies have applied population genetic models to estimate the mutation rate, leading to estimates varying widely from around 10xe2x81xbbxe2x81xb5 to 10xe2x81xbbxc2xb2 per locus per year. Resolving this issue using more detailed models and statistical methods would lead to improved inference in the molecular epidemiology of tuberculosis. Here, we use a model-based approach that incorporates two alternative forms of a stepwise mutation process for VNTR evolution within an epidemiological model of disease transmission. Using this model in a Bayesian framework we estimate the mutation rate of VNTR in M. tuberculosis from four published data sets of VNTR profiles from Albania, Iran, Morocco and Venezuela. In the first variant, the mutation rate increases linearly with respect to repeat numbers (linear model), in the second, the mutation rate is constant across repeat numbers (constant model). We find that under the constant model, the mean mutation rate per locus is 10xe2x81xbbxc2xb2xc2xb7xe2x81xb0xe2x81xb6 (95% CI: 10xe2x81xbbxc2xb2xc2xb7xe2x81xb6xc2xb9,10xe2x81xbbxc2xb9xc2xb7xe2x81xb5xe2x81xb8)and under the linear model, the mean mutation rate per locus per repeat unit is 10xe2x81xbbxc2xb2xc2xb7xe2x81xb4xe2x81xb5 (95% CI: 10xe2x81xbbxc2xb3xc2xb7xe2x81xb0xe2x81xb7,10xe2x81xbbxc2xb9xc2xb7xe2x81xb9xe2x81xb4). These new estimates represent a high rate of mutation at VNTR loci compared to previous estimates. To compare the two models we use posterior predictive checks to ascertain which of the two models is better able to reproduce the observed data. From this procedure we find that the linear model performs better than the constant model. The general framework we use allows the possibility of extending the analysis to more complex models in the future.'),
(85543, 2012, 'plos', 'Deceleration of fusion-fission cycles improves mitochondrial quality control during aging', 'Figge, Marc Thilo|Reichert, Andreas S|Meyer-Hermann, Michael|Osiewacz, Heinz D', 'Applied Systems Biology, Leibniz-Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute and Friedrich Schiller University, Jena, Germany.|Applied Systems Biology, Leibniz-Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute and Friedrich Schiller University, Jena, Germany.|Applied Systems Biology, Leibniz-Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute and Friedrich Schiller University, Jena, Germany.|Applied Systems Biology, Leibniz-Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute and Friedrich Schiller University, Jena, Germany.', 'Germany|Germany|Germany|Germany', 0, 'Aging|Animals|Autophagy|Computational Biology|Computer Simulation|Energy Metabolism|Humans|Membrane Fusion|Membrane Potential, Mitochondrial|Mitochondria|Models, Biological|Neurodegenerative Diseases|Reactive Oxygen Species|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002576', '22761564', 'Mitochondrial dynamics and mitophagy play a key role in ensuring mitochondrial quality control. Impairment thereof was proposed to be causative to neurodegenerative diseases, diabetes, and cancer. Accumulation of mitochondrial dysfunction was further linked to aging. Here we applied a probabilistic modeling approach integrating our current knowledge on mitochondrial biology allowing us to simulate mitochondrial function and quality control during aging in silico. We demonstrate that cycles of fusion and fission and mitophagy indeed are essential for ensuring a high average quality of mitochondria, even under conditions in which random molecular damage is present. Prompted by earlier observations that mitochondrial fission itself can cause a partial drop in mitochondrial membrane potential, we tested the consequences of mitochondrial dynamics being harmful on its own. Next to directly impairing mitochondrial function, pre-existing molecular damage may be propagated and enhanced across the mitochondrial population by content mixing. In this situation, such an infection-like phenomenon impairs mitochondrial quality control progressively. However, when imposing an age-dependent deceleration of cycles of fusion and fission, we observe a delay in the loss of average quality of mitochondria. This provides a rational why fusion and fission rates are reduced during aging and why loss of a mitochondrial fission factor can extend life span in fungi. We propose the mitochondrial infectious damage adaptation (MIDA) model according to which a deceleration of fusion-fission cycles reflects a systemic adaptation increasing life span.'),
(85544, 2012, 'plos', 'Quantifying the contribution of the liver to glucose homeostasis: a detailed kinetic model of human hepatic glucose metabolism', 'König, Matthias|Bulik, Sascha|Holzhütter, Hermann-Georg', 'Institute of Biochemistry, University Medicine Charité Berlin, Berlin, Germany. matthias.koenig@charite.de|Institute of Biochemistry, University Medicine Charité Berlin, Berlin, Germany. matthias.koenig@charite.de|Institute of Biochemistry, University Medicine Charité Berlin, Berlin, Germany. matthias.koenig@charite.de', 'Germany|Germany|Germany', 0, 'Computational Biology|Computer Simulation|Fasting|Glucagon|Gluconeogenesis|Glucose|Glycogenolysis|Homeostasis|Humans|Hyperglycemia|Hypoglycemia|Insulin|Kinetics|Liver|Liver Glycogen|Models, Biological|Postprandial Period', 'Journal Article', '10.1371/journal.pcbi.1002577', '22761565', 'Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways by insulin, glucagon and epinephrine. Model simulations are in good agreement with experimental data on (i) the quantitative contributions of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization under varying physiological states. (ii) the time courses of postprandial glycogen storage as well as glycogen depletion in overnight fasting and short term fasting (iii) the switch from net hepatic glucose production under hypoglycemia to net hepatic glucose utilization under hyperglycemia essential for glucose homeostasis (iv) hormone perturbations of hepatic glucose metabolism. Response analysis reveals an extra high capacity of the liver to counteract changes of plasma glucose level below 5 mM (hypoglycemia) and above 7.5 mM (hyperglycemia). Our model may serve as an important module of a whole-body model of human glucose metabolism and as a valuable tool for understanding the role of the liver in glucose homeostasis under normal conditions and in diseases like diabetes or glycogen storage diseases.'),
(85545, 2012, 'plos', 'From dynamic expression patterns to boundary formation in the presomitic mesoderm', 'Tiedemann, Hendrik B|Schneltzer, Elida|Zeiser, Stefan|Hoesel, Bastian|Beckers, Johannes|Przemeck, Gerhard K H|de Angelis, Martin Hrabxc4x9b', 'Institute of Experimental Genetics, Helmholtz Zentrum Mxc3xbcnchen-German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Experimental Genetics, Helmholtz Zentrum Mxc3xbcnchen-German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Experimental Genetics, Helmholtz Zentrum Mxc3xbcnchen-German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Experimental Genetics, Helmholtz Zentrum Mxc3xbcnchen-German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Experimental Genetics, Helmholtz Zentrum Mxc3xbcnchen-German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Experimental Genetics, Helmholtz Zentrum Mxc3xbcnchen-German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Experimental Genetics, Helmholtz Zentrum Mxc3xbcnchen-German Research Center for Environmental Health, Neuherberg, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany', 13, 'Animals|Basic Helix-Loop-Helix Transcription Factors|Biological Clocks|Body Patterning|Computational Biology|Computer Simulation|Feedback, Physiological|Fibroblast Growth Factor 8|Gene Expression Regulation, Developmental|Gene Regulatory Networks|Mesoderm|Mice|Models, Biological|RNA, Messenger|Signal Transduction|Somites|Wnt3A Protein', 'Journal Article', '10.1371/journal.pcbi.1002586', '22761566', 'The segmentation of the vertebrate body is laid down during early embryogenesis. The formation of signaling gradients, the periodic expression of genes of the Notch-, Fgf- and Wnt-pathways and their interplay in the unsegmented presomitic mesoderm (PSM) precedes the rhythmic budding of nascent somites at its anterior end, which later develops into epithelialized structures, the somites. Although many in silico models describing partial aspects of somitogenesis already exist, simulations of a complete causal chain from gene expression in the growth zone via the interaction of multiple cells to segmentation are rare. Here, we present an enhanced gene regulatory network (GRN) for mice in a simulation program that models the growing PSM by many virtual cells and integrates WNT3A and FGF8 gradient formation, periodic gene expression and Delta/Notch signaling. Assuming Hes7 as core of the somitogenesis clock and LFNG as modulator, we postulate a negative feedback of HES7 on Dll1 leading to an oscillating Dll1 expression as seen in vivo. Furthermore, we are able to simulate the experimentally observed wave of activated NOTCH (NICD) as a result of the interactions in the GRN. We esteem our model as robust for a wide range of parameter values with the Hes7 mRNA and protein decays exerting a strong influence on the core oscillator. Moreover, our model predicts interference between Hes1 and HES7 oscillators when their intrinsic frequencies differ. In conclusion, we have built a comprehensive model of somitogenesis with HES7 as core oscillator that is able to reproduce many experimentally observed data in mice.'),
(85546, 2012, 'plos', 'Modeling within-host dynamics of influenza virus infection including immune responses', 'Pawelek, Kasia A|Huynh, Giao T|Quinlivan, Michelle|Cullinane, Ann|Rong, Libin|Perelson, Alan S', 'Department of Mathematics and Statistics, Oakland University, Rochester, Michigan, United States of America.|Department of Mathematics and Statistics, Oakland University, Rochester, Michigan, United States of America.|Department of Mathematics and Statistics, Oakland University, Rochester, Michigan, United States of America.|Department of Mathematics and Statistics, Oakland University, Rochester, Michigan, United States of America.|Department of Mathematics and Statistics, Oakland University, Rochester, Michigan, United States of America.|Department of Mathematics and Statistics, Oakland University, Rochester, Michigan, United States of America.', 'United States|United States|United States|United States|United States|United States', 0, 'Adaptive Immunity|Animals|Computational Biology|Computer Simulation|Horse Diseases|Horses|Host-Pathogen Interactions|Humans|Immunity, Innate|Influenza A Virus, H3N8 Subtype|Influenza, Human|Models, Immunological|Orthomyxoviridae Infections|Time Factors|Viral Load', 'Journal Article', '10.1371/journal.pcbi.1002588', '22761567', 'Influenza virus infection remains a public health problem worldwide. The mechanisms underlying viral control during an uncomplicated influenza virus infection are not fully understood. Here, we developed a mathematical model including both innate and adaptive immune responses to study the within-host dynamics of equine influenza virus infection in horses. By comparing modeling predictions with both interferon and viral kinetic data, we examined the relative roles of target cell availability, and innate and adaptive immune responses in controlling the virus. Our results show that the rapid and substantial viral decline (about 2 to 4 logs within 1 day) after the peak can be explained by the killing of infected cells mediated by interferon activated cells, such as natural killer cells, during the innate immune response. After the viral load declines to a lower level, the loss of interferon-induced antiviral effect and an increased availability of target cells due to loss of the antiviral state can explain the observed short phase of viral plateau in which the viral level remains unchanged or even experiences a minor second peak in some animals. An adaptive immune response is needed in our model to explain the eventual viral clearance. This study provides a quantitative understanding of the biological factors that can explain the viral and interferon kinetics during a typical influenza virus infection.'),
(85547, 2012, 'plos', 'Learning with slight forgetting optimizes sensorimotor transformation in redundant motor systems', 'Hirashima, Masaya|Nozaki, Daichi', 'Division of Physical and Health Education, Graduate School of Education, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. hira@p.u-tokyo.ac.jp|Division of Physical and Health Education, Graduate School of Education, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. hira@p.u-tokyo.ac.jp', 'Japan|Japan', 14, 'Biomechanical Phenomena|Computational Biology|Computer Simulation|Humans|Imaging, Three-Dimensional|Learning|Linear Models|Memory|Models, Neurological|Models, Psychological|Motor Cortex|Movement|Nerve Net|Neurons|Nonlinear Dynamics|Psychomotor Performance', 'Journal Article', '10.1371/journal.pcbi.1002590', '22761568', 'Recent theoretical studies have proposed that the redundant motor system in humans achieves well-organized stereotypical movements by minimizing motor effort cost and motor error. However, it is unclear how this optimization process is implemented in the brain, presumably because conventional schemes have assumed a priori that the brain somehow constructs the optimal motor command, and largely ignored the underlying trial-by-trial learning process. In contrast, recent studies focusing on the trial-by-trial modification of motor commands based on error information suggested that forgetting (i.e., memory decay), which is usually considered as an inconvenient factor in motor learning, plays an important role in minimizing the motor effort cost. Here, we examine whether trial-by-trial error-feedback learning with slight forgetting could minimize the motor effort and error in a highly redundant neural network for sensorimotor transformation and whether it could predict the stereotypical activation patterns observed in primary motor cortex (M1) neurons. First, using a simple linear neural network model, we theoretically demonstrated that: 1) this algorithm consistently leads the neural network to converge at a unique optimal state, 2) the biomechanical properties of the musculoskeletal system necessarily determine the distribution of the preferred directions (PD, the direction in which the neuron is maximally active) of M1 neurons, and 3) the bias of the PDs is steadily formed during the minimization of the motor effort. Furthermore, using a non-linear network model with realistic musculoskeletal data, we demonstrated numerically that this algorithm could consistently reproduce the PD distribution observed in various motor tasks, including two-dimensional isometric torque production, two-dimensional reaching, and even three-dimensional reaching tasks. These results may suggest that slight forgetting in the sensorimotor transformation network is responsible for solving the redundancy problem in motor control.'),
(85548, 2012, 'plos', 'Fast spatiotemporal smoothing of calcium measurements in dendritic trees', 'Pnevmatikakis, Eftychios A|Kelleher, Keith|Chen, Rebecca|Saggau, Petter|Josixc4x87, Krexc5xa1imir|Paninski, Liam', 'Department of Statistics and Center for Theoretical Neuroscience, Columbia University, New York, New York, USA. eftychios@stat.columbia.edu|Department of Statistics and Center for Theoretical Neuroscience, Columbia University, New York, New York, USA. eftychios@stat.columbia.edu|Department of Statistics and Center for Theoretical Neuroscience, Columbia University, New York, New York, USA. eftychios@stat.columbia.edu|Department of Statistics and Center for Theoretical Neuroscience, Columbia University, New York, New York, USA. eftychios@stat.columbia.edu|Department of Statistics and Center for Theoretical Neuroscience, Columbia University, New York, New York, USA. eftychios@stat.columbia.edu|Department of Statistics and Center for Theoretical Neuroscience, Columbia University, New York, New York, USA. eftychios@stat.columbia.edu', 'United States|United States|United States|United States|United States|United States', 8, 'Action Potentials|Algorithms|Animals|Calcium|Calcium Signaling|Computational Biology|Dendrites|Hippocampus|Microscopy, Fluorescence, Multiphoton|Models, Neurological|Rats|Reproducibility of Results|Signal Processing, Computer-Assisted', 'Journal Article', '10.1371/journal.pcbi.1002569', '22787437', 'We discuss methods for fast spatiotemporal smoothing of calcium signals in dendritic trees, given single-trial, spatially localized imaging data obtained via multi-photon microscopy. By analyzing the dynamics of calcium binding to probe molecules and the effects of the imaging procedure, we show that calcium concentration can be estimated up to an affine transformation, i.e., an additive and multiplicative constant. To obtain a full spatiotemporal estimate, we model calcium dynamics within the cell using a functional approach. The evolution of calcium concentration is represented through a smaller set of hidden variables that incorporate fast transients due to backpropagating action potentials (bAPs), or other forms of stimulation. Because of the resulting state space structure, inference can be done in linear time using forward-backward maximum-a-posteriori methods. Non-negativity constraints on the calcium concentration can also be incorporated using a log-barrier method that does not affect the computational scaling. Moreover, by exploiting the neuronal tree structure we show that the cost of the algorithm is also linear in the size of the dendritic tree, making the approach applicable to arbitrarily large trees. We apply this algorithm to data obtained from hippocampal CA1 pyramidal cells with experimentally evoked bAPs, some of which were paired with excitatory postsynaptic potentials (EPSPs). The algorithm recovers the timing of the bAPs and provides an estimate of the induced calcium transient throughout the tree. The proposed methods could be used to further understand the interplay between bAPs and EPSPs in synaptic strength modification. More generally, this approach allows us to infer the concentration on intracellular calcium across the dendritic tree from noisy observations at a discrete set of points in space.'),
(85549, 2012, 'plos', 'Prediction of microbial growth rate versus biomass yield by a metabolic network with kinetic parameters', 'Adadi, Roi|Volkmer, Benjamin|Milo, Ron|Heinemann, Matthias|Shlomi, Tomer', 'Department of Computer Science, Technion, Haifa, Israel.|Department of Computer Science, Technion, Haifa, Israel.|Department of Computer Science, Technion, Haifa, Israel.|Department of Computer Science, Technion, Haifa, Israel.|Department of Computer Science, Technion, Haifa, Israel.', 'Israel|Israel|Israel|Israel|Israel', 0, 'Biomass|Computer Simulation|Escherichia coli|Kinetics|Metabolic Networks and Pathways|Models, Biological|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002575', '22792053', 'Identifying the factors that determine microbial growth rate under various environmental and genetic conditions is a major challenge of systems biology. While current genome-scale metabolic modeling approaches enable us to successfully predict a variety of metabolic phenotypes, including maximal biomass yield, the prediction of actual growth rate is a long standing goal. This gap stems from strictly relying on data regarding reaction stoichiometry and directionality, without accounting for enzyme kinetic considerations. Here we present a novel metabolic network-based approach, MetabOlic Modeling with ENzyme kineTics (MOMENT), which predicts metabolic flux rate and growth rate by utilizing prior data on enzyme turnover rates and enzyme molecular weights, without requiring measurements of nutrient uptake rates. The method is based on an identified design principle of metabolism in which enzymes catalyzing high flux reactions across different media tend to be more efficient in terms of having higher turnover numbers. Extending upon previous attempts to utilize kinetic data in genome-scale metabolic modeling, our approach takes into account the requirement for specific enzyme concentrations for catalyzing predicted metabolic flux rates, considering isozymes, protein complexes, and multi-functional enzymes. MOMENT is shown to significantly improve the prediction accuracy of various metabolic phenotypes in E. coli, including intracellular flux rates and changes in gene expression levels under different growth rates. Most importantly, MOMENT is shown to predict growth rates of E. coli under a diverse set of media that are correlated with experimental measurements, markedly improving upon existing state-of-the art stoichiometric modeling approaches. These results support the view that a physiological bound on cellular enzyme concentrations is a key factor that determines microbial growth rate.'),
(85550, 2012, 'plos', 'The generation of phase differences and frequency changes in a network model of inferior olive subthreshold oscillations', 'Torben-Nielsen, Benjamin|Segev, Idan|Yarom, Yosef', 'Department of Neurobiology, Hebrew University, Jerusalem, Israel. btorbennielsen@gmail.com|Department of Neurobiology, Hebrew University, Jerusalem, Israel. btorbennielsen@gmail.com|Department of Neurobiology, Hebrew University, Jerusalem, Israel. btorbennielsen@gmail.com', 'Israel|Israel|Israel', 0, 'Animals|Calcium|Computer Simulation|Models, Neurological|Neurons|Olivary Nucleus', 'Journal Article', '10.1371/journal.pcbi.1002580', '22792054', 'It is commonly accepted that the Inferior Olive (IO) provides a timing signal to the cerebellum. Stable subthreshold oscillations in the IO can facilitate accurate timing by phase-locking spikes to the peaks of the oscillation. Several theoretical models accounting for the synchronized subthreshold oscillations have been proposed, however, two experimental observations remain an enigma. The first is the observation of frequent alterations in the frequency of the oscillations. The second is the observation of constant phase differences between simultaneously recorded neurons. In order to account for these two observations we constructed a canonical network model based on anatomical and physiological data from the IO. The constructed network is characterized by clustering of neurons with similar conductance densities, and by electrical coupling between neurons. Neurons inside a cluster are densely connected with weak strengths, while neurons belonging to different clusters are sparsely connected with stronger connections. We found that this type of network can robustly display stable subthreshold oscillations. The overall frequency of the network changes with the strength of the inter-cluster connections, and phase differences occur between neurons of different clusters. Moreover, the phase differences provide a mechanistic explanation for the experimentally observed propagating waves of activity in the IO. We conclude that the architecture of the network of electrically coupled neurons in combination with modulation of the inter-cluster coupling strengths can account for the experimentally observed frequency changes and the phase differences.'),
(85551, 2012, 'plos', 'Quantifying and analyzing the network basis of genetic complexity', 'Thompson, Ethan G|Galitski, Timothy', 'Institute for Systems Biology, Seattle, Washington, United States of America.|Institute for Systems Biology, Seattle, Washington, United States of America.', 'United States|United States', 0, 'Cell Cycle|Gene Regulatory Networks|Genes, Fungal|Genomics|Genotype|Models, Genetic|Phenotype|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1002583', '22792055', 'Genotype-to-phenotype maps exhibit complexity. This genetic complexity is mentioned frequently in the literature, but a consistent and quantitative definition is lacking. Here, we derive such a definition and investigate its consequences for model genetic systems. The definition equates genetic complexity with a surplus of genotypic diversity over phenotypic diversity. Applying this definition to ensembles of Boolean network models, we found that the in-degree distribution and the number of periodic attractors produced determine the relative complexity of different topology classes. We found evidence that networks that are difficult to control, or that exhibit a hierarchical structure, are genetically complex. We analyzed the complexity of the cell cycle network of Sacchoromyces cerevisiae and pinpointed genes and interactions that are most important for its high genetic complexity. The rigorous definition of genetic complexity is a tool for unraveling the structure and properties of genotype-to-phenotype maps by enabling the quantitative comparison of the relative complexities of different genetic systems. The definition also allows the identification of specific network elements and subnetworks that have the greatest effects on genetic complexity. Moreover, it suggests ways to engineer biological systems with desired genetic properties.'),
(85552, 2012, 'plos', 'Spectral analysis of input spike trains by spike-timing-dependent plasticity', 'Gilson, Matthieu|Fukai, Tomoki|Burkitt, Anthony N', 'Riken Brain Science Institute, Wako-shi, Saitama, Japan. gilson@brain.riken.jp|Riken Brain Science Institute, Wako-shi, Saitama, Japan. gilson@brain.riken.jp|Riken Brain Science Institute, Wako-shi, Saitama, Japan. gilson@brain.riken.jp', 'Japan|Japan|Japan', 9, 'Action Potentials|Algorithms|Computational Biology|Models, Neurological|Nerve Net|Neuronal Plasticity|Neurons|Poisson Distribution|Principal Component Analysis', 'Journal Article', '10.1371/journal.pcbi.1002584', '22792056', 'Spike-timing-dependent plasticity (STDP) has been observed in many brain areas such as sensory cortices, where it is hypothesized to structure synaptic connections between neurons. Previous studies have demonstrated how STDP can capture spiking information at short timescales using specific input configurations, such as coincident spiking, spike patterns and oscillatory spike trains. However, the corresponding computation in the case of arbitrary input signals is still unclear. This paper provides an overarching picture of the algorithm inherent to STDP, tying together many previous results for commonly used models of pairwise STDP. For a single neuron with plastic excitatory synapses, we show how STDP performs a spectral analysis on the temporal cross-correlograms between its afferent spike trains. The postsynaptic responses and STDP learning window determine kernel functions that specify how the neuron sees the input correlations. We thus denote this unsupervised learning scheme as kernel spectral component analysis (kSCA). In particular, the whole input correlation structure must be considered since all plastic synapses compete with each other. We find that kSCA is enhanced when weight-dependent STDP induces gradual synaptic competition. For a spiking neuron with a linear response and pairwise STDP alone, we find that kSCA resembles principal component analysis (PCA). However, plain STDP does not isolate correlation sources in general, e.g., when they are mixed among the input spike trains. In other words, it does not perform independent component analysis (ICA). Tuning the neuron to a single correlation source can be achieved when STDP is paired with a homeostatic mechanism that reinforces the competition between synaptic inputs. Our results suggest that neuronal networks equipped with STDP can process signals encoded in the transient spiking activity at the timescales of tens of milliseconds for usual STDP.'),
(85553, 2012, 'plos', 'Network-assisted investigation of combined causal signals from genome-wide association studies in schizophrenia', 'Jia, Peilin|Wang, Lily|Fanous, Ayman H|Pato, Carlos N|Edwards, Todd L|International Schizophrenia Consortium|Zhao, Zhongming', 'Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.|Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.|Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.|Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.|Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.|Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.|Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 77, 'Algorithms|Databases, Genetic|Genome-Wide Association Study|Genomics|Humans|Polymorphism, Single Nucleotide|Protein Interaction Mapping|Reproducibility of Results|Schizophrenia', 'Journal Article', '10.1371/journal.pcbi.1002587', '22792057', 'With the recent success of genome-wide association studies (GWAS), a wealth of association data has been accomplished for more than 200 complex diseases/traits, proposing a strong demand for data integration and interpretation. A combinatory analysis of multiple GWAS datasets, or an integrative analysis of GWAS data and other high-throughput data, has been particularly promising. In this study, we proposed an integrative analysis framework of multiple GWAS datasets by overlaying association signals onto the protein-protein interaction network, and demonstrated it using schizophrenia datasets. Building on a dense module search algorithm, we first searched for significantly enriched subnetworks for schizophrenia in each single GWAS dataset and then implemented a discovery-evaluation strategy to identify module genes with consistent association signals. We validated the module genes in an independent dataset, and also examined them through meta-analysis of the related SNPs using multiple GWAS datasets. As a result, we identified 205 module genes with a joint effect significantly associated with schizophrenia, these module genes included a number of well-studied candidate genes such as DISC1, GNA12, GNA13, GNAI1, GPR17, and GRIN2B. Further functional analysis suggested these genes are involved in neuronal related processes. Additionally, meta-analysis found that 18 SNPs in 9 module genes had P(meta)<1 xc3x97 10xe2x81xbbxe2x81xb4, including the gene HLA-DQA1 located in the MHC region on chromosome 6, which was reported in previous studies using the largest cohort of schizophrenia patients to date. These results demonstrated our bi-directional network-based strategy is efficient for identifying disease-associated genes with modest signals in GWAS datasets. This approach can be applied to any other complex diseases/traits where multiple GWAS datasets are available.'),
(85554, 2012, 'plos', 'Automated tracking of whiskers in videos of head fixed rodents', 'Clack, Nathan G|OConnor, Daniel H|Huber, Daniel|Petreanu, Leopoldo|Hires, Andrew|Peron, Simon|Svoboda, Karel|Myers, Eugene W', 'Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America. clackn@janelia.hhmi.org|Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America. clackn@janelia.hhmi.org|Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America. clackn@janelia.hhmi.org|Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America. clackn@janelia.hhmi.org|Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America. clackn@janelia.hhmi.org|Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America. clackn@janelia.hhmi.org|Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America. clackn@janelia.hhmi.org|Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America. clackn@janelia.hhmi.org', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Animals|Computational Biology|Exploratory Behavior|Image Processing, Computer-Assisted|Mice|Vibrissae|Videotape Recording', 'Journal Article', '10.1371/journal.pcbi.1002591', '22792058', 'We have developed software for fully automated tracking of vibrissae (whiskers) in high-speed videos (>500 Hz) of head-fixed, behaving rodents trimmed to a single row of whiskers. Performance was assessed against a manually curated dataset consisting of 1.32 million video frames comprising 4.5 million whisker traces. The current implementation detects whiskers with a recall of 99.998% and identifies individual whiskers with 99.997% accuracy. The average processing rate for these images was 8 Mpx/s/cpu (2.6 GHz Intel Core2, 2 GB RAM). This translates to 35 processed frames per second for a 640 px×352 px video of 4 whiskers. The speed and accuracy achieved enables quantitative behavioral studies where the analysis of millions of video frames is required. We used the software to analyze the evolving whisking strategies as mice learned a whisker-based detection task over the course of 6 days (8148 trials, 25 million frames) and measure the forces at the sensory follicle that most underlie haptic perception.'),
(85555, 2012, 'plos', 'Predicting signatures of synthetic associations and natural associations from empirical patterns of human genetic variation', 'Chang, Diana|Keinan, Alon', 'Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.|Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.', 'United States|United States', 12, 'Computer Simulation|Databases, Genetic|Evolution, Molecular|Gene Frequency|Genetic Variation|Genome-Wide Association Study|Genomics|HapMap Project|Humans|Linkage Disequilibrium|Models, Genetic|Polymorphism, Single Nucleotide', 'Journal Article', '10.1371/journal.pcbi.1002600', '22792059', 'Genome-wide association studies (GWAS) have in recent years discovered thousands of associated markers for hundreds of phenotypes. However, associated loci often only explain a relatively small fraction of heritability and the link between association and causality has yet to be uncovered for most loci. Rare causal variants have been suggested as one scenario that may partially explain these shortcomings. Specifically, Dickson et al. recently reported simulations of rare causal variants that lead to association signals of common, tag single nucleotide polymorphisms, dubbed synthetic associations. However, an open question is what practical implications synthetic associations have for GWAS. Here, we explore the signatures exhibited by such synthetic associations and their implications based on patterns of genetic variation observed in human populations, thus accounting for human evolutionary history -a force disregarded in previous simulation studies. This is made possible by human population genetic data from HapMap 3 consisting of both resequencing and array-based genotyping data for the same set of individuals from multiple populations. We report that synthetic associations tend to be further away from the underlying risk alleles compared to natural associations (i.e. associations due to underlying common causal variants), but to a much lesser extent than previously predicted, with both the age and the effect size of the risk allele playing a part in this phenomenon. We find that while a synthetic association has a lower probability of capturing causal variants within its linkage disequilibrium block, sequencing around the associated variant need not extend substantially to have a high probability of capturing at least one causal variant. We also show that the minor allele frequency of synthetic associations is lower than of natural associations for most, but not all, loci that we explored. Finally, we find the variance in associated allele frequency to be a potential indicator of synthetic associations.'),
(85556, 2012, 'plos', 'Data sharing in the post-genomic world: the experience of the International Cancer Genome Consortium (ICGC) Data Access Compliance Office (DACO)', 'Joly, Yann|Dove, Edward S|Knoppers, Bartha M|Bobrow, Martin|Chalmers, Don', 'International Data Access Committee, International Cancer Genome Consortium, Toronto, Ontario, Canada. yann.joly@mail.mcgill.ca|International Data Access Committee, International Cancer Genome Consortium, Toronto, Ontario, Canada. yann.joly@mail.mcgill.ca|International Data Access Committee, International Cancer Genome Consortium, Toronto, Ontario, Canada. yann.joly@mail.mcgill.ca|International Data Access Committee, International Cancer Genome Consortium, Toronto, Ontario, Canada. yann.joly@mail.mcgill.ca|International Data Access Committee, International Cancer Genome Consortium, Toronto, Ontario, Canada. yann.joly@mail.mcgill.ca', 'Canada|Canada|Canada|Canada|Canada', 64, 'Database Management Systems|Databases, Genetic|Genomics|Humans|Information Dissemination|International Cooperation|Neoplasms', 'Journal Article', '10.1371/journal.pcbi.1002549', '22807659', '-'),
(85557, 2012, 'plos', 'Bioinformatics meets user-centred design: a perspective', 'Pavelin, Katrina|Cham, Jennifer A|de Matos, Paula|Brooksbank, Cath|Cameron, Graham|Steinbeck, Christoph', 'EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.|EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.|EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.|EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.|EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.|EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 31, 'Computational Biology|Humans|Software Design|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1002554', '22807660', 'Designers have a saying that the joy of an early release lasts but a short time. The bitterness of an unusable system lasts for years. It is indeed disappointing to discover that your data resources are not being used to their full potential. Not only have you invested your time, effort, and research grant on the project, but you may face costly redesigns if you want to improve the system later. This scenario would be less likely if the product was designed to provide users with exactly what they need, so that it is fit for purpose before its launch. We work at EMBL-European Bioinformatics Institute (EMBL-EBI), and we consult extensively with life science researchers to find out what they need from biological data resources. We have found that although users believe that the bioinformatics community is providing accurate and valuable data, they often find the interfaces to these resources tricky to use and navigate. We believe that if you can find out what your users want even before you create the first mock-up of a system, the final product will provide a better user experience. This would encourage more people to use the resource and they would have greater access to the data, which could ultimately lead to more scientific discoveries. In this paper, we explore the need for a user-centred design (UCD) strategy when designing bioinformatics resources and illustrate this with examples from our work at EMBL-EBI. Our aim is to introduce the reader to how selected UCD techniques may be successfully applied to software design for bioinformatics.'),
(85558, 2012, 'plos', 'Excitatory local interneurons enhance tuning of sensory information', 'Assisi, Collins|Stopfer, Mark|Bazhenov, Maxim', 'Department of Cell Biology and Neuroscience, University of California, Riverside, California, United States of America.|Department of Cell Biology and Neuroscience, University of California, Riverside, California, United States of America.|Department of Cell Biology and Neuroscience, University of California, Riverside, California, United States of America.', 'United States|United States|United States', 11, 'Animals|Arthropod Antennae|Computational Biology|Computer Simulation|Insecta|Interneurons|Models, Neurological|Odorants|Olfactory Pathways|Olfactory Receptor Neurons', 'Journal Article', '10.1371/journal.pcbi.1002563', '22807661', 'Neurons in the insect antennal lobe represent odors as spatiotemporal patterns of activity that unfold over multiple time scales. As these patterns unspool they decrease the overlap between odor representations and thereby increase the ability of the olfactory system to discriminate odors. Using a realistic model of the insect antennal lobe we examined two competing components of this process -lateral excitation from local excitatory interneurons, and slow inhibition from local inhibitory interneurons. We found that lateral excitation amplified differences between representations of similar odors by recruiting projection neurons that did not receive direct input from olfactory receptors. However, this increased sensitivity also amplified noisy variations in input and compromised the ability of the system to respond reliably to multiple presentations of the same odor. Slow inhibition curtailed the spread of projection neuron activity and increased response reliability. These competing influences must be finely balanced in order to decorrelate odor representations.'),
(85559, 2012, 'plos', 'Coding conspecific identity and motion in the electric sense', 'Yu, Na|Hupé, Ginette|Garfinkle, Charles|Lewis, John E|Longtin, André', 'Department of Physics, University of Ottawa, Ottawa, Ontario, Canada. na.yu@uottawa.ca|Department of Physics, University of Ottawa, Ottawa, Ontario, Canada. na.yu@uottawa.ca|Department of Physics, University of Ottawa, Ottawa, Ontario, Canada. na.yu@uottawa.ca|Department of Physics, University of Ottawa, Ottawa, Ontario, Canada. na.yu@uottawa.ca|Department of Physics, University of Ottawa, Ottawa, Ontario, Canada. na.yu@uottawa.ca', 'Canada|Canada|Canada|Canada|Canada', 36, 'Animal Communication|Animals|Computational Biology|Electric Organ|Electricity|Female|Gymnotiformes|Male|Models, Theoretical|Swimming', 'Journal Article', '10.1371/journal.pcbi.1002564', '22807662', 'Interactions among animals can result in complex sensory signals containing a variety of socially relevant information, including the number, identity, and relative motion of conspecifics. How the spatiotemporal properties of such evolving naturalistic signals are encoded is a key question in sensory neuroscience. Here, we present results from experiments and modeling that address this issue in the context of the electric sense, which combines the spatial aspects of vision and touch, with the temporal aspects of audition. Wave-type electric fish, such as the brown ghost knifefish, Apteronotus leptorhynchus, used in this study, are uniquely identified by the frequency of their electric organ discharge (EOD). Multiple beat frequencies arise from the superposition of the EODs of each fish. We record the natural electrical signals near the skin of a receiving fish that are produced by stationary and freely swimming conspecifics. Using spectral analysis, we find that the primary beats, and the secondary beats between them (beats of beats), can be greatly influenced by fish swimming, the resulting motion produces low-frequency envelopes that broaden all the beat peaks and reshape the noise floor. We assess the consequences of this motion on sensory coding using a model electroreceptor. We show that the primary and secondary beats are encoded in the afferent spike train, but that motion acts to degrade this encoding. We also simulate the response of a realistic population of receptors, and find that it can encode the motion envelope well, primarily due to the receptors with lower firing rates. We discuss the implications of our results for the identification of conspecifics through specific beat frequencies and its possible hindrance by active swimming.'),
(85560, 2012, 'plos', 'Adaptive temperature compensation in circadian oscillations', 'François, Paul|Despierre, Nicolas|Siggia, Eric D', 'Ernest Rutherford Physics Building, McGill University, Montreal, Quebec, Canada. paulf@physics.mcgill.ca|Ernest Rutherford Physics Building, McGill University, Montreal, Quebec, Canada. paulf@physics.mcgill.ca|Ernest Rutherford Physics Building, McGill University, Montreal, Quebec, Canada. paulf@physics.mcgill.ca', 'Canada|Canada|Canada', 30, 'Circadian Clocks|Computer Simulation|Models, Biological|Neurospora|Temperature', 'Journal Article', '10.1371/journal.pcbi.1002585', '22807663', 'A temperature independent period and temperature entrainment are two defining features of circadian oscillators. A default model of distributed temperature compensation satisfies these basic facts yet is not easily reconciled with other properties of circadian clocks, such as many mutants with altered but temperature compensated periods. The default model also suggests that the shape of the circadian limit cycle and the associated phase response curves (PRC) will vary since the average concentrations of clock proteins change with temperature. We propose an alternative class of models where the twin properties of a fixed period and entrainment are structural and arise from an underlying adaptive system that buffers temperature changes. These models are distinguished by a PRC whose shape is temperature independent and orbits whose extrema are temperature independent. They are readily evolved by local, hill climbing, optimization of gene networks for a common quality measure of biological clocks, phase anticipation. Interestingly a standard realization of the Goodwin model for temperature compensation displays properties of adaptive rather than distributed temperature compensation.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85561, 2012, 'plos', 'Efficient reverse-engineering of a developmental gene regulatory network', 'Crombach, Anton|Wotton, Karl R|Cicin-Sain, Damjan|Ashyraliyev, Maksat|Jaeger, Johannes', 'EMBL/CRG Research Unit in Systems Biology, Centre for Genomic Regulation-CRG and Universitat Pompeu Fabra-UPF, Barcelona, Spain.|EMBL/CRG Research Unit in Systems Biology, Centre for Genomic Regulation-CRG and Universitat Pompeu Fabra-UPF, Barcelona, Spain.|EMBL/CRG Research Unit in Systems Biology, Centre for Genomic Regulation-CRG and Universitat Pompeu Fabra-UPF, Barcelona, Spain.|EMBL/CRG Research Unit in Systems Biology, Centre for Genomic Regulation-CRG and Universitat Pompeu Fabra-UPF, Barcelona, Spain.|EMBL/CRG Research Unit in Systems Biology, Centre for Genomic Regulation-CRG and Universitat Pompeu Fabra-UPF, Barcelona, Spain.', 'Spain|Spain|Spain|Spain|Spain', 60, 'Animals|Computational Biology|Computer Simulation|Drosophila Proteins|Drosophila melanogaster|Gene Expression|Gene Regulatory Networks|Genes, Insect|Hybridization, Genetic|Models, Genetic|RNA, Messenger', 'Journal Article', '10.1371/journal.pcbi.1002589', '22807664', 'Understanding the complex regulatory networks underlying development and evolution of multi-cellular organisms is a major problem in biology. Computational models can be used as tools to extract the regulatory structure and dynamics of such networks from gene expression data. This approach is called reverse engineering. It has been successfully applied to many gene networks in various biological systems. However, to reconstitute the structure and non-linear dynamics of a developmental gene network in its spatial context remains a considerable challenge. Here, we address this challenge using a case study: the gap gene network involved in segment determination during early development of Drosophila melanogaster. A major problem for reverse-engineering pattern-forming networks is the significant amount of time and effort required to acquire and quantify spatial gene expression data. We have developed a simplified data processing pipeline that considerably increases the throughput of the method, but results in data of reduced accuracy compared to those previously used for gap gene network inference. We demonstrate that we can infer the correct network structure using our reduced data set, and investigate minimal data requirements for successful reverse engineering. Our results show that timing and position of expression domain boundaries are the crucial features for determining regulatory network structure from data, while it is less important to precisely measure expression levels. Based on this, we define minimal data requirements for gap gene network inference. Our results demonstrate the feasibility of reverse-engineering with much reduced experimental effort. This enables more widespread use of the method in different developmental contexts and organisms. Such systematic application of data-driven models to real-world networks has enormous potential. Only the quantitative investigation of a large number of developmental gene regulatory networks will allow us to discover whether there are rules or regularities governing development and evolution of complex multi-cellular organisms.'),
(85562, 2012, 'plos', 'Sparse codes for speech predict spectrotemporal receptive fields in the inferior colliculus', 'Carlson, Nicole L|Ming, Vivienne L|Deweese, Michael Robert', 'Redwood Center for Theoretical Neuroscience, University of California, Berkeley, California, United States of America.|Redwood Center for Theoretical Neuroscience, University of California, Berkeley, California, United States of America.|Redwood Center for Theoretical Neuroscience, University of California, Berkeley, California, United States of America.', 'United States|United States|United States', 37, 'Algorithms|Auditory Pathways|Computational Biology|Humans|Inferior Colliculi|Mesencephalon|Models, Neurological|Neurons|Speech|Thalamus', 'Journal Article', '10.1371/journal.pcbi.1002594', '22807665', 'We have developed a sparse mathematical representation of speech that minimizes the number of active model neurons needed to represent typical speech sounds. The model learns several well-known acoustic features of speech such as harmonic stacks, formants, onsets and terminations, but we also find more exotic structures in the spectrogram representation of sound such as localized checkerboard patterns and frequency-modulated excitatory subregions flanked by suppressive sidebands. Moreover, several of these novel features resemble neuronal receptive fields reported in the Inferior Colliculus (IC), as well as auditory thalamus and cortex, and our model neurons exhibit the same tradeoff in spectrotemporal resolution as has been observed in IC. To our knowledge, this is the first demonstration that receptive fields of neurons in the ascending mammalian auditory pathway beyond the auditory nerve can be predicted based on coding principles and the statistical properties of recorded sounds.'),
(85563, 2012, 'plos', 'A nonlinear dynamic approach reveals a long-term stroke effect on cerebral blood flow regulation at multiple time scales', 'Hu, Kun|Lo, Men-Tzung|Peng, Chung-Kang|Liu, Yanhui|Novak, Vera', 'Division of Sleep Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. khu@bics.bwh.harvard.edu|Division of Sleep Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. khu@bics.bwh.harvard.edu|Division of Sleep Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. khu@bics.bwh.harvard.edu|Division of Sleep Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. khu@bics.bwh.harvard.edu|Division of Sleep Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. khu@bics.bwh.harvard.edu', 'United States|United States|United States|United States|United States', 23, 'Aged|Aged, 80 and over|Case-Control Studies|Cerebrovascular Circulation|Computational Biology|Computer Simulation|Female|Homeostasis|Humans|Male|Middle Aged|Nonlinear Dynamics|Stroke', 'Journal Article', '10.1371/journal.pcbi.1002601', '22807666', 'Cerebral autoregulation (CA) is an important vascular control mechanism responsible for relatively stable cerebral blood flow despite changes of systemic blood pressure (BP). Impaired CA may leave brain tissue unprotected against potentially harmful effects of BP fluctuations. It is generally accepted that CA is less effective or even inactive at frequencies >xe2x88xbc0.1 Hz. Without any physiological foundation, this concept is based on studies that quantified the coupling between BP and cerebral blood flow velocity (BFV) using transfer function analysis. This traditional analysis assumes stationary oscillations with constant amplitude and period, and may be unreliable or even invalid for analysis of nonstationary BP and BFV signals. In this study we propose a novel computational tool for CA assessment that is based on nonlinear dynamic theory without the assumption of stationary signals. Using this method, we studied BP and BFV recordings collected from 39 patients with chronic ischemic infarctions and 40 age-matched non-stroke subjects during baseline resting conditions. The active CA function in non-stroke subjects was associated with an advanced phase in BFV oscillations compared to BP oscillations at frequencies from xe2x88xbc0.02 to 0.38 Hz. The phase shift was reduced in stroke patients even at >xe2x80x8a=xe2x80x8a6 months after stroke, and the reduction was consistent at all tested frequencies and in both stroke and non-stroke hemispheres. These results provide strong evidence that CA may be active in a much wider frequency region than previously believed and that the altered multiscale CA in different vascular territories following stroke may have important clinical implications for post-stroke recovery. Moreover, the stroke effects on multiscale cerebral blood flow regulation could not be detected by transfer function analysis, suggesting that nonlinear approaches without the assumption of stationarity are more sensitive for the assessment of the coupling of nonstationary physiological signals.'),
(85564, 2012, 'plos', 'Efficiency and power as a function of sequence coverage, SNP array density, and imputation', 'Flannick, Jason|Korn, Joshua M|Fontanillas, Pierre|Grant, George B|Banks, Eric|Depristo, Mark A|Altshuler, David', 'Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 16, 'Algorithms|Cluster Analysis|Databases, Genetic|European Continental Ancestry Group|Genome-Wide Association Study|Genomics|Genotype|Humans|Oligonucleotide Array Sequence Analysis|Polymorphism, Single Nucleotide|Sensitivity and Specificity|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1002604', '22807667', 'High coverage whole genome sequencing provides near complete information about genetic variation. However, other technologies can be more efficient in some settings by (a) reducing redundant coverage within samples and (b) exploiting patterns of genetic variation across samples. To characterize as many samples as possible, many genetic studies therefore employ lower coverage sequencing or SNP array genotyping coupled to statistical imputation. To compare these approaches individually and in conjunction, we developed a statistical framework to estimate genotypes jointly from sequence reads, array intensities, and imputation. In European samples, we find similar sensitivity (89%) and specificity (99.6%) from imputation with either 1× sequencing or 1 M SNP arrays. Sensitivity is increased, particularly for low-frequency polymorphisms (MAF < 5%), when low coverage sequence reads are added to dense genome-wide SNP arrays--the converse, however, is not true. At sites where sequence reads and array intensities produce different sample genotypes, joint analysis reduces genotype errors and identifies novel error modes. Our joint framework informs the use of next-generation sequencing in genome wide association studies and supports development of improved methods for genotype calling.'),
(85565, 2012, 'plos', 'Microbial co-occurrence relationships in the human microbiome', 'Faust, Karoline|Sathirapongsasuti, J Fah|Izard, Jacques|Segata, Nicola|Gevers, Dirk|Raes, Jeroen|Huttenhower, Curtis', 'Department of Structural Biology, VIB, Brussels, Belgium.|Department of Structural Biology, VIB, Brussels, Belgium.|Department of Structural Biology, VIB, Brussels, Belgium.|Department of Structural Biology, VIB, Brussels, Belgium.|Department of Structural Biology, VIB, Brussels, Belgium.|Department of Structural Biology, VIB, Brussels, Belgium.|Department of Structural Biology, VIB, Brussels, Belgium.', 'Belgium|Belgium|Belgium|Belgium|Belgium|Belgium|Belgium', 667, 'Bacteria|Bacterial Physiological Phenomena|Computational Biology|DNA, Bacterial|Ecosystem|Female|Gastrointestinal Tract|Genes, rRNA|Humans|Linear Models|Male|Metagenome|Microbial Interactions|Nasal Cavity|Phylogeny|Skin|Vagina', 'Journal Article', '10.1371/journal.pcbi.1002606', '22807668', 'The healthy microbiota show remarkable variability within and among individuals. In addition to external exposures, ecological relationships (both oppositional and symbiotic) between microbial inhabitants are important contributors to this variation. It is thus of interest to assess what relationships might exist among microbes and determine their underlying reasons. The initial Human Microbiome Project (HMP) cohort, comprising 239 individuals and 18 different microbial habitats, provides an unprecedented resource to detect, catalog, and analyze such relationships. Here, we applied an ensemble method based on multiple similarity measures in combination with generalized boosted linear models (GBLMs) to taxonomic marker (16S rRNA gene) profiles of this cohort, resulting in a global network of 3,005 significant co-occurrence and co-exclusion relationships between 197 clades occurring throughout the human microbiome. This network revealed strong niche specialization, with most microbial associations occurring within body sites and a number of accompanying inter-body site relationships. Microbial communities within the oropharynx grouped into three distinct habitats, which themselves showed no direct influence on the composition of the gut microbiota. Conversely, niches such as the vagina demonstrated little to no decomposition into region-specific interactions. Diverse mechanisms underlay individual interactions, with some such as the co-exclusion of Porphyromonaceae family members and Streptococcus in the subgingival plaque supported by known biochemical dependencies. These differences varied among broad phylogenetic groups as well, with the Bacilli and Fusobacteria, for example, both enriched for exclusion of taxa from other clades. Comparing phylogenetic versus functional similarities among bacteria, we show that dominant commensal taxa (such as Prevotellaceae and Bacteroides in the gut) often compete, while potential pathogens (e.g. Treponema and Prevotella in the dental plaque) are more likely to co-occur in complementary niches. This approach thus serves to open new opportunities for future targeted mechanistic studies of the microbial ecology of the human microbiome.'),
(85566, 2012, 'plos', 'Importance of electrostatic interactions in the association of intrinsically disordered histone chaperone Chz1 and histone H2AZ-H2B', 'Chu, Xiakun|Wang, Yong|Gan, Linfeng|Bai, Yawen|Han, Wei|Wang, Erkang|Wang, Jin', 'College of Physics, Jilin University, Changchun, Jilin, P.R. China.|College of Physics, Jilin University, Changchun, Jilin, P.R. China.|College of Physics, Jilin University, Changchun, Jilin, P.R. China.|College of Physics, Jilin University, Changchun, Jilin, P.R. China.|College of Physics, Jilin University, Changchun, Jilin, P.R. China.|College of Physics, Jilin University, Changchun, Jilin, P.R. China.|College of Physics, Jilin University, Changchun, Jilin, P.R. China.', 'China|China|China|China|China|China|China', 51, 'Histone Chaperones|Histones|Models, Chemical|Models, Molecular|Protein Binding|Protein Folding|Sodium Chloride|Static Electricity|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002608', '22807669', 'Histone chaperones facilitate assembly and disassembly of nucleosomes. Understanding the process of how histone chaperones associate and dissociate from the histones can help clarify their roles in chromosome metabolism. Some histone chaperones are intrinsically disordered proteins (IDPs). Recent studies of IDPs revealed that the recognition of the biomolecules is realized by the flexibility and dynamics, challenging the century-old structure-function paradigm. Here we investigate the binding between intrinsically disordered chaperone Chz1 and histone variant H2A.Z-H2B by developing a structure-based coarse-grained model, in which Debye-Hückel model is implemented for describing electrostatic interactions due to highly charged characteristic of Chz1 and H2A.Z-H2B. We find that major structural changes of Chz1 only occur after the rate-limiting electrostatic dominant transition state and Chz1 undergoes folding coupled binding through two parallel pathways. Interestingly, although the electrostatic interactions stabilize bound complex and facilitate the recognition at first stage, the rate for formation of the complex is not always accelerated due to slow escape of conformations with non-native electrostatic interactions at low salt concentrations. Our studies provide an ionic-strength-controlled binding/folding mechanism, leading to a cooperative mechanism of local collapse or trapping and fly-casting together and a new understanding of the roles of electrostatic interactions in IDPs binding.'),
(85567, 2012, 'plos', 'Rational engineering of enzyme allosteric regulation through sequence evolution analysis', 'Yang, Jae-Seong|Seo, Sang Woo|Jang, Sungho|Jung, Gyoo Yeol|Kim, Sanguk', 'School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.|School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.|School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.|School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.|School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.', '-|-|-|-|-', 46, 'Adenosine Monophosphate|Allosteric Regulation|Amino Acid Sequence|Catalytic Domain|Computational Biology|Escherichia coli Proteins|Evolution, Molecular|Fructose-Bisphosphatase|Glucose-6-Phosphate|Hydrophobic and Hydrophilic Interactions|Models, Molecular|Molecular Sequence Data|Mutation|Protein Engineering|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1002612', '22807670', 'Control of enzyme allosteric regulation is required to drive metabolic flux toward desired levels. Although the three-dimensional (3D) structures of many enzyme-ligand complexes are available, it is still difficult to rationally engineer an allosterically regulatable enzyme without decreasing its catalytic activity. Here, we describe an effective strategy to deregulate the allosteric inhibition of enzymes based on the molecular evolution and physicochemical characteristics of allosteric ligand-binding sites. We found that allosteric sites are evolutionarily variable and comprised of more hydrophobic residues than catalytic sites. We applied our findings to design mutations in selected target residues that deregulate the allosteric activity of fructose-1,6-bisphosphatase (FBPase). Specifically, charged amino acids at less conserved positions were substituted with hydrophobic or neutral amino acids with similar sizes. The engineered proteins successfully diminished the allosteric inhibition of E. coli FBPase without affecting its catalytic efficiency. We expect that our method will aid the rational design of enzyme allosteric regulation strategies and facilitate the control of metabolic flux.'),
(85568, 2012, 'plos', 'Uncovering MicroRNA and Transcription Factor Mediated Regulatory Networks in Glioblastoma', 'Sun, Jingchun|Gong, Xue|Purow, Benjamin|Zhao, Zhongming', 'Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.|Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.|Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.|Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.', 'United States|United States|United States|United States', 0, 'Brain Neoplasms|Computational Biology|Databases, Genetic|Gene Expression Profiling|Gene Regulatory Networks|Glioblastoma|Humans|MicroRNAs|Oligonucleotide Array Sequence Analysis|Receptors, Notch|Signal Transduction|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002488', '22829753', 'Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in humans. Recent studies revealed that patterns of microRNA (miRNA) expression in GBM tissue samples are different from those in normal brain tissues, suggesting that a number of miRNAs play critical roles in the pathogenesis of GBM. However, little is yet known about which miRNAs play central roles in the pathology of GBM and their regulatory mechanisms of action. To address this issue, in this study, we systematically explored the main regulation format (feed-forward loops, FFLs) consisting of miRNAs, transcription factors (TFs) and their impacting GBM-related genes, and developed a computational approach to construct a miRNA-TF regulatory network. First, we compiled GBM-related miRNAs, GBM-related genes, and known human TFs. We then identified 1,128 3-node FFLs and 805 4-node FFLs with statistical significance. By merging these FFLs together, we constructed a comprehensive GBM-specific miRNA-TF mediated regulatory network. Then, from the network, we extracted a composite GBM-specific regulatory network. To illustrate the GBM-specific regulatory network is promising for identification of critical miRNA components, we specifically examined a Notch signaling pathway subnetwork. Our follow up topological and functional analyses of the subnetwork revealed that six miRNAs (miR-124, miR-137, miR-219-5p, miR-34a, miR-9, and miR-92b) might play important roles in GBM, including some results that are supported by previous studies. In this study, we have developed a computational framework to construct a miRNA-TF regulatory network and generated the first miRNA-TF regulatory network for GBM, providing a valuable resource for further understanding the complex regulatory mechanisms in GBM. The observation of critical miRNAs in the Notch signaling pathway, with partial verification from previous studies, demonstrates that our network-based approach is promising for the identification of new and important miRNAs in GBM and, potentially, other cancers.'),
(85569, 2012, 'plos', 'Shaping the dynamics of a bidirectional neural interface', 'Vato, Alessandro|Semprini, Marianna|Maggiolini, Emma|Szymanski, Francois D|Fadiga, Luciano|Panzeri, Stefano|Mussa-Ivaldi, Ferdinando A', 'Department of Robotics, Brain and Cognitive Sciences, Istituto Italiano di Tecnologia, Genova, Italy.|Department of Robotics, Brain and Cognitive Sciences, Istituto Italiano di Tecnologia, Genova, Italy.|Department of Robotics, Brain and Cognitive Sciences, Istituto Italiano di Tecnologia, Genova, Italy.|Department of Robotics, Brain and Cognitive Sciences, Istituto Italiano di Tecnologia, Genova, Italy.|Department of Robotics, Brain and Cognitive Sciences, Istituto Italiano di Tecnologia, Genova, Italy.|Department of Robotics, Brain and Cognitive Sciences, Istituto Italiano di Tecnologia, Genova, Italy.|Department of Robotics, Brain and Cognitive Sciences, Istituto Italiano di Tecnologia, Genova, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy|Italy', 23, 'Animals|Calibration|Deep Brain Stimulation|Electron Transport Complex IV|Evoked Potentials, Motor|Histocytochemistry|Male|Models, Neurological|Motor Cortex|Neurons|Neurophysiology|Rats|Rats, Long-Evans|Somatosensory Cortex|Staining and Labeling', 'Journal Article', '10.1371/journal.pcbi.1002578', '22829754', 'Progress in decoding neural signals has enabled the development of interfaces that translate cortical brain activities into commands for operating robotic arms and other devices. The electrical stimulation of sensory areas provides a means to create artificial sensory information about the state of a device. Taken together, neural activity recording and microstimulation techniques allow us to embed a portion of the central nervous system within a closed-loop system, whose behavior emerges from the combined dynamical properties of its neural and artificial components. In this study we asked if it is possible to concurrently regulate this bidirectional brain-machine interaction so as to shape a desired dynamical behavior of the combined system. To this end, we followed a well-known biological pathway. In vertebrates, the communications between brain and limb mechanics are mediated by the spinal cord, which combines brain instructions with sensory information and organizes coordinated patterns of muscle forces driving the limbs along dynamically stable trajectories. We report the creation and testing of the first neural interface that emulates this sensory-motor interaction. The interface organizes a bidirectional communication between sensory and motor areas of the brain of anaesthetized rats and an external dynamical object with programmable properties. The system includes (a) a motor interface decoding signals from a motor cortical area, and (b) a sensory interface encoding the state of the external object into electrical stimuli to a somatosensory area. The interactions between brain activities and the state of the external object generate a family of trajectories converging upon a selected equilibrium point from arbitrary starting locations. Thus, the bidirectional interface establishes the possibility to specify not only a particular movement trajectory but an entire family of motions, which includes the prescribed reactions to unexpected perturbations.'),
(85570, 2012, 'plos', 'Modular design of artificial tissue homeostasis: robust control through synthetic cellular heterogeneity', 'Miller, Miles|Hafner, Marc|Sontag, Eduardo|Davidsohn, Noah|Subramanian, Sairam|Purnick, Priscilla E M|Lauffenburger, Douglas|Weiss, Ron', 'Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Bayes Theorem|Cell Physiological Phenomena|Computer Simulation|Gene Regulatory Networks|HEK293 Cells|Homeostasis|Humans|Insulin-Secreting Cells|Models, Biological|Phenotype|Stem Cells|Synthetic Biology|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002579', '22829755', 'Synthetic biology efforts have largely focused on small engineered gene networks, yet understanding how to integrate multiple synthetic modules and interface them with endogenous pathways remains a challenge. Here we present the design, system integration, and analysis of several large scale synthetic gene circuits for artificial tissue homeostasis. Diabetes therapy represents a possible application for engineered homeostasis, where genetically programmed stem cells maintain a steady population of xcexb2-cells despite continuous turnover. We develop a new iterative process that incorporates modular design principles with hierarchical performance optimization targeted for environments with uncertainty and incomplete information. We employ theoretical analysis and computational simulations of multicellular reaction/diffusion models to design and understand system behavior, and find that certain features often associated with robustness (e.g., multicellular synchronization and noise attenuation) are actually detrimental for tissue homeostasis. We overcome these problems by engineering a new class of genetic modules for synthetic cellular heterogeneity that function to generate beneficial population diversity. We design two such modules (an asynchronous genetic oscillator and a signaling throttle mechanism), demonstrate their capacity for enhancing robust control, and provide guidance for experimental implementation with various computational techniques. We found that designing modules for synthetic heterogeneity can be complex, and in general requires a framework for non-linear and multifactorial analysis. Consequently, we adapt a phenotypic sensitivity analysis method to determine how functional module behaviors combine to achieve optimal system performance. We ultimately combine this analysis with Bayesian network inference to extract critical, causal relationships between a modules biochemical rate-constants, its high level functional behavior in isolation, and its impact on overall system performance once integrated.'),
(85571, 2012, 'plos', 'Individual rules for trail pattern formation in Argentine ants (Linepithema humile)', 'Perna, Andrea|Granovskiy, Boris|Garnier, Simon|Nicolis, Stamatios C|Labédan, Marjorie|Theraulaz, Guy|Fourcassié, Vincent|Sumpter, David J T', 'Complex Systems Institute of Paris Ile de France, Paris, France. perna@math.uu.se|Complex Systems Institute of Paris Ile de France, Paris, France. perna@math.uu.se|Complex Systems Institute of Paris Ile de France, Paris, France. perna@math.uu.se|Complex Systems Institute of Paris Ile de France, Paris, France. perna@math.uu.se|Complex Systems Institute of Paris Ile de France, Paris, France. perna@math.uu.se|Complex Systems Institute of Paris Ile de France, Paris, France. perna@math.uu.se|Complex Systems Institute of Paris Ile de France, Paris, France. perna@math.uu.se|Complex Systems Institute of Paris Ile de France, Paris, France. perna@math.uu.se', 'France|France|France|France|France|France|France|France', 60, 'Animals|Ants|Behavior, Animal|Computational Biology|Computer Simulation|Feedback, Physiological|Models, Biological|Pheromones', 'Journal Article', '10.1371/journal.pcbi.1002592', '22829756', 'We studied the formation of trail patterns by Argentine ants exploring an empty arena. Using a novel imaging and analysis technique we estimated pheromone concentrations at all spatial positions in the experimental arena and at different times. Then we derived the response function of individual ants to pheromone concentrations by looking at correlations between concentrations and changes in speed or direction of the ants. Ants were found to turn in response to local pheromone concentrations, while their speed was largely unaffected by these concentrations. Ants did not integrate pheromone concentrations over time, with the concentration of pheromone in a 1 cm radius in front of the ant determining the turning angle. The response to pheromone was found to follow a Webers Law, such that the difference between quantities of pheromone on the two sides of the ant divided by their sum determines the magnitude of the turning angle. This proportional response is in apparent contradiction with the well-established non-linear choice function used in the literature to model the results of binary bridge experiments in ant colonies (Deneubourg et al. 1990). However, agent based simulations implementing the Webers Law response function led to the formation of trails and reproduced results reported in the literature. We show analytically that a sigmoidal response, analogous to that in the classical Deneubourg model for collective decision making, can be derived from the individual Weber-type response to pheromone concentrations that we have established in our experiments when directional noise around the preferred direction of movement of the ants is assumed.'),
(85572, 2012, 'plos', 'GDP release preferentially occurs on the phosphate side in heterotrimeric G-proteins', 'Louet, Maxime|Martinez, Jean|Floquet, Nicolas', 'Institut des Biomolxc3xa9cules Max Mousseron-IBMM, CNRS UMR5247, Universitxc3xa9 Montpellier 1, Universitxc3xa9 Montpellier 2, Facultxc3xa9 de Pharmacie, Montpellier, France.|Institut des Biomolxc3xa9cules Max Mousseron-IBMM, CNRS UMR5247, Universitxc3xa9 Montpellier 1, Universitxc3xa9 Montpellier 2, Facultxc3xa9 de Pharmacie, Montpellier, France.|Institut des Biomolxc3xa9cules Max Mousseron-IBMM, CNRS UMR5247, Universitxc3xa9 Montpellier 1, Universitxc3xa9 Montpellier 2, Facultxc3xa9 de Pharmacie, Montpellier, France.', 'France|France|France', 15, 'Computational Biology|Guanosine Diphosphate|Heterotrimeric GTP-Binding Proteins|Molecular Dynamics Simulation|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002595', '22829757', 'After extra-cellular stimulation of G-Protein Coupled Receptors (GPCRs), GDP/GTP exchange appears as the key, rate limiting step of the intracellular activation cycle of heterotrimeric G-proteins. Despite the availability of a large number of X-ray structures, the mechanism of GDP release out of heterotrimeric G-proteins still remains unknown at the molecular level. Starting from the available X-ray structure, extensive unconstrained/constrained molecular dynamics simulations were performed on the complete membrane-anchored Gi heterotrimer complexed to GDP, for a total simulation time overcoming 500 ns. By combining Targeted Molecular Dynamics (TMD) and free energy profiles reconstruction by umbrella sampling, our data suggest that the release of GDP was much more favored on its phosphate side. Interestingly, upon the forced extraction of GDP on this side, the whole protein encountered large, collective motions in perfect agreement with those we described previously including a domain to domain motion between the two ras-like and helical sub-domains of G(xcexb1).'),
(85573, 2012, 'plos', 'Suppressed expression of T-box transcription factors is involved in senescence in chronic obstructive pulmonary disease', 'Acquaah-Mensah, George K|Malhotra, Deepti|Vulimiri, Madhulika|McDermott, Jason E|Biswal, Shyam', 'Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Worcester, Massachusetts, United States of America. george.acquaah-mensah@mcphs.edu|Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Worcester, Massachusetts, United States of America. george.acquaah-mensah@mcphs.edu|Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Worcester, Massachusetts, United States of America. george.acquaah-mensah@mcphs.edu|Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Worcester, Massachusetts, United States of America. george.acquaah-mensah@mcphs.edu|Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Worcester, Massachusetts, United States of America. george.acquaah-mensah@mcphs.edu', 'United States|United States|United States|United States|United States', 14, 'Aged|Aged, 80 and over|Apoptosis|Cellular Senescence|Databases, Genetic|Female|Gene Expression Profiling|Humans|Inflammation|Lung|Male|Middle Aged|Oxidative Stress|Pulmonary Disease, Chronic Obstructive|Signal Transduction|T-Box Domain Proteins', 'Journal Article', '10.1371/journal.pcbi.1002597', '22829758', 'Chronic obstructive pulmonary disease (COPD) is a major global health problem. The etiology of COPD has been associated with apoptosis, oxidative stress, and inflammation. However, understanding of the molecular interactions that modulate COPD pathogenesis remains only partly resolved. We conducted an exploratory study on COPD etiology to identify the key molecular participants. We used information-theoretic algorithms including Context Likelihood of Relatedness (CLR), Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNE), and Inferelator. We captured direct functional associations among genes, given a compendium of gene expression profiles of human lung epithelial cells. A set of genes differentially expressed in COPD, as reported in a previous study were superposed with the resulting transcriptional regulatory networks. After factoring in the properties of the networks, an established COPD susceptibility locus and domain-domain interactions involving protein products of genes in the generated networks, several molecular candidates were predicted to be involved in the etiology of COPD. These include COL4A3, CFLAR, GULP1, PDCD1, CASP10, PAX3, BOK, HSPD1, PITX2, and PML. Furthermore, T-box (TBX) genes and cyclin-dependent kinase inhibitor 2A (CDKN2A), which are in a direct transcriptional regulatory relationship, emerged as preeminent participants in the etiology of COPD by means of senescence. Contrary to observations in neoplasms, our study reveals that the expression of genes and proteins in the lung samples from patients with COPD indicate an increased tendency towards cellular senescence. The expression of the anti-senescence mediators TBX transcription factors, chromatin modifiers histone deacetylases, and sirtuins was suppressed, while the expression of TBX-regulated cellular senescence markers such as CDKN2A, CDKN1A, and CAV1 was elevated in the peripheral lung tissue samples from patients with COPD. The critical balance between senescence and anti-senescence factors is disrupted towards senescence in COPD lungs.'),
(85574, 2012, 'plos', 'Location-dependent excitatory synaptic interactions in pyramidal neuron dendrites', 'Behabadi, Bardia F|Polsky, Alon|Jadi, Monika|Schiller, Jackie|Mel, Bartlett W', 'Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America. behabadi@qualcomm.com|Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America. behabadi@qualcomm.com|Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America. behabadi@qualcomm.com|Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America. behabadi@qualcomm.com|Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America. behabadi@qualcomm.com', 'United States|United States|United States|United States|United States', 37, 'Action Potentials|Animals|Dendrites|Excitatory Postsynaptic Potentials|Models, Neurological|N-Methylaspartate|Neural Conduction|Patch-Clamp Techniques|Pyramidal Cells|Rats|Rats, Wistar|Synapses|alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid', 'Journal Article', '10.1371/journal.pcbi.1002599', '22829759', 'Neocortical pyramidal neurons (PNs) receive thousands of excitatory synaptic contacts on their basal dendrites. Some act as classical driver inputs while others are thought to modulate PN responses based on sensory or behavioral context, but the biophysical mechanisms that mediate classical-contextual interactions in these dendrites remain poorly understood. We hypothesized that if two excitatory pathways bias their synaptic projections towards proximal vs. distal ends of the basal branches, the very different local spike thresholds and attenuation factors for inputs near and far from the soma might provide the basis for a classical-contextual functional asymmetry. Supporting this possibility, we found both in compartmental models and electrophysiological recordings in brain slices that the responses of basal dendrites to spatially separated inputs are indeed strongly asymmetric. Distal excitation lowers the local spike threshold for more proximal inputs, while having little effect on peak responses at the soma. In contrast, proximal excitation lowers the threshold, but also substantially increases the gain of distally-driven responses. Our findings support the view that PN basal dendrites possess significant analog computing capabilities, and suggest that the diverse forms of nonlinear response modulation seen in the neocortex, including uni-modal, cross-modal, and attentional effects, could depend in part on pathway-specific biases in the spatial distribution of excitatory synaptic contacts onto PN basal dendritic arbors.'),
(85575, 2012, 'plos', 'A preformed binding interface in the unbound ensemble of an intrinsically disordered protein: evidence from molecular simulations', 'Knott, Michael|Best, Robert B', 'University of Cambridge, Department of Chemistry, Cambridge, United Kingdom.|University of Cambridge, Department of Chemistry, Cambridge, United Kingdom.', 'United Kingdom|United Kingdom', 87, 'Amino Acid Sequence|Binding Sites|CREB-Binding Protein|Humans|Molecular Dynamics Simulation|Molecular Sequence Data|Nuclear Magnetic Resonance, Biomolecular|Protein Binding|Protein Conformation|Proteins|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1002605', '22829760', 'Intrinsically disordered proteins play an important role in cellular signalling, mediated by their interactions with other biomolecules. A key question concerns the nature of their binding mechanism, and whether the bound structure is induced only by proximity to the binding partner. This is difficult to answer through experiment alone because of the very heterogeneous nature of the unbound ensemble, and the probable rapid interconversion of the various unbound structures. Here we report the most extensive set of simulations on NCBD to date: we use large-scale replica exchange molecular dynamics to explore the unbound state. An important feature of the study is the use of an atomistic force field that has been parametrised against experimental data for weakly structured peptides, together with an accurate explicit water model. Neither the force field nor the starting conformations are biased towards a particular structure. The regions of NCBD that have high helical propensity in the simulations correspond closely to helices in the core unbound conformation determined by NMR, although no single member of the simulated unbound ensemble closely resembles the core conformation, or either of the two known bound conformations. We have validated the results against NMR spectroscopy and SAXS measurements, obtaining reasonable agreement. The two helices which most stabilise the binding of NCBD with ACTR are formed readily, the third helix, which is less important for binding but is involved in most of the intraprotein contacts of NCBD in the bound conformation, is formed more rarely, and tends not to coexist with the other helices. These results support a mechanism by which NCBD gains the advantages of disorder, while forming binding-competent structures in the unbound state. We obtain support for this mechanism from coarse-grained simulations of NCBD with, and without, its binding partner.'),
(85576, 2012, 'plos', 'A range-normalization model of context-dependent choice: a new model and evidence', 'Soltani, Alireza|De Martino, Benedetto|Camerer, Colin', 'Howard Hughes Medical Institute and Department of Neurobiology, Stanford University School of Medicine, Stanford, California, United States of America. asoltani@stanford.edu|Howard Hughes Medical Institute and Department of Neurobiology, Stanford University School of Medicine, Stanford, California, United States of America. asoltani@stanford.edu|Howard Hughes Medical Institute and Department of Neurobiology, Stanford University School of Medicine, Stanford, California, United States of America. asoltani@stanford.edu', 'United States|United States|United States', 64, 'Adult|Attitude|Choice Behavior|Computational Biology|Humans|Male|Models, Psychological|Risk-Taking', 'Journal Article', '10.1371/journal.pcbi.1002607', '22829761', 'Most utility theories of choice assume that the introduction of an irrelevant option (called the decoy) to a choice set does not change the preference between existing options. On the contrary, a wealth of behavioral data demonstrates the dependence of preference on the decoy and on the context in which the options are presented. Nevertheless, neural mechanisms underlying context-dependent preference are poorly understood. In order to shed light on these mechanisms, we design and perform a novel experiment to measure within-subject decoy effects. We find within-subject decoy effects similar to what have been shown previously with between-subject designs. More importantly, we find that not only are the decoy effects correlated, pointing to similar underlying mechanisms, but also these effects increase with the distance of the decoy from the original options. To explain these observations, we construct a plausible neuronal model that can account for decoy effects based on the trial-by-trial adjustment of neural representations to the set of available options. This adjustment mechanism, which we call range normalization, occurs when the nervous system is required to represent different stimuli distinguishably, while being limited to using bounded neural activity. The proposed model captures our experimental observations and makes new predictions about the influence of the choice set size on the decoy effects, which are in contrast to previous models of context-dependent choice preference. Critically, unlike previous psychological models, the computational resource required by our range-normalization model does not increase exponentially as the set size increases. Our results show that context-dependent choice behavior, which is commonly perceived as an irrational response to the presence of irrelevant options, could be a natural consequence of the biophysical limits of neural representation in the brain.'),
(85577, 2012, 'plos', 'Which of our modeling predictions are robust?', 'De Boer, Rob J', 'Theoretical Biology & Bioinformatics, Utrecht University, Utrecht, the Netherlands. r.j.deboer@uu.nl', 'Netherlands', 25, 'Chronic Disease|Computational Biology|Humans|Models, Biological|Virus Diseases', 'Journal Article', '10.1371/journal.pcbi.1002593', '22844235', 'In theoretical ecology it is well known that the steady state expressions of the variables in a food chain crucially depend on the parity of the length of the chain. This poses a major problem for modeling real food webs because it is difficult to establish their true number of trophic levels, with sometimes rare predators and often rampant pathogens. Similar problems arise in the modeling of chronic viral infections. We review examples where seemingly general interpretations strongly depend on the number of levels in a model, and on its specific equations. This Perspective aims to open the discussion on this problem.'),
(85578, 2012, 'plos', 'A quick guide to software licensing for the scientist-programmer', 'Morin, Andrew|Urban, Jennifer|Sliz, Piotr', 'Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.', 'United States|United States|United States', 39, 'Computational Biology|Licensure|Software|United States', 'Journal Article', '10.1371/journal.pcbi.1002598', '22844236', '-');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85579, 2012, 'plos', 'An integrated regulatory network reveals pervasive cross-regulation among transcription and splicing factors', 'Kosti, Idit|Radivojac, Predrag|Mandel-Gutfreund, Yael', 'Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.|Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.|Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.', 'Israel|Israel|Israel', 10, 'Alternative Splicing|Animals|Cluster Analysis|Computational Biology|Databases, Genetic|Drosophila|Gene Expression Regulation|Gene Regulatory Networks|Humans|Models, Genetic|Muscles|Myocardium|Organ Specificity|Phosphorylation|Phosphotransferases|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002603', '22844237', 'Traditionally the gene expression pathway has been regarded as being comprised of independent steps, from RNA transcription to protein translation. To date there is increasing evidence of coupling between the different processes of the pathway, specifically between transcription and splicing. To study the interplay between these processes we derived a transcription-splicing integrated network. The nodes of the network included experimentally verified human proteins belonging to three groups of regulators: transcription factors, splicing factors and kinases. The nodes were wired by instances of predicted transcriptional and alternative splicing regulation. Analysis of the network indicated a pervasive cross-regulation among the nodes, specifically, splicing factors are significantly more connected by alternative splicing regulatory edges relative to the two other subgroups, while transcription factors are more extensively controlled by transcriptional regulation. Furthermore, we found that splicing factors are the most regulated of the three regulatory groups and are subject to extensive combinatorial control by alternative splicing and transcriptional regulation. Consistent with the network results, our bioinformatics analyses showed that the subgroup of kinases have the highest density of predicted phosphorylation sites. Overall, our systematic study reveals that an organizing principle in the logic of integrated networks favor the regulation of regulatory proteins by the specific regulation they conduct. Based on these results, we propose a new regulatory paradigm postulating that gene expression regulation of the master regulators in the cell is predominantly achieved by cross-regulation.'),
(85580, 2012, 'plos', 'Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse', 'Zheng, Fang|Zhan, Chang-Guo', 'Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, United States of America.|Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, United States of America.', 'United States|United States', 30, 'Area Under Curve|Carboxylic Ester Hydrolases|Cocaine|Computational Biology|Enzyme Therapy|Humans|Kinetics|Models, Biological|Positron-Emission Tomography|Substance-Related Disorders', 'Journal Article', '10.1371/journal.pcbi.1002610', '22844238', 'A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly dependent on the initial cocaine concentration in plasma. The threshold concentration of cocaine in brain required to produce physiological effects has been estimated to be 0.22xc2xb10.07 xc2xb5M, and the threshold area under the cocaine concentration versus time curve (AUC) value in brain (denoted by AUC2(xe2x88x9e)) required to produce physiological effects has been estimated to be 7.9xc2xb12.7 xc2xb5Mxc2xb7min. It has been demonstrated that administration of a cocaine hydrolase/esterase (CocH/CocE) can considerably decrease the cocaine half-lives in both brain and plasma, the peak cocaine concentration in brain, and the AUC2(xe2x88x9e). The estimated maximum cocaine plasma concentration which a given concentration of drug-metabolizing enzyme can effectively prevent from entering brain and producing physiological effects can be used to guide future preclinical/clinical studies on cocaine-metabolizing enzymes. Understanding of drug-metabolizing enzymes is key to the science of pharmacokinetics. The general insights into the effects of a drug-metabolizing enzyme on drug kinetics in human should be valuable also in future development of enzyme therapies for other drugs of abuse.'),
(85581, 2012, 'plos', 'Why SIT works: normal function despite typical myofiber pattern in Situs Inversus Totalis (SIT) hearts derived by shear-induced myofiber reorientation', 'Pluijmert, Marieke|Kroon, Wilco|Rossi, Alessandro C|Bovendeerd, Peter H M|Delhaas, Tammo', 'Department of Biomedical Engineering/Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. marieke.pluijmert@maastrichtuniversity.nl|Department of Biomedical Engineering/Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. marieke.pluijmert@maastrichtuniversity.nl|Department of Biomedical Engineering/Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. marieke.pluijmert@maastrichtuniversity.nl|Department of Biomedical Engineering/Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. marieke.pluijmert@maastrichtuniversity.nl|Department of Biomedical Engineering/Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. marieke.pluijmert@maastrichtuniversity.nl', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 8, 'Computational Biology|Heart|Heart Ventricles|Humans|Models, Cardiovascular|Myocardium|Myofibrils|Situs Inversus|Torsion Abnormality|Ventricular Function', 'Journal Article', '10.1371/journal.pcbi.1002611', '22844239', 'The left ventricle (LV) of mammals with Situs Solitus (SS, normal organ arrangement) displays hardly any interindividual variation in myofiber pattern and experimentally determined torsion. SS LV myofiber pattern has been suggested to result from adaptive myofiber reorientation, in turn leading to efficient pump and myofiber function. Limited data from the Situs Inversus Totalis (SIT, a complete mirror image of organ anatomy and position) LV demonstrated an essential different myofiber pattern, being normal at the apex but mirrored at the base. Considerable differences in torsion patterns in between human SIT LVs even suggest variation in myofiber pattern among SIT LVs themselves. We addressed whether different myofiber patterns in the SIT LV can be predicted by adaptive myofiber reorientation and whether they yield similar pump and myofiber function as in the SS LV. With a mathematical model of LV mechanics including shear induced myofiber reorientation, we predicted myofiber patterns of one SS and three different SIT LVs. Initial conditions for SIT were based on scarce information on the helix angle. The transverse angle was set to zero. During reorientation, a non-zero transverse angle developed, pump function increased, and myofiber function increased and became more homogeneous. Three continuous SIT structures emerged with a different location of transition between normal and mirrored myofiber orientation pattern. Predicted SIT torsion patterns matched experimentally determined ones. Pump and myofiber function in SIT and SS LVs are similar, despite essential differences in myocardial structure. SS and SIT LV structure and function may originate from same processes of adaptive myofiber reorientation.'),
(85582, 2012, 'plos', 'Genome-wide localization of protein-DNA binding and histone modification by a Bayesian change-point method with ChIP-seq data', 'Xing, Haipeng|Mo, Yifan|Liao, Will|Zhang, Michael Q', 'Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York, United States of America. xing@ams.sunysb.edu|Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York, United States of America. xing@ams.sunysb.edu|Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York, United States of America. xing@ams.sunysb.edu|Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York, United States of America. xing@ams.sunysb.edu', 'United States|United States|United States|United States', 30, 'Algorithms|Bayes Theorem|Binding Sites|Chromatin Immunoprecipitation|DNA|Epigenomics|Genome, Human|Histones|Humans|Markov Chains|Reproducibility of Results|Sequence Analysis, DNA|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002613', '22844240', 'Next-generation sequencing (NGS) technologies have matured considerably since their introduction and a focus has been placed on developing sophisticated analytical tools to deal with the amassing volumes of data. Chromatin immunoprecipitation sequencing (ChIP-seq), a major application of NGS, is a widely adopted technique for examining protein-DNA interactions and is commonly used to investigate epigenetic signatures of diffuse histone marks. These datasets have notoriously high variance and subtle levels of enrichment across large expanses, making them exceedingly difficult to define. Windows-based, heuristic models and finite-state hidden Markov models (HMMs) have been used with some success in analyzing ChIP-seq data but with lingering limitations. To improve the ability to detect broad regions of enrichment, we developed a stochastic Bayesian Change-Point (BCP) method, which addresses some of these unresolved issues. BCP makes use of recent advances in infinite-state HMMs by obtaining explicit formulas for posterior means of read densities. These posterior means can be used to categorize the genome into enriched and unenriched segments, as is customarily done, or examined for more detailed relationships since the underlying subpeaks are preserved rather than simplified into a binary classification. BCP performs a near exhaustive search of all possible change points between different posterior means at high-resolution to minimize the subjectivity of window sizes and is computationally efficient, due to a speed-up algorithm and the explicit formulas it employs. In the absence of a well-established gold standard for diffuse histone mark enrichment, we corroborated BCPs island detection accuracy and reproducibility using various forms of empirical evidence. We show that BCP is especially suited for analysis of diffuse histone ChIP-seq data but also effective in analyzing punctate transcription factor ChIP datasets, making it widely applicable for numerous experiment types.'),
(85583, 2012, 'plos', 'Digital epidemiology', 'Salathé, Marcel|Bengtsson, Linus|Bodnar, Todd J|Brewer, Devon D|Brownstein, John S|Buckee, Caroline|Campbell, Ellsworth M|Cattuto, Ciro|Khandelwal, Shashank|Mabry, Patricia L|Vespignani, Alessandro', 'Center for Infectious Disease Dynamics, Penn State University, University Park, Pennsylvania, United States of America. salathe@psu.edu|Center for Infectious Disease Dynamics, Penn State University, University Park, Pennsylvania, United States of America. salathe@psu.edu|Center for Infectious Disease Dynamics, Penn State University, University Park, Pennsylvania, United States of America. salathe@psu.edu|Center for Infectious Disease Dynamics, Penn State University, University Park, Pennsylvania, United States of America. salathe@psu.edu|Center for Infectious Disease Dynamics, Penn State University, University Park, Pennsylvania, United States of America. salathe@psu.edu|Center for Infectious Disease Dynamics, Penn State University, University Park, Pennsylvania, United States of America. salathe@psu.edu|Center for Infectious Disease Dynamics, Penn State University, University Park, Pennsylvania, United States of America. salathe@psu.edu|Center for Infectious Disease Dynamics, Penn State University, University Park, Pennsylvania, United States of America. salathe@psu.edu|Center for Infectious Disease Dynamics, Penn State University, University Park, Pennsylvania, United States of America. salathe@psu.edu|Center for Infectious Disease Dynamics, Penn State University, University Park, Pennsylvania, United States of America. salathe@psu.edu|Center for Infectious Disease Dynamics, Penn State University, University Park, Pennsylvania, United States of America. salathe@psu.edu', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Algorithms|Cell Phone|Computational Biology|Data Mining|Databases, Factual|Epidemiologic Methods|Humans|Internet|Software', 'Journal Article', '10.1371/journal.pcbi.1002616', '22844241', 'Mobile, social, real-time: the ongoing revolution in the way people communicate has given rise to a new kind of epidemiology. Digital data sources, when harnessed appropriately, can provide local and timely information about disease and health dynamics in populations around the world. The rapid, unprecedented increase in the availability of relevant data from various digital sources creates considerable technical and computational challenges.'),
(85584, 2012, 'plos', 'Finding a needle in a haystack: the role of electrostatics in target lipid recognition by PH domains', 'Lumb, Craig N|Sansom, Mark S P', 'Department of Biochemistry, University of Oxford, Oxford, United Kingdom.|Department of Biochemistry, University of Oxford, Oxford, United Kingdom.', 'United Kingdom|United Kingdom', 28, 'Anions|Blood Proteins|Cell Membrane|Humans|Lipid Bilayers|Molecular Dynamics Simulation|Phosphatidylinositol Phosphates|Phosphoproteins|Protein Binding|Protein Structure, Tertiary|Receptors, Cytoplasmic and Nuclear|Static Electricity', 'Journal Article', '10.1371/journal.pcbi.1002617', '22844242', 'Interactions between protein domains and lipid molecules play key roles in controlling cell membrane signalling and trafficking. The pleckstrin homology (PH) domain is one of the most widespread, binding specifically to phosphatidylinositol phosphates (PIPs) in cell membranes. PH domains must locate specific PIPs in the presence of a background of approximately 20% anionic lipids within the cytoplasmic leaflet of the plasma membrane. We investigate the mechanism of such recognition via a multiscale procedure combining Brownian dynamics (BD) and molecular dynamics (MD) simulations of the GRP1 PH domain interacting with phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)Pxe2x82x83). The interaction of GRP1-PH with PI(3,4,5)Pxe2x82x83 in a zwitterionic bilayer is compared with the interaction in bilayers containing different levels of anionic decoy lipids. BD simulations reveal both translational and orientational electrostatic steering of the PH domain towards the PI(3,4,5)Pxe2x82x83-containing anionic bilayer surface. There is a payoff between non-PIP anionic lipids attracting the PH domain to the bilayer surface in a favourable orientation and their role as decoys, disrupting the interaction of GRP1-PH with the PI(3,4,5)Pxe2x82x83 molecule. Significantly, approximately 20% anionic lipid in the cytoplasmic leaflet of the bilayer is nearly optimal to both enhance orientational steering and to localise GRP1-PH proximal to the surface of the membrane without sacrificing its ability to locate PI(3,4,5)Pxe2x82x83 within the bilayer plane. Subsequent MD simulations reveal binding to PI(3,4,5)Pxe2x82x83, forming protein-phosphate contacts comparable to those in X-ray structures. These studies demonstrate a computational framework which addresses lipid recognition within a cell membrane environment, offering a link between structural and cell biological characterisation.'),
(85585, 2012, 'plos', 'Assessing drug target association using semantic linked data', 'Chen, Bin|Ding, Ying|Wild, David J', 'School of Informatics and Computing, Indiana University, Bloomington, IN, USA.|School of Informatics and Computing, Indiana University, Bloomington, IN, USA.|School of Informatics and Computing, Indiana University, Bloomington, IN, USA.', 'India|India|India', 93, 'Algorithms|Computational Biology|Data Mining|Databases, Factual|Drug Discovery|Humans|Models, Theoretical|Reproducibility of Results|Semantics', 'Journal Article', '10.1371/journal.pcbi.1002574', '22859915', 'The rapidly increasing amount of public data in chemistry and biology provides new opportunities for large-scale data mining for drug discovery. Systematic integration of these heterogeneous sets and provision of algorithms to data mine the integrated sets would permit investigation of complex mechanisms of action of drugs. In this work we integrated and annotated data from public datasets relating to drugs, chemical compounds, protein targets, diseases, side effects and pathways, building a semantic linked network consisting of over 290,000 nodes and 720,000 edges. We developed a statistical model to assess the association of drug target pairs based on their relation with other linked objects. Validation experiments demonstrate the model can correctly identify known direct drug target pairs with high precision. Indirect drug target pairs (for example drugs which change gene expression level) are also identified but not as strongly as direct pairs. We further calculated the association scores for 157 drugs from 10 disease areas against 1683 human targets, and measured their similarity using a [Formula: see text] score matrix. The similarity network indicates that drugs from the same disease area tend to cluster together in ways that are not captured by structural similarity, with several potential new drug pairings being identified. This work thus provides a novel, validated alternative to existing drug target prediction algorithms. The web service is freely available at: http://chem2bio2rdf.org/slap.'),
(85586, 2012, 'plos', 'Interplay between the localization and kinetics of phosphorylation in flagellar pole development of the bacterium Caulobacter crescentus', 'Tropini, Carolina|Huang, Kerwyn Casey', 'Biophysics Program, Stanford University, Stanford, California, United States of America.|Biophysics Program, Stanford University, Stanford, California, United States of America.', 'United States|United States', 5, 'Bacterial Proteins|Caulobacter crescentus|Kinetics|Models, Theoretical|Phosphorylation', 'Journal Article', '10.1371/journal.pcbi.1002602', '22876167', 'Bacterial cells maintain sophisticated levels of intracellular organization that allow for signal amplification, response to stimuli, cell division, and many other critical processes. The mechanisms underlying localization and their contribution to fitness have been difficult to uncover, due to the often challenging task of creating mutants with systematically perturbed localization but normal enzymatic activity, and the lack of quantitative models through which to interpret subtle phenotypic changes. Focusing on the model bacterium Caulobacter crescentus, which generates two different types of daughter cells from an underlying asymmetric distribution of protein phosphorylation, we use mathematical modeling to investigate the contribution of the localization of histidine kinases to the establishment of cellular asymmetry and subsequent developmental outcomes. We use existing mutant phenotypes and fluorescence data to parameterize a reaction-diffusion model of the kinases PleC and DivJ and their cognate response regulator DivK. We then present a systematic computational analysis of the effects of changes in protein localization and abundance to determine whether PleC localization is required for correct developmental timing in Caulobacter. Our model predicts the developmental phenotypes of several localization mutants, and suggests that a novel strain with co-localization of PleC and DivJ could provide quantitative insight into the signaling threshold required for flagellar pole development. Our analysis indicates that normal development can be maintained through a wide range of localization phenotypes, and that developmental defects due to changes in PleC localization can be rescued by increased PleC expression. We also show that the system is remarkably robust to perturbation of the kinetic parameters, and while the localization of either PleC or DivJ is required for asymmetric development, the delocalization of one of these two components does not prevent flagellar pole development. We further find that allosteric regulation of PleC observed in vitro does not affect the predicted in vivo developmental phenotypes. Taken together, our model suggests that cells can tolerate perturbations to localization phenotypes, whose evolutionary origins may be connected with reducing protein expression or with decoupling pre- and post-division phenotypes.'),
(85587, 2012, 'plos', 'Mutation induced extinction in finite populations: lethal mutagenesis and lethal isolation', 'Wylie, C Scott|Shakhnovich, Eugene I', 'Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.', 'United States|United States', 16, 'Biophysics|Genes, Lethal|Models, Theoretical|Mutagenesis|Mutation', 'Journal Article', '10.1371/journal.pcbi.1002609', '22876168', 'Reproduction is inherently risky, in part because genomic replication can introduce new mutations that are usually deleterious toward fitness. This risk is especially severe for organisms whose genomes replicate semi-conservatively, e.g. viruses and bacteria, where no master copy of the genome is preserved. Lethal mutagenesis refers to extinction of populations due to an unbearably high mutation rate (U), and is important both theoretically and clinically, where drugs can extinguish pathogens by increasing their mutation rate. Previous theoretical models of lethal mutagenesis assume infinite population size (N). However, in addition to high U, small N can accelerate extinction by strengthening genetic drift and relaxing selection. Here, we examine how the time until extinction depends jointly on N and U. We first analytically compute the mean time until extinction (xcfx84) in a simplistic model where all mutations are either lethal or neutral. The solution motivates the definition of two distinct regimes: a survival phase and an extinction phase, which differ dramatically in both how xcfx84 scales with N and in the coefficient of variation in time until extinction. Next, we perform stochastic population-genetics simulations on a realistic fitness landscape that both (i) features an epistatic distribution of fitness effects that agrees with experimental data on viruses and (ii) is based on the biophysics of protein folding. More specifically, we assume that mutations inflict fitness penalties proportional to the extent that they unfold proteins. We find that decreasing N can cause phase transition-like behavior from survival to extinction, which motivates the concept of lethal isolation. Furthermore, we find that lethal mutagenesis and lethal isolation interact synergistically, which may have clinical implications for treating infections. Broadly, we conclude that stably folded proteins are only possible in ecological settings that support sufficiently large populations.'),
(85588, 2012, 'plos', 'Molecular constraints on synaptic tagging and maintenance of long-term potentiation: a predictive model', 'Smolen, Paul|Baxter, Douglas A|Byrne, John H', 'Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, The University of Texas Medical School at Houston, Houston, Texas, United States of America. Paul.D.Smolen@uth.tmc.edu|Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, The University of Texas Medical School at Houston, Houston, Texas, United States of America. Paul.D.Smolen@uth.tmc.edu|Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, The University of Texas Medical School at Houston, Houston, Texas, United States of America. Paul.D.Smolen@uth.tmc.edu', 'United States|United States|United States', 27, 'Humans|Long-Term Potentiation|Models, Biological|Protein Kinase C|Stochastic Processes|Synapses', 'Journal Article', '10.1371/journal.pcbi.1002620', '22876169', 'Protein synthesis-dependent, late long-term potentiation (LTP) and depression (LTD) at glutamatergic hippocampal synapses are well characterized examples of long-term synaptic plasticity. Persistent increased activity of protein kinase M xcexb6 (PKMxcexb6) is thought essential for maintaining LTP. Additional spatial and temporal features that govern LTP and LTD induction are embodied in the synaptic tagging and capture (STC) and cross capture hypotheses. Only synapses that have been tagged by a stimulus sufficient for LTP and learning can capture PKMxcexb6. A model was developed to simulate the dynamics of key molecules required for LTP and LTD. The model concisely represents relationships between tagging, capture, LTD, and LTP maintenance. The model successfully simulated LTP maintained by persistent synaptic PKMxcexb6, STC, LTD, and cross capture, and makes testable predictions concerning the dynamics of PKMxcexb6. The maintenance of LTP, and consequently of at least some forms of long-term memory, is predicted to require continual positive feedback in which PKMxcexb6 enhances its own synthesis only at potentiated synapses. This feedback underlies bistability in the activity of PKMxcexb6. Second, cross capture requires the induction of LTD to induce dendritic PKMxcexb6 synthesis, although this may require tagging of a nearby synapse for LTP. The model also simulates the effects of PKMxcexb6 inhibition, and makes additional predictions for the dynamics of CaM kinases. Experiments testing the above predictions would significantly advance the understanding of memory maintenance.'),
(85589, 2012, 'plos', 'Alternative protein-protein interfaces are frequent exceptions', 'Hamp, Tobias|Rost, Burkhard', 'TUM, Bioinformatik - I12, Informatik, Garching, Germany.|TUM, Bioinformatik - I12, Informatik, Garching, Germany.', 'Germany|Germany', 23, 'Binding Sites|Proteins', 'Journal Article', '10.1371/journal.pcbi.1002623', '22876170', 'The intricate molecular details of protein-protein interactions (PPIs) are crucial for function. Therefore, measuring the same interacting protein pair again, we expect the same result. This work measured the similarity in the molecular details of interaction for the same and for homologous protein pairs between different experiments. All scores analyzed suggested that different experiments often find exceptions in the interfaces of similar PPIs: up to 22% of all comparisons revealed some differences even for sequence-identical pairs of proteins. The corresponding number for pairs of close homologs reached 68%. Conversely, the interfaces differed entirely for 12-29% of all comparisons. All these estimates were calculated after redundancy reduction. The magnitude of interface differences ranged from subtle to the extreme, as illustrated by a few examples. An extreme case was a change of the interacting domains between two observations of the same biological interaction. One reason for different interfaces was the number of copies of an interaction in the same complex: the probability of observing alternative binding modes increases with the number of copies. Even after removing the special cases with alternative hetero-interfaces to the same homomer, a substantial variability remained. Our results strongly support the surprising notion that there are many alternative solutions to make the intricate molecular details of PPIs crucial for function.'),
(85590, 2012, 'plos', 'Inferring dynamic signatures of microbes in complex host ecosystems', 'Gerber, Georg K|Onderdonk, Andrew B|Bry, Lynn', 'Department of Pathology, Brigham and Womens Hospital, Boston, Massachusetts, United States of America.|Department of Pathology, Brigham and Womens Hospital, Boston, Massachusetts, United States of America.|Department of Pathology, Brigham and Womens Hospital, Boston, Massachusetts, United States of America.', 'United States|United States|United States', 32, 'Algorithms|Automation|Ecosystem|Humans|Metagenome|Phylogeny|RNA, Ribosomal, 16S', 'Journal Article', '10.1371/journal.pcbi.1002624', '22876171', 'The human gut microbiota comprise a complex and dynamic ecosystem that profoundly affects host development and physiology. Standard approaches for analyzing time-series data of the microbiota involve computation of measures of ecological community diversity at each time-point, or measures of dissimilarity between pairs of time-points. Although these approaches, which treat data as static snapshots of microbial communities, can identify shifts in overall community structure, they fail to capture the dynamic properties of individual members of the microbiota and their contributions to the underlying time-varying behavior of host ecosystems. To address the limitations of current methods, we present a computational framework that uses continuous-time dynamical models coupled with Bayesian dimensionality adaptation methods to identify time-dependent signatures of individual microbial taxa within a host as well as across multiple hosts. We apply our framework to a publicly available dataset of 16S rRNA gene sequences from stool samples collected over ten months from multiple human subjects, each of whom received repeated courses of oral antibiotics. Using new diversity measures enabled by our framework, we discover groups of both phylogenetically close and distant bacterial taxa that exhibit consensus responses to antibiotic exposure across multiple human subjects. These consensus responses reveal a timeline for equilibration of sub-communities of micro-organisms with distinct physiologies, yielding insights into the successive changes that occur in microbial populations in the human gut after antibiotic treatments. Additionally, our framework leverages microbial signatures shared among human subjects to automatically design optimal experiments to interrogate dynamic properties of the microbiota in new studies. Overall, our approach provides a powerful, general-purpose framework for understanding the dynamic behaviors of complex microbial ecosystems, which we believe will prove instrumental for future studies in this field.'),
(85591, 2012, 'plos', 'The role of local backrub motions in evolved and designed mutations', 'Keedy, Daniel A|Georgiev, Ivelin|Triplett, Edward B|Donald, Bruce R|Richardson, David C|Richardson, Jane S', 'Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, United States of America. daniel.keedy@gmail.com|Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, United States of America. daniel.keedy@gmail.com|Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, United States of America. daniel.keedy@gmail.com|Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, United States of America. daniel.keedy@gmail.com|Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, United States of America. daniel.keedy@gmail.com|Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, United States of America. daniel.keedy@gmail.com', 'United States|United States|United States|United States|United States|United States', 23, 'Algorithms|Amino Acids|Movement|Mutation|Uncertainty', 'Journal Article', '10.1371/journal.pcbi.1002629', '22876172', 'Amino acid substitutions in protein structures often require subtle backbone adjustments that are difficult to model in atomic detail. An improved ability to predict realistic backbone changes in response to engineered mutations would be of great utility for the blossoming field of rational protein design. One model that has recently grown in acceptance is the backrub motion, a low-energy dipeptide rotation with single-peptide counter-rotations, that is coupled to dynamic two-state sidechain rotamer jumps, as evidenced by alternate conformations in very high-resolution crystal structures. It has been speculated that backrubs may facilitate sequence changes equally well as rotamer changes. However, backrub-induced shifts and experimental uncertainty are of similar magnitude for backbone atoms in even high-resolution structures, so comparison of wildtype-vs.-mutant crystal structure pairs is not sufficient to directly link backrubs to mutations. In this study, we use two alternative approaches that bypass this limitation. First, we use a quality-filtered structure database to aggregate many examples for precisely defined motifs with single amino acid differences, and find that the effectively amplified backbone differences closely resemble backrubs. Second, we directly apply a provably-accurate, backrub-enabled protein design algorithm to idealized versions of these motifs, and discover that the lowest-energy computed models match the average-coordinate experimental structures. These results support the hypothesis that backrubs participate in natural protein evolution and validate their continued use for design of synthetic proteins.'),
(85592, 2012, 'plos', 'Retraction: Multi-scale inference of interaction rules in animal groups using Bayesian model selection', '-', '-', '-', 0, '-', 'Retraction of Publication', '10.1371/annotation/7bc3a37e-db82-4813-8242-7d34877125c5', '22879819', '-'),
(85593, 2012, 'plos', 'A topological paradigm for hippocampal spatial map formation using persistent homology', 'Dabaghian, Y|Mémoli, F|Frank, L|Carlsson, G', 'Jan & Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, Texas, United States of America. dabaghia@bcm.edu|Jan & Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, Texas, United States of America. dabaghia@bcm.edu|Jan & Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, Texas, United States of America. dabaghia@bcm.edu|Jan & Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, Texas, United States of America. dabaghia@bcm.edu', 'United States|United States|United States|United States', 88, 'Action Potentials|Animals|Hippocampus|Models, Theoretical|Rats', 'Journal Article', '10.1371/journal.pcbi.1002581', '22912564', 'An animals ability to navigate through space rests on its ability to create a mental map of its environment. The hippocampus is the brain region centrally responsible for such maps, and it has been assumed to encode geometric information (distances, angles). Given, however, that hippocampal output consists of patterns of spiking across many neurons, and downstream regions must be able to translate those patterns into accurate information about an animals spatial environment, we hypothesized that 1) the temporal pattern of neuronal firing, particularly co-firing, is key to decoding spatial information, and 2) since co-firing implies spatial overlap of place fields, a map encoded by co-firing will be based on connectivity and adjacency, i.e., it will be a topological map. Here we test this topological hypothesis with a simple model of hippocampal activity, varying three parameters (firing rate, place field size, and number of neurons) in computer simulations of rat trajectories in three topologically and geometrically distinct test environments. Using a computational algorithm based on recently developed tools from Persistent Homology theory in the field of algebraic topology, we find that the patterns of neuronal co-firing can, in fact, convey topological information about the environment in a biologically realistic length of time. Furthermore, our simulations reveal a learning region that highlights the interplay between the parameters in combining to produce hippocampal states that are more or less adept at map formation. For example, within the learning region a lower number of neurons firing can be compensated by adjustments in firing rate or place field size, but beyond a certain point map formation begins to fail. We propose that this learning region provides a coherent theoretical lens through which to view conditions that impair spatial learning by altering place cell firing rates or spatial specificity.'),
(85594, 2012, 'plos', 'Literature based drug interaction prediction with clinical assessment using electronic medical records: novel myopathy associated drug interactions', 'Duke, Jon D|Han, Xu|Wang, Zhiping|Subhadarshini, Abhinita|Karnik, Shreyas D|Li, Xiaochun|Hall, Stephen D|Jin, Yan|Callaghan, J Thomas|Overhage, Marcus J|Flockhart, David A|Strother, R Matthew|Quinney, Sara K|Li, Lang', 'Regenstrief Institute, Indianapolis, Indiana, United States of America.|Regenstrief Institute, Indianapolis, Indiana, United States of America.|Regenstrief Institute, Indianapolis, Indiana, United States of America.|Regenstrief Institute, Indianapolis, Indiana, United States of America.|Regenstrief Institute, Indianapolis, Indiana, United States of America.|Regenstrief Institute, Indianapolis, Indiana, United States of America.|Regenstrief Institute, Indianapolis, Indiana, United States of America.|Regenstrief Institute, Indianapolis, Indiana, United States of America.|Regenstrief Institute, Indianapolis, Indiana, United States of America.|Regenstrief Institute, Indianapolis, Indiana, United States of America.|Regenstrief Institute, Indianapolis, Indiana, United States of America.|Regenstrief Institute, Indianapolis, Indiana, United States of America.|Regenstrief Institute, Indianapolis, Indiana, United States of America.|Regenstrief Institute, Indianapolis, Indiana, United States of America.', 'India|India|India|India|India|India|India|India|India|India|India|India|India|India', 69, 'Alprazolam|Databases, Factual|Drug Interactions|Duloxetine Hydrochloride|Electronic Health Records|Humans|Indoles|Loratadine|Muscular Diseases|Promethazine|Simvastatin|Thiophenes', 'Journal Article', '10.1371/journal.pcbi.1002614', '22912565', 'Drug-drug interactions (DDIs) are a common cause of adverse drug events. In this paper, we combined a literature discovery approach with analysis of a large electronic medical record database method to predict and evaluate novel DDIs. We predicted an initial set of 13197 potential DDIs based on substrates and inhibitors of cytochrome P450 (CYP) metabolism enzymes identified from published in vitro pharmacology experiments. Using a clinical repository of over 800,000 patients, we narrowed this theoretical set of DDIs to 3670 drug pairs actually taken by patients. Finally, we sought to identify novel combinations that synergistically increased the risk of myopathy. Five pairs were identified with their p-values less than 1E-06: loratadine and simvastatin (relative risk or RRxe2x80x8a=xe2x80x8a1.69), loratadine and alprazolam (RRxe2x80x8a=xe2x80x8a1.86), loratadine and duloxetine (RRxe2x80x8a=xe2x80x8a1.94), loratadine and ropinirole (RRxe2x80x8a=xe2x80x8a3.21), and promethazine and tegaserod (RRxe2x80x8a=xe2x80x8a3.00). When taken together, each drug pair showed a significantly increased risk of myopathy when compared to the expected additive myopathy risk from taking either of the drugs alone. Based on additional literature data on in vitro drug metabolism and inhibition potency, loratadine and simvastatin and tegaserod and promethazine were predicted to have a strong DDI through the CYP3A4 and CYP2D6 enzymes, respectively. This new translational biomedical informatics approach supports not only detection of new clinically significant DDI signals, but also evaluation of their potential molecular mechanisms.'),
(85595, 2012, 'plos', 'Hybrid models and biological model reduction with PyDSTool', 'Clewley, Robert', 'Neuroscience Institute, Georgia State University, Atlanta, Georgia, United States of America. rclewley@gsu.edu', 'Georgia', 41, 'Biophysics|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002628', '22912566', 'The PyDSTool software environment is designed to develop, simulate, and analyze dynamical systems models, particularly for biological applications. Unlike the engineering application focus and graphical specification environments of most general purpose simulation tools, PyDSTool provides a programmatic environment well suited to exploratory data- and hypothesis-driven biological modeling problems. In this work, we show how the environment facilitates the application of hybrid dynamical modeling to the reverse engineering of complex biophysical dynamics, in this case, of an excitable membrane. The example demonstrates how the software provides novel tools that support the inference and validation of mechanistic hypotheses and the inclusion of data constraints in both quantitative and qualitative ways. The biophysical application is broadly relevant to models in the biosciences. The open source and platform-independent PyDSTool package is freely available under the BSD license from http://sourceforge.net/projects/pydstool/. The hosting service provides links to documentation and online forums for user support.'),
(85596, 2012, 'plos', 'A canonical model of multistability and scale-invariance in biological systems', 'Freyer, Frank|Roberts, James A|Ritter, Petra|Breakspear, Michael', 'Bernstein Focus State Dependencies of Learning & Bernstein Center for Computational Neuroscience, Berlin, Germany.|Bernstein Focus State Dependencies of Learning & Bernstein Center for Computational Neuroscience, Berlin, Germany.|Bernstein Focus State Dependencies of Learning & Bernstein Center for Computational Neuroscience, Berlin, Germany.|Bernstein Focus State Dependencies of Learning & Bernstein Center for Computational Neuroscience, Berlin, Germany.', 'Germany|Germany|Germany|Germany', 69, 'Biophysics|Gene Regulatory Networks|Humans|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1002634', '22912567', 'Multistability and scale-invariant fluctuations occur in a wide variety of biological organisms from bacteria to humans as well as financial, chemical and complex physical systems. Multistability refers to noise driven switches between multiple weakly stable states. Scale-invariant fluctuations arise when there is an approximately constant ratio between the mean and standard deviation of a systems fluctuations. Both are an important property of human perception, movement, decision making and computation and they occur together in the human alpha rhythm, imparting it with complex dynamical behavior. Here, we elucidate their fundamental dynamical mechanisms in a canonical model of nonlinear bifurcations under stochastic fluctuations. We find that the co-occurrence of multistability and scale-invariant fluctuations mandates two important dynamical properties: Multistability arises in the presence of a subcritical Hopf bifurcation, which generates co-existing attractors, whilst the introduction of multiplicative (state-dependent) noise ensures that as the system jumps between these attractors, fluctuations remain in constant proportion to their mean and their temporal statistics become long-tailed. The simple algebraic construction of this model affords a systematic analysis of the contribution of stochastic and nonlinear processes to cortical rhythms, complementing a recently proposed biophysical model. Similar dynamics also occur in a kinetic model of gene regulation, suggesting universality across a broad class of biological phenomena.'),
(85597, 2012, 'plos', 'High resolution genome wide binding event finding and motif discovery reveals transcription factor spatial binding constraints', 'Guo, Yuchun|Mahony, Shaun|Gifford, David K', 'Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States', 133, 'Binding Sites|Chromatin Immunoprecipitation|Genome, Human|Humans|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002638', '22912568', 'An essential component of genome function is the syntax of genomic regulatory elements that determine how diverse transcription factors interact to orchestrate a program of regulatory control. A precise characterization of in vivo spacing constraints between key transcription factors would reveal key aspects of this genomic regulatory language. To discover novel transcription factor spatial binding constraints in vivo, we developed a new integrative computational method, genome wide event finding and motif discovery (GEM). GEM resolves ChIP data into explanatory motifs and binding events at high spatial resolution by linking binding event discovery and motif discovery with positional priors in the context of a generative probabilistic model of ChIP data and genome sequence. GEM analysis of 63 transcription factors in 214 ENCODE human ChIP-Seq experiments recovers more known factor motifs than other contemporary methods, and discovers six new motifs for factors with unknown binding specificity. GEMs adaptive learning of binding-event read distributions allows it to further improve upon previous methods for processing ChIP-Seq and ChIP-exo data to yield unsurpassed spatial resolution and discovery of closely spaced binding events of the same factor. In a systematic analysis of in vivo sequence-specific transcription factor binding using GEM, we have found hundreds of spatial binding constraints between factors. GEM found 37 examples of factor binding constraints in mouse ES cells, including strong distance-specific constraints between Klf4 and other key regulatory factors. In human ENCODE data, GEM found 390 examples of spatially constrained pair-wise binding, including such novel pairs as c-Fos:c-Jun/USF1, CTCF/Egr1, and HNF4A/FOXA1. The discovery of new factor-factor spatial constraints in ChIP data is significant because it proposes testable models for regulatory factor interactions that will help elucidate genome function and the implementation of combinatorial control.'),
(85598, 2012, 'plos', 'Intrinsic disorder in the human spliceosomal proteome', 'Korneta, Iga|Bujnicki, Janusz M', 'Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.|Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.', 'Poland|Poland', 59, 'Humans|Introns|Proteome|RNA Splicing|RNA, Messenger', 'Journal Article', '10.1371/journal.pcbi.1002641', '22912569', 'The spliceosome is a molecular machine that performs the excision of introns from eukaryotic pre-mRNAs. This macromolecular complex comprises in human cells five RNAs and over one hundred proteins. In recent years, many spliceosomal proteins have been found to exhibit intrinsic disorder, that is to lack stable native three-dimensional structure in solution. Building on the previous body of proteomic, structural and functional data, we have carried out a systematic bioinformatics analysis of intrinsic disorder in the proteome of the human spliceosome. We discovered that almost a half of the combined sequence of proteins abundant in the spliceosome is predicted to be intrinsically disordered, at least when the individual proteins are considered in isolation. The distribution of intrinsic order and disorder throughout the spliceosome is uneven, and is related to the various functions performed by the intrinsic disorder of the spliceosomal proteins in the complex. In particular, proteins involved in the secondary functions of the spliceosome, such as mRNA recognition, intron/exon definition and spliceosomal assembly and dynamics, are more disordered than proteins directly involved in assisting splicing catalysis. Conserved disordered regions in spliceosomal proteins are evolutionarily younger and less widespread than ordered domains of essential spliceosomal proteins at the core of the spliceosome, suggesting that disordered regions were added to a preexistent ordered functional core. Finally, the spliceosomal proteome contains a much higher amount of intrinsic disorder predicted to lack secondary structure than the proteome of the ribosome, another large RNP machine. This result agrees with the currently recognized different functions of proteins in these two complexes.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85599, 2012, 'plos', 'The landscape of the prion proteins structural response to mutation revealed by principal component analysis of multiple NMR ensembles', 'Gendoo, Deena M A|Harrison, Paul M', 'Department of Biology, McGill University, Montreal, Quebec, Canada.|Department of Biology, McGill University, Montreal, Quebec, Canada.', 'Canada|Canada', 10, 'Amino Acid Sequence|Animals|Humans|Mice|Molecular Sequence Data|Mutation|Nuclear Magnetic Resonance, Biomolecular|Phylogeny|Principal Component Analysis|Prions|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1002646', '22912570', 'Prion Proteins (PrP) are among a small number of proteins for which large numbers of NMR ensembles have been resolved for sequence mutants and diverse species. Here, we perform a comprehensive principle components analysis (PCA) on the tertiary structures of PrP globular proteins to discern PrP subdomains that exhibit conformational change in response to point mutations and clade-specific evolutionary sequence mutation trends. This is to our knowledge the first such large-scale analysis of multiple NMR ensembles of protein structures, and the first study of its kind for PrPs. We conducted PCA on human (nxe2x80x8a=xe2x80x8a11), mouse (nxe2x80x8a=xe2x80x8a14), and wildtype (nxe2x80x8a=xe2x80x8a21) sets of PrP globular structures, from which we identified five conformationally variable subdomains within PrP. PCA shows that different non-local patterns and rankings of variable subdomains arise for different pathogenic mutants. These subdomains may thus be key areas for initiating PrP conversion during disease. Furthermore, we have observed the conformational clustering of divergent TSE-non-susceptible species pairs, these non-phylogenetic clusterings indicate structural solutions towards TSE resistance that do not necessarily coincide with evolutionary divergence. We discuss the novelty of our approach and the importance of PrP subdomains in structural conversion during disease.'),
(85600, 2012, 'plos', 'Activity dependent degeneration explains hub vulnerability in Alzheimers disease', 'de Haan, Willem|Mott, Katherine|van Straaten, Elisabeth C W|Scheltens, Philip|Stam, Cornelis J', 'Department of Clinical Neurophysiology and MEG, VU University Medical Center, Amsterdam, The Netherlands. w.dehaan@vumc.nl|Department of Clinical Neurophysiology and MEG, VU University Medical Center, Amsterdam, The Netherlands. w.dehaan@vumc.nl|Department of Clinical Neurophysiology and MEG, VU University Medical Center, Amsterdam, The Netherlands. w.dehaan@vumc.nl|Department of Clinical Neurophysiology and MEG, VU University Medical Center, Amsterdam, The Netherlands. w.dehaan@vumc.nl|Department of Clinical Neurophysiology and MEG, VU University Medical Center, Amsterdam, The Netherlands. w.dehaan@vumc.nl', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 0, 'Action Potentials|Alzheimer Disease|Humans', 'Journal Article', '10.1371/journal.pcbi.1002582', '22915996', 'Brain connectivity studies have revealed that highly connected hub regions are particularly vulnerable to Alzheimer pathology: they show marked amyloid-xcexb2 deposition at an early stage. Recently, excessive local neuronal activity has been shown to increase amyloid deposition. In this study we use a computational model to test the hypothesis that hub regions possess the highest level of activity and that hub vulnerability in Alzheimers disease is due to this feature. Cortical brain regions were modeled as neural masses, each describing the average activity (spike density and spectral power) of a large number of interconnected excitatory and inhibitory neurons. The large-scale network consisted of 78 neural masses, connected according to a human DTI-based cortical topology. Spike density and spectral power were positively correlated with structural and functional node degrees, confirming the high activity of hub regions, also offering a possible explanation for high resting state Default Mode Network activity. Activity dependent degeneration (ADD) was simulated by lowering synaptic strength as a function of the spike density of the main excitatory neurons, and compared to random degeneration. Resulting structural and functional network changes were assessed with graph theoretical analysis. Effects of ADD included oscillatory slowing, loss of spectral power and long-range synchronization, hub vulnerability, and disrupted functional network topology. Observed transient increases in spike density and functional connectivity match reports in Mild Cognitive Impairment (MCI) patients, and may not be compensatory but pathological. In conclusion, the assumption of excessive neuronal activity leading to degeneration provides a possible explanation for hub vulnerability in Alzheimers disease, supported by the observed relation between connectivity and activity and the reproduction of several neurophysiologic hallmarks. The insight that neuronal activity might play a causal role in Alzheimers disease can have implications for early detection and interventional strategies.'),
(85601, 2012, 'plos', 'Combining the finite element method with structural connectome-based analysis for modeling neurotrauma: connectome neurotrauma mechanics', 'Kraft, Reuben H|McKee, Phillip Justin|Dagro, Amy M|Grafton, Scott T', 'Soldier Protection Sciences Branch, Protection Division, U.S. Army Research Laboratory, Aberdeen Proving Ground, Maryland, United States of America. reuben.kraft@gmail.com|Soldier Protection Sciences Branch, Protection Division, U.S. Army Research Laboratory, Aberdeen Proving Ground, Maryland, United States of America. reuben.kraft@gmail.com|Soldier Protection Sciences Branch, Protection Division, U.S. Army Research Laboratory, Aberdeen Proving Ground, Maryland, United States of America. reuben.kraft@gmail.com|Soldier Protection Sciences Branch, Protection Division, U.S. Army Research Laboratory, Aberdeen Proving Ground, Maryland, United States of America. reuben.kraft@gmail.com', 'United States|United States|United States|United States', 52, 'Brain Injuries|Finite Element Analysis|Humans|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002619', '22915997', 'This article presents the integration of brain injury biomechanics and graph theoretical analysis of neuronal connections, or connectomics, to form a neurocomputational model that captures spatiotemporal characteristics of trauma. We relate localized mechanical brain damage predicted from biofidelic finite element simulations of the human head subjected to impact with degradation in the structural connectome for a single individual. The finite element model incorporates various length scales into the full head simulations by including anisotropic constitutive laws informed by diffusion tensor imaging. Coupling between the finite element analysis and network-based tools is established through experimentally-based cellular injury thresholds for white matter regions. Once edges are degraded, graph theoretical measures are computed on the damaged network. For a frontal impact, the simulations predict that the temporal and occipital regions undergo the most axonal strain and strain rate at short times (less than 24 hrs), which leads to cellular death initiation, which results in damage that shows dependence on angle of impact and underlying microstructure of brain tissue. The monotonic cellular death relationships predict a spatiotemporal change of structural damage. Interestingly, at 96 hrs post-impact, computations predict no network nodes were completely disconnected from the network, despite significant damage to network edges. At early times (t < 24 hrs) network measures of global and local efficiency were degraded little, however, as time increased to 96 hrs the network properties were significantly reduced. In the future, this computational framework could help inform functional networks from physics-based structural brain biomechanics to obtain not only a biomechanics-based understanding of injury, but also neurophysiological insight.'),
(85602, 2012, 'plos', 'Single nucleotide polymorphisms can create alternative polyadenylation signals and affect gene expression through loss of microRNA-regulation', 'Thomas, Laurent F|Sætrom, Pål', 'Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.', 'Norway|Norway', 29, '3 Untranslated Regions|Alleles|Gene Expression Regulation|Genetic Predisposition to Disease|Genotype|Humans|MicroRNAs|Mutation|Poly A|Polymorphism, Single Nucleotide|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002621', '22915998', 'Alternative polyadenylation (APA) can for example occur when a protein-coding gene has several polyadenylation (polyA) signals in its last exon, resulting in messenger RNAs (mRNAs) with different 3 untranslated region (UTR) lengths. Different 3UTR lengths can give different microRNA (miRNA) regulation such that shortened transcripts have increased expression. The APA process is part of human cells natural regulatory processes, but APA also seems to play an important role in many human diseases. Although altered APA in disease can have many causes, we reasoned that mutations in DNA elements that are important for the polyA process, such as the polyA signal and the downstream GU-rich region, can be one important mechanism. To test this hypothesis, we identified single nucleotide polymorphisms (SNPs) that can create or disrupt APA signals (APA-SNPs). By using a data-integrative approach, we show that APA-SNPs can affect 3UTR length, miRNA regulation, and mRNA expression--both between homozygote individuals and within heterozygote individuals. Furthermore, we show that a significant fraction of the alleles that cause APA are strongly and positively linked with alleles found by genome-wide studies to be associated with disease. Our results confirm that APA-SNPs can give altered gene regulation and that APA alleles that give shortened transcripts and increased gene expression can be important hereditary causes for disease.'),
(85603, 2012, 'plos', 'Unifying time to contact estimation and collision avoidance across species', 'Keil, Matthias S|Lxc3xb3pez-Moliner, Joan', 'University of Barcelona, Faculty for Psychology, Basic Psychology Department, Barcelona, Spain. matskeil@ub.edu|University of Barcelona, Faculty for Psychology, Basic Psychology Department, Barcelona, Spain. matskeil@ub.edu', 'Spain|Spain', 12, 'Animals|Humans|Models, Theoretical|Neurons|Psychophysics|Species Specificity|tau Proteins', 'Journal Article', '10.1371/journal.pcbi.1002625', '22915999', 'The xcfx84-function and the xcexb7-function are phenomenological models that are widely used in the context of timing interceptive actions and collision avoidance, respectively. Both models were previously considered to be unrelated to each other: xcfx84 is a decreasing function that provides an estimation of time-to-contact (ttc) in the early phase of an object approach, in contrast, g has a maximum before ttc. Furthermore, it is not clear how both functions could be implemented at the neuronal level in a biophysically plausible fashion. Here we propose a new framework--the corrected modified Tau function--capable of predicting both xcfx84-type (xcfx84(cm)) and g-type (t(mod)) responses. The outstanding property of our new framework is its resilience to noise. We show that t(mod) can be derived from a firing rate equation, and, as g, serves to describe the response curves of collision sensitive neurons. Furthermore, we show that tcm predicts the psychophysical performance of subjects determining ttc. Our new framework is thus validated successfully against published and novel experimental data. Within the framework, links between xcfx84-type and xcexb7-type neurons are established. Therefore, it could possibly serve as a model for explaining the co-occurrence of such neurons in the brain.'),
(85604, 2012, 'plos', 'Evolution of stress response in the face of unreliable environmental signals', 'Arnoldini, Markus|Mostowy, Rafal|Bonhoeffer, Sebastian|Ackermann, Martin', 'Institute of Biogeochemistry and Pollutant Dynamics, Department of Environmental Systems Science, ETH Zurich, Switzerland. markus.arnoldini@env.ethz.ch|Institute of Biogeochemistry and Pollutant Dynamics, Department of Environmental Systems Science, ETH Zurich, Switzerland. markus.arnoldini@env.ethz.ch|Institute of Biogeochemistry and Pollutant Dynamics, Department of Environmental Systems Science, ETH Zurich, Switzerland. markus.arnoldini@env.ethz.ch|Institute of Biogeochemistry and Pollutant Dynamics, Department of Environmental Systems Science, ETH Zurich, Switzerland. markus.arnoldini@env.ethz.ch', 'Switzerland|Switzerland|Switzerland|Switzerland', 36, 'Biological Evolution|Models, Theoretical|Stress, Physiological', 'Journal Article', '10.1371/journal.pcbi.1002627', '22916000', 'Most organisms live in ever-changing environments, and have to cope with a range of different conditions. Often, the set of biological traits that are needed to grow, reproduce, and survive varies between conditions. As a consequence, organisms have evolved sensory systems to detect environmental signals, and to modify the expression of biological traits in response. However, there are limits to the ability of such plastic responses to cope with changing environments. Sometimes, environmental shifts might occur suddenly, and without preceding signals, so that organisms might not have time to react. Other times, signals might be unreliable, causing organisms to prepare themselves for changes that then do not occur. Here, we focus on such unreliable signals that indicate the onset of adverse conditions. We use analytical and individual-based models to investigate the evolution of simple rules that organisms use to decide whether or not to switch to a protective state. We find evolutionary transitions towards organisms that use a combination of random switching and switching in response to the signal. We also observe that, in spatially heterogeneous environments, selection on the switching strategy depends on the composition of the population, and on population size. These results are in line with recent experiments that showed that many unicellular organisms can attain different phenotypic states in a probabilistic manner, and lead to testable predictions about how this could help organisms cope with unreliable signals.'),
(85605, 2012, 'plos', 'Gene network homology in prokaryotes using a similarity search approach: queries of quorum sensing signal transduction', 'Quan, David N|Bentley, William E', 'Fischell Department of Bioengineering, University of Maryland College Park, College Park, Maryland, United States of America.|Fischell Department of Bioengineering, University of Maryland College Park, College Park, Maryland, United States of America.', 'United States|United States', 19, 'Bacterial Physiological Phenomena|Gene Regulatory Networks|Operon|Prokaryotic Cells|Quorum Sensing|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002637', '22916001', 'Bacterial cell-cell communication is mediated by small signaling molecules known as autoinducers. Importantly, autoinducer-2 (AI-2) is synthesized via the enzyme LuxS in over 80 species, some of which mediate their pathogenicity by recognizing and transducing this signal in a cell density dependent manner. AI-2 mediated phenotypes are not well understood however, as the means for signal transduction appears varied among species, while AI-2 synthesis processes appear conserved. Approaches to reveal the recognition pathways of AI-2 will shed light on pathogenicity as we believe recognition of the signal is likely as important, if not more, than the signal synthesis. LMNAST (Local Modular Network Alignment Similarity Tool) uses a local similarity search heuristic to study gene order, generating homology hits for the genomic arrangement of a query gene sequence. We develop and apply this tool for the E. coli lac and LuxS regulated (Lsr) systems. Lsr is of great interest as it mediates AI-2 uptake and processing. Both test searches generated results that were subsequently analyzed through a number of different lenses, each with its own level of granularity, from a binary phylogenetic representation down to trackback plots that preserve genomic organizational information. Through a survey of these results, we demonstrate the identification of orthologs, paralogs, hitchhiking genes, gene loss, gene rearrangement within an operon context, and also horizontal gene transfer (HGT). We found a variety of operon structures that are consistent with our hypothesis that the signal can be perceived and transduced by homologous protein complexes, while their regulation may be key to defining subsequent phenotypic behavior.'),
(85606, 2012, 'plos', 'A network-based approach for predicting missing pathway interactions', 'Navlakha, Saket|Gitter, Anthony|Bar-Joseph, Ziv', 'School of Computer Science and Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|School of Computer Science and Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|School of Computer Science and Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.', 'United States|United States|United States', 22, 'Algorithms|Osmotic Pressure|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002640', '22916002', 'Embedded within large-scale protein interaction networks are signaling pathways that encode response cascades in the cell. Unfortunately, even for well-studied species like S. cerevisiae, only a fraction of all true protein interactions are known, which makes it difficult to reason about the exact flow of signals and the corresponding causal relations in the network. To help address this problem, we introduce a framework for predicting new interactions that aid connectivity between upstream proteins (sources) and downstream transcription factors (targets) of a particular pathway. Our algorithms attempt to globally minimize the distance between sources and targets by finding a small set of shortcut edges to add to the network. Unlike existing algorithms for predicting general protein interactions, by focusing on proteins involved in specific responses our approach homes-in on pathway-consistent interactions. We applied our method to extend pathways in osmotic stress response in yeast and identified several missing interactions, some of which are supported by published reports. We also performed experiments that support a novel interaction not previously reported. Our framework is general and may be applicable to edge prediction problems in other domains.'),
(85607, 2012, 'plos', 'Locust dynamics: behavioral phase change and swarming', 'Topaz, Chad M|DOrsogna, Maria R|Edelstein-Keshet, Leah|Bernoff, Andrew J', 'Department of Mathematics, Statistics, and Computer Science, Macalester College, Saint Paul, Minnesota, United States of America. ctopaz@macalester.edu|Department of Mathematics, Statistics, and Computer Science, Macalester College, Saint Paul, Minnesota, United States of America. ctopaz@macalester.edu|Department of Mathematics, Statistics, and Computer Science, Macalester College, Saint Paul, Minnesota, United States of America. ctopaz@macalester.edu|Department of Mathematics, Statistics, and Computer Science, Macalester College, Saint Paul, Minnesota, United States of America. ctopaz@macalester.edu', 'United States|United States|United States|United States', 45, 'Animals|Behavior, Animal|Grasshoppers|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002642', '22916003', 'Locusts exhibit two interconvertible behavioral phases, solitarious and gregarious. While solitarious individuals are repelled from other locusts, gregarious insects are attracted to conspecifics and can form large aggregations such as marching hopper bands. Numerous biological experiments at the individual level have shown how crowding biases conversion towards the gregarious form. To understand the formation of marching locust hopper bands, we study phase change at the collective level, and in a quantitative framework. Specifically, we construct a partial integrodifferential equation model incorporating the interplay between phase change and spatial movement at the individual level in order to predict the dynamics of hopper band formation at the population level. Stability analysis of our model reveals conditions for an outbreak, characterized by a large scale transition to the gregarious phase. A model reduction enables quantification of the temporal dynamics of each phase, of the proportion of the population that will eventually gregarize, and of the time scale for this to occur. Numerical simulations provide descriptions of the aggregations structure and reveal transiently traveling clumps of gregarious insects. Our predictions of aggregation and mass gregarization suggest several possible future biological experiments.'),
(85608, 2012, 'plos', 'A simple histone code opens many paths to epigenetics', 'Sneppen, Kim|Dodd, Ian B', 'Niels Bohr Institute/CMOL, University of Copenhagen, Copenhagen, Denmark. sneppen@nbi.dk|Niels Bohr Institute/CMOL, University of Copenhagen, Copenhagen, Denmark. sneppen@nbi.dk', 'Denmark|Denmark', 29, 'DNA Replication|Epigenesis, Genetic|Histones', 'Journal Article', '10.1371/journal.pcbi.1002643', '22916004', 'Nucleosomes can be covalently modified by addition of various chemical groups on several of their exposed histone amino acids. These modifications are added and removed by enzymes (writers) and can be recognized by nucleosome-binding proteins (readers). Linking a reader domain and a writer domain that recognize and create the same modification state should allow nucleosomes in a particular modification state to recruit enzymes that create that modification state on nearby nucleosomes. This positive feedback has the potential to provide the alternative stable and heritable states required for epigenetic memory. However, analysis of simple histone codes involving interconversions between only two or three types of modified nucleosomes has revealed only a few circuit designs that allow heritable bistability. Here we show by computer simulations that a histone code involving alternative modifications at two histone positions, producing four modification states, combined with reader-writer proteins able to distinguish these states, allows for hundreds of different circuits capable of heritable bistability. These expanded possibilities result from multiple ways of generating two-step cooperativity in the positive feedback--through alternative pathways and an additional, novel cooperativity motif. Our analysis reveals other properties of such epigenetic circuits. They are most robust when the dominant nucleosome types are different at both modification positions and are not the type inserted after DNA replication. The dominant nucleosome types often recruit enzymes that create their own type or destroy the opposing type, but never catalyze their own destruction. The circuits appear to be evolutionary accessible, most circuits can be changed stepwise into almost any other circuit without losing heritable bistability. Thus, our analysis indicates that systems that utilize an expanded histone code have huge potential for generating stable and heritable nucleosome modification states and identifies the critical features of such systems.'),
(85609, 2012, 'plos', 'Assessing the relative stability of dimer interfaces in g protein-coupled receptors', 'Johnston, Jennifer M|Wang, Hao|Provasi, Davide|Filizola, Marta', 'Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York, United States of America.', 'United States|United States|United States|United States', 80, 'Dimerization|Humans|Lipid Bilayers|Molecular Dynamics Simulation|Molecular Structure|Receptors, G-Protein-Coupled', 'Journal Article', '10.1371/journal.pcbi.1002649', '22916005', 'Considerable evidence has accumulated in recent years suggesting that G protein-coupled receptors (GPCRs) associate in the plasma membrane to form homo- and/or heteromers. Nevertheless, the stoichiometry, fraction and lifetime of such receptor complexes in living cells remain topics of intense debate. Motivated by experimental data suggesting differing stabilities for homomers of the cognate human xcexb21- and xcexb22-adrenergic receptors, we have carried out approximately 160 microseconds of biased molecular dynamics simulations to calculate the dimerization free energy of crystal structure-based models of these receptors, interacting at two interfaces that have often been implicated in GPCR association under physiological conditions. Specifically, results are presented for simulations of coarse-grained (MARTINI-based) and atomistic representations of each receptor, in homodimeric configurations with either transmembrane helices TM1/H8 or TM4/3 at the interface, in an explicit lipid bilayer. Our results support a definite contribution to the relative stability of GPCR dimers from both interface sequence and configuration. We conclude that xcexb21- and xcexb22-adrenergic receptor homodimers with TM1/H8 at the interface are more stable than those involving TM4/3, and that this might be reconciled with experimental studies by considering a model of oligomerization in which more stable TM1 homodimers diffuse through the membrane, transiently interacting with other protomers at interfaces involving other TM helices.'),
(85610, 2012, 'plos', 'Maintaining a cognitive map in darkness: the need to fuse boundary knowledge with path integration', 'Cheung, Allen|Ball, David|Milford, Michael|Wyeth, Gordon|Wiles, Janet', 'The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia. a.cheung@uq.edu.au|The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia. a.cheung@uq.edu.au|The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia. a.cheung@uq.edu.au|The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia. a.cheung@uq.edu.au|The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia. a.cheung@uq.edu.au', 'Australia|Australia|Australia|Australia|Australia', 36, 'Animals|Cognition|Darkness|Rats|Vision, Ocular', 'Journal Article', '10.1371/journal.pcbi.1002651', '22916006', 'Spatial navigation requires the processing of complex, disparate and often ambiguous sensory data. The neurocomputations underpinning this vital ability remain poorly understood. Controversy remains as to whether multimodal sensory information must be combined into a unified representation, consistent with Tolmans cognitive map, or whether differential activation of independent navigation modules suffice to explain observed navigation behaviour. Here we demonstrate that key neural correlates of spatial navigation in darkness cannot be explained if the path integration system acted independently of boundary (landmark) information. In vivo recordings demonstrate that the rodent head direction (HD) system becomes unstable within three minutes without vision. In contrast, rodents maintain stable place fields and grid fields for over half an hour without vision. Using a simple HD error model, we show analytically that idiothetic path integration (iPI) alone cannot be used to maintain any stable place representation beyond two to three minutes. We then use a measure of place stability based on information theoretic principles to prove that featureless boundaries alone cannot be used to improve localization above chance level. Having shown that neither iPI nor boundaries alone are sufficient, we then address the question of whether their combination is sufficient and--we conjecture--necessary to maintain place stability for prolonged periods without vision. We addressed this question in simulations and robot experiments using a navigation model comprising of a particle filter and boundary map. The model replicates published experimental results on place field and grid field stability without vision, and makes testable predictions including place field splitting and grid field rescaling if the true arena geometry differs from the acquired boundary map. We discuss our findings in light of current theories of animal navigation and neuronal computation, and elaborate on their implications and significance for the design, analysis and interpretation of experiments.'),
(85611, 2012, 'plos', 'Functional roles for synaptic-depression within a model of the fly antennal lobe', 'Rangan, Aaditya V', 'Courant Institute of Mathematical Sciences, New York University, New York, New York, United States of America. rangan@cims.nyu.edu', 'United States', 3, 'Action Potentials|Animals|Arthropod Antennae|Drosophila|Models, Theoretical|Synapses', 'Journal Article', '10.1371/journal.pcbi.1002622', '22927802', 'Several experiments indicate that there exists substantial synaptic-depression at the synapses between olfactory receptor neurons (ORNs) and neurons within the drosophila antenna lobe (AL). This synaptic-depression may be partly caused by vesicle-depletion, and partly caused by presynaptic-inhibition due to the activity of inhibitory local neurons within the AL. While it has been proposed that this synaptic-depression contributes to the nonlinear relationship between ORN and projection neuron (PN) firing-rates, the precise functional role of synaptic-depression at the ORN synapses is not yet fully understood. In this paper we propose two hypotheses linking the information-coding properties of the fly AL with the network mechanisms responsible for ORN-->AL synaptic-depression. Our first hypothesis is related to variance coding of ORN firing-rate information--once stimulation to the ORNs is sufficiently high to saturate glomerular responses, further stimulation of the ORNs increases the regularity of PN spiking activity while maintaining PN firing-rates. The second hypothesis proposes a tradeoff between spike-time reliability and coding-capacity governed by the relative contribution of vesicle-depletion and presynaptic-inhibition to ORN-->AL synaptic-depression. Synaptic-depression caused primarily by vesicle-depletion will give rise to a very reliable system, whereas an equivalent amount of synaptic-depression caused primarily by presynaptic-inhibition will give rise to a less reliable system that is more sensitive to small shifts in odor stimulation. These two hypotheses are substantiated by several small analyzable toy models of the fly AL, as well as a more physiologically realistic large-scale computational model of the fly AL involving 5 glomerular channels.'),
(85612, 2012, 'plos', 'Modeling of gap gene expression in Drosophila Kruppel mutants', 'Kozlov, Konstantin|Surkova, Svetlana|Myasnikova, Ekaterina|Reinitz, John|Samsonova, Maria', 'Department of Computational Biology/Center for Advanced Studies, St. Petersburg State Polytechnical University, St. Petersburg, Russia.|Department of Computational Biology/Center for Advanced Studies, St. Petersburg State Polytechnical University, St. Petersburg, Russia.|Department of Computational Biology/Center for Advanced Studies, St. Petersburg State Polytechnical University, St. Petersburg, Russia.|Department of Computational Biology/Center for Advanced Studies, St. Petersburg State Polytechnical University, St. Petersburg, Russia.|Department of Computational Biology/Center for Advanced Studies, St. Petersburg State Polytechnical University, St. Petersburg, Russia.', '-|-|-|-|-', 31, 'Animals|Drosophila|Drosophila Proteins|Gene Expression|Kruppel-Like Transcription Factors|Models, Theoretical|Mutation', 'Journal Article', '10.1371/journal.pcbi.1002635', '22927803', 'The segmentation gene network in Drosophila embryo solves the fundamental problem of embryonic patterning: how to establish a periodic pattern of gene expression, which determines both the positions and the identities of body segments. The gap gene network constitutes the first zygotic regulatory tier in this process. Here we have applied the systems-level approach to investigate the regulatory effect of gap gene Kruppel (Kr) on segmentation gene expression. We acquired a large dataset on the expression of gap genes in Kr null mutants and demonstrated that the expression levels of these genes are significantly reduced in the second half of cycle 14A. To explain this novel biological result we applied the gene circuit method which extracts regulatory information from spatial gene expression data. Previous attempts to use this formalism to correctly and quantitatively reproduce gap gene expression in mutants for a trunk gap gene failed, therefore here we constructed a revised model and showed that it correctly reproduces the expression patterns of gap genes in Kr null mutants. We found that the remarkable alteration of gap gene expression patterns in Kr mutants can be explained by the dynamic decrease of activating effect of Cad on a target gene and exclusion of Kr gene from the complex network of gap gene interactions, that makes it possible for other interactions, in particular, between hb and gt, to come into effect. The successful modeling of the quantitative aspects of gap gene expression in mutant for the trunk gap gene Kr is a significant achievement of this work. This result also clearly indicates that the oversimplified representation of transcriptional regulation in the previous models is one of the reasons for unsuccessful attempts of mutant simulations.'),
(85613, 2012, 'plos', 'Prediction of mutational tolerance in HIV-1 protease and reverse transcriptase using flexible backbone protein design', 'Humphris-Narayanan, Elisabeth|Akiva, Eyal|Varela, Rocco|Ó Conchúir, Shane|Kortemme, Tanja', 'Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California, United States of America.|Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California, United States of America.|Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California, United States of America.|Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California, United States of America.|Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California, United States of America.', 'United States|United States|United States|United States|United States', 16, 'HIV Protease|HIV Reverse Transcriptase|Models, Molecular|Mutation|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1002639', '22927804', 'Predicting which mutations proteins tolerate while maintaining their structure and function has important applications for modeling fundamental properties of proteins and their evolution, it also drives progress in protein design. Here we develop a computational model to predict the tolerated sequence space of HIV-1 protease reachable by single mutations. We assess the model by comparison to the observed variability in more than 50,000 HIV-1 protease sequences, one of the most comprehensive datasets on tolerated sequence space. We then extend the model to a second protein, reverse transcriptase. The model integrates multiple structural and functional constraints acting on a protein and uses ensembles of protein conformations. We find the model correctly captures a considerable fraction of protease and reverse-transcriptase mutational tolerance and shows comparable accuracy using either experimentally determined or computationally generated structural ensembles. Predictions of tolerated sequence space afforded by the model provide insights into stability-function tradeoffs in the emergence of resistance mutations and into strengths and limitations of the computational model.'),
(85614, 2012, 'plos', 'Defining the nature of thermal intermediate in 3 state folding proteins: apoflavodoxin, a study case', 'García-Fandiño, Rebeca|Bernadó, Pau|Ayuso-Tejedor, Sara|Sancho, Javier|Orozco, Modesto', 'Joint IRB BSC Program in Computational Biology, Institute for Research in Biomedicine, Barcelona, Spain.|Joint IRB BSC Program in Computational Biology, Institute for Research in Biomedicine, Barcelona, Spain.|Joint IRB BSC Program in Computational Biology, Institute for Research in Biomedicine, Barcelona, Spain.|Joint IRB BSC Program in Computational Biology, Institute for Research in Biomedicine, Barcelona, Spain.|Joint IRB BSC Program in Computational Biology, Institute for Research in Biomedicine, Barcelona, Spain.', 'Spain|Spain|Spain|Spain|Spain', 7, 'Amino Acid Sequence|Apoproteins|Flavodoxin|Kinetics|Models, Molecular|Molecular Dynamics Simulation|Molecular Sequence Data|Protein Folding|Protein Structure, Secondary', 'Journal Article', '10.1371/journal.pcbi.1002647', '22927805', 'The early stages of the thermal unfolding of apoflavodoxin have been determined by using atomistic multi microsecond-scale molecular dynamics (MD) simulations complemented with a variety of experimental techniques. Results strongly suggest that the intermediate is reached very early in the thermal unfolding process and that it has the properties of an activated form of the native state, where thermal fluctuations in the loops break loop-loop contacts. The unrestrained loops gain then kinetic energy corrupting short secondary structure elements without corrupting the core of the protein. The MD-derived ensembles agree with experimental observables and draw a picture of the intermediate state inconsistent with a well-defined structure and characteristic of a typical partially disordered protein. Our results allow us to speculate that proteins with a well packed core connected by long loops might behave as partially disordered proteins under native conditions, or alternatively behave as three state folders. Small details in the sequence, easily tunable by evolution, can yield to one or the other type of proteins.'),
(85615, 2012, 'plos', 'Diversity and noise effects in a model of homeostatic regulation of the sleep-wake cycle', 'Patriarca, Marco|Postnova, Svetlana|Braun, Hans A|Hernández-García, Emilio|Toral, Raúl', 'IFISC, Instituto de Física Interdisciplinar y Sistemas Complejos-CSIC-UIB, Campus Universitat de les Illes Balears, Palma de Mallorca, Spain. marco.patriarca@ifisc.uib-csic.es|IFISC, Instituto de Física Interdisciplinar y Sistemas Complejos-CSIC-UIB, Campus Universitat de les Illes Balears, Palma de Mallorca, Spain. marco.patriarca@ifisc.uib-csic.es|IFISC, Instituto de Física Interdisciplinar y Sistemas Complejos-CSIC-UIB, Campus Universitat de les Illes Balears, Palma de Mallorca, Spain. marco.patriarca@ifisc.uib-csic.es|IFISC, Instituto de Física Interdisciplinar y Sistemas Complejos-CSIC-UIB, Campus Universitat de les Illes Balears, Palma de Mallorca, Spain. marco.patriarca@ifisc.uib-csic.es|IFISC, Instituto de Física Interdisciplinar y Sistemas Complejos-CSIC-UIB, Campus Universitat de les Illes Balears, Palma de Mallorca, Spain. marco.patriarca@ifisc.uib-csic.es', 'Spain|Spain|Spain|Spain|Spain', 11, 'Animals|Homeostasis|Models, Biological|Neurons|Noise|Sleep|Stochastic Processes|Wakefulness', 'Journal Article', '10.1371/journal.pcbi.1002650', '22927806', 'Recent advances in sleep neurobiology have allowed development of physiologically based mathematical models of sleep regulation that account for the neuronal dynamics responsible for the regulation of sleep-wake cycles and allow detailed examination of the underlying mechanisms. Neuronal systems in general, and those involved in sleep regulation in particular, are noisy and heterogeneous by their nature. It has been shown in various systems that certain levels of noise and diversity can significantly improve signal encoding. However, these phenomena, especially the effects of diversity, are rarely considered in the models of sleep regulation. The present paper is focused on a neuron-based physiologically motivated model of sleep-wake cycles that proposes a novel mechanism of the homeostatic regulation of sleep based on the dynamics of a wake-promoting neuropeptide orexin. Here this model is generalized by the introduction of intrinsic diversity and noise in the orexin-producing neurons, in order to study the effect of their presence on the sleep-wake cycle. A simple quantitative measure of the quality of a sleep-wake cycle is introduced and used to systematically study the generalized model for different levels of noise and diversity. The model is shown to exhibit a clear diversity-induced resonance: that is, the best wake-sleep cycle turns out to correspond to an intermediate level of diversity at the synapses of the orexin-producing neurons. On the other hand, only a mild evidence of stochastic resonance is found, when the level of noise is varied. These results show that disorder, especially in the form of quenched diversity, can be a key-element for an efficient or optimal functioning of the homeostatic regulation of the sleep-wake cycle. Furthermore, this study provides an example of a constructive role of diversity in a neuronal system that can be extended beyond the system studied here.'),
(85616, 2012, 'plos', 'Evolutionary dynamics of strategic behavior in a collective-risk dilemma', 'Abou Chakra, Maria|Traulsen, Arne', 'Evolutionary Theory Group, Max-Planck-Institute for Evolutionary Biology, Plön, Germany.|Evolutionary Theory Group, Max-Planck-Institute for Evolutionary Biology, Plön, Germany.', 'Germany|Germany', 29, 'Biological Evolution|Climate Change|Humans|Risk Assessment', 'Journal Article', '10.1371/journal.pcbi.1002652', '22927807', 'A collective-risk social dilemma arises when a group must cooperate to reach a common target in order to avoid the risk of collective loss while each individual is tempted to free-ride on the contributions of others. In contrast to the prisoners dilemma or public goods games, the collective-risk dilemma encompasses the risk that all individuals lose everything. These characteristics have potential relevance for dangerous climate change and other risky social dilemmas. Cooperation is costly to the individual and it only benefits all individuals if the common target is reached. An individual thus invests without guarantee that the investment is worthwhile for anyone. If there are several subsequent stages of investment, it is not clear when individuals should contribute. For example, they could invest early, thereby signaling their willingness to cooperate in the future, constantly invest their fair share, or wait and compensate missing contributions. To investigate the strategic behavior in such situations, we have simulated the evolutionary dynamics of such collective-risk dilemmas in a finite population. Contributions depend individually on the stage of the game and on the sum of contributions made so far. Every individual takes part in many games and successful behaviors spread in the population. It turns out that constant contributors, such as constant fair sharers, quickly lose out against those who initially do not contribute, but compensate this in later stages of the game. In particular for high risks, such late contributors are favored.'),
(85617, 2012, 'plos', 'Model-free reconstruction of excitatory neuronal connectivity from calcium imaging signals', 'Stetter, Olav|Battaglia, Demian|Soriano, Jordi|Geisel, Theo', 'Max Planck Institute for Dynamics and Self-Organization, Göttingen, Germany.|Max Planck Institute for Dynamics and Self-Organization, Göttingen, Germany.|Max Planck Institute for Dynamics and Self-Organization, Göttingen, Germany.|Max Planck Institute for Dynamics and Self-Organization, Göttingen, Germany.', 'Germany|Germany|Germany|Germany', 127, 'Animals|Calcium|Cells, Cultured|Cluster Analysis|Fluorescence|Models, Biological|Neurons|Rats|Rats, Sprague-Dawley', 'Journal Article', '10.1371/journal.pcbi.1002653', '22927808', 'A systematic assessment of global neural network connectivity through direct electrophysiological assays has remained technically infeasible, even in simpler systems like dissociated neuronal cultures. We introduce an improved algorithmic approach based on Transfer Entropy to reconstruct structural connectivity from network activity monitored through calcium imaging. We focus in this study on the inference of excitatory synaptic links. Based on information theory, our method requires no prior assumptions on the statistics of neuronal firing and neuronal connections. The performance of our algorithm is benchmarked on surrogate time series of calcium fluorescence generated by the simulated dynamics of a network with known ground-truth topology. We find that the functional network topology revealed by Transfer Entropy depends qualitatively on the time-dependent dynamic state of the network (bursting or non-bursting). Thus by conditioning with respect to the global mean activity, we improve the performance of our method. This allows us to focus the analysis to specific dynamical regimes of the network in which the inferred functional connectivity is shaped by monosynaptic excitatory connections, rather than by collective synchrony. Our method can discriminate between actual causal influences between neurons and spurious non-causal correlations due to light scattering artifacts, which inherently affect the quality of fluorescence imaging. Compared to other reconstruction strategies such as cross-correlation or Granger Causality methods, our method based on improved Transfer Entropy is remarkably more accurate. In particular, it provides a good estimation of the excitatory network clustering coefficient, allowing for discrimination between weakly and strongly clustered topologies. Finally, we demonstrate the applicability of our method to analyses of real recordings of in vitro disinhibited cortical cultures where we suggest that excitatory connections are characterized by an elevated level of clustering compared to a random graph (although not extreme) and can be markedly non-local.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85618, 2012, 'plos', 'Artificial neural networks trained to detect viral and phage structural proteins', 'Seguritan, Victor|Alves, Nelson|Arnoult, Michael|Raymond, Amy|Lorimer, Don|Burgin, Alex B|Salamon, Peter|Segall, Anca M', 'Program of Computational Science, San Diego State University, San Diego, California, United States of America.|Program of Computational Science, San Diego State University, San Diego, California, United States of America.|Program of Computational Science, San Diego State University, San Diego, California, United States of America.|Program of Computational Science, San Diego State University, San Diego, California, United States of America.|Program of Computational Science, San Diego State University, San Diego, California, United States of America.|Program of Computational Science, San Diego State University, San Diego, California, United States of America.|Program of Computational Science, San Diego State University, San Diego, California, United States of America.|Program of Computational Science, San Diego State University, San Diego, California, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 44, 'Bacteriophages|Genes, Viral|Neural Networks (Computer)|Open Reading Frames|Viral Proteins', 'Journal Article', '10.1371/journal.pcbi.1002657', '22927809', 'Phages play critical roles in the survival and pathogenicity of their hosts, via lysogenic conversion factors, and in nutrient redistribution, via cell lysis. Analyses of phage- and viral-encoded genes in environmental samples provide insights into the physiological impact of viruses on microbial communities and human health. However, phage ORFs are extremely diverse of which over 70% of them are dissimilar to any genes with annotated functions in GenBank. Better identification of viruses would also aid in better detection and diagnosis of disease, in vaccine development, and generally in better understanding the physiological potential of any environment. In contrast to enzymes, viral structural protein function can be much more challenging to detect from sequence data because of low sequence conservation, few known conserved catalytic sites or sequence domains, and relatively limited experimental data. We have designed a method of predicting phage structural protein sequences that uses Artificial Neural Networks (ANNs). First, we trained ANNs to classify viral structural proteins using amino acid frequency, these correctly classify a large fraction of test cases with a high degree of specificity and sensitivity. Subsequently, we added estimates of protein isoelectric points as a feature to ANNs that classify specialized families of proteins, namely major capsid and tail proteins. As expected, these more specialized ANNs are more accurate than the structural ANNs. To experimentally validate the ANN predictions, several ORFs with no significant similarities to known sequences that are ANN-predicted structural proteins were examined by transmission electron microscopy. Some of these self-assembled into structures strongly resembling virion structures. Thus, our ANNs are new tools for identifying phage and potential prophage structural proteins that are difficult or impossible to detect by other bioinformatic analysis. The networks will be valuable when sequence is available but in vitro propagation of the phage may not be practical or possible.'),
(85619, 2012, 'plos', 'Allosteric communication across the native and mutated KIT receptor tyrosine kinase', 'Laine, Elodie|Auclair, Christian|Tchertanov, Luba', 'LBPA, CNRS-ENS de Cachan, LabEx LERMIT, Cachan, France.|LBPA, CNRS-ENS de Cachan, LabEx LERMIT, Cachan, France.|LBPA, CNRS-ENS de Cachan, LabEx LERMIT, Cachan, France.', 'France|France|France', 40, 'Allosteric Regulation|Models, Molecular|Mutation|Proto-Oncogene Proteins c-kit', 'Journal Article', '10.1371/journal.pcbi.1002661', '22927810', 'A fundamental goal in cellular signaling is to understand allosteric communication, the process by which signals originated at one site in a protein propagate dependably to affect remote functional sites. Here, we describe the allosteric regulation of the receptor tyrosine kinase KIT. Our analysis evidenced that communication routes established between the activation loop (A-loop) and the distant juxtamembrane region (JMR) in the native protein were disrupted by the oncogenic mutation D816V positioned in the A-loop. In silico mutagenesis provided a plausible way of restoring the protein communication detected in the native KIT by introducing a counter-balancing second mutation D792E. The communication patterns observed in the native and mutated KIT correlate perfectly with the structural and dynamical features of these proteins. Particularly, a long-distance effect of the D816V mutation manifested as an important structural re-organization of the JMR in the oncogenic mutant was completely vanished in the double mutant D816V/D792E. This detailed characterization of the allosteric communication in the different forms of KIT, native and mutants, was performed by using a modular network representation composed of communication pathways and independent dynamic segments. Such representation permits to enrich a purely mechanistic interaction-based model of protein communication by the introduction of concerted local atomic fluctuations. This method, validated on KIT receptor, may guide a rational modulation of the physiopathological activities of other receptor tyrosine kinases.'),
(85620, 2012, 'plos', 'The regulation of ant colony foraging activity without spatial information', 'Prabhakar, Balaji|Dektar, Katherine N|Gordon, Deborah M', 'Departments of Computer Science and Electrical Engineering, Stanford University, Stanford, California, United States of America.|Departments of Computer Science and Electrical Engineering, Stanford University, Stanford, California, United States of America.|Departments of Computer Science and Electrical Engineering, Stanford University, Stanford, California, United States of America.', 'United States|United States|United States', 53, 'Animals|Ants|Feeding Behavior|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002670', '22927811', 'Many dynamical networks, such as the ones that produce the collective behavior of social insects, operate without any central control, instead arising from local interactions among individuals. A well-studied example is the formation of recruitment trails in ant colonies, but many ant species do not use pheromone trails. We present a model of the regulation of foraging by harvester ant (Pogonomyrmex barbatus) colonies. This species forages for scattered seeds that one ant can retrieve on its own, so there is no need for spatial information such as pheromone trails that lead ants to specific locations. Previous work shows that colony foraging activity, the rate at which ants go out to search individually for seeds, is regulated in response to current food availability throughout the colonys foraging area. Ants use the rate of brief antennal contacts inside the nest between foragers returning with food and outgoing foragers available to leave the nest on the next foraging trip. Here we present a feedback-based algorithm that captures the main features of data from field experiments in which the rate of returning foragers was manipulated. The algorithm draws on our finding that the distribution of intervals between successive ants returning to the nest is a Poisson process. We fitted the parameter that estimates the effect of each returning forager on the rate at which outgoing foragers leave the nest. We found that correlations between observed rates of returning foragers and simulated rates of outgoing foragers, using our model, were similar to those in the data. Our simple stochastic model shows how the regulation of ant colony foraging can operate without spatial information, describing a process at the level of individual ants that predicts the overall foraging activity of the colony.'),
(85621, 2012, 'plos', 'Coupling mechanical deformations and planar cell polarity to create regular patterns in the zebrafish retina', 'Salbreux, Guillaume|Barthel, Linda K|Raymond, Pamela A|Lubensky, David K', 'Department of Physics, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Physics, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Physics, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Physics, University of Michigan, Ann Arbor, Michigan, United States of America.', 'United States|United States|United States|United States', 44, 'Animals|Cell Polarity|Retina|Zebrafish', 'Journal Article', '10.1371/journal.pcbi.1002618', '22936893', 'The orderly packing and precise arrangement of epithelial cells is essential to the functioning of many tissues, and refinement of this packing during development is a central theme in animal morphogenesis. The mechanisms that determine epithelial cell shape and position, however, remain incompletely understood. Here, we investigate these mechanisms in a striking example of planar order in a vertebrate epithelium: The periodic, almost crystalline distribution of cone photoreceptors in the adult teleost fish retina. Based on observations of the emergence of photoreceptor packing near the retinal margin, we propose a mathematical model in which ordered columns of cells form as a result of coupling between planar cell polarity (PCP) and anisotropic tissue-scale mechanical stresses. This model recapitulates many observed features of cone photoreceptor organization during retinal growth and regeneration. Consistent with the models predictions, we report a planar-polarized distribution of Crumbs2a protein in cone photoreceptors in both unperturbed and regenerated tissue. We further show that the pattern perturbations predicted by the model to occur if the imposed stresses become isotropic closely resemble defects in the cone pattern in zebrafish lrp2 mutants, in which intraocular pressure is increased, resulting in altered mechanical stress and ocular enlargement. Evidence of interactions linking PCP, cell shape, and mechanical stresses has recently emerged in a number of systems, several of which show signs of columnar cell packing akin to that described here. Our results may hence have broader relevance for the organization of cells in epithelia. Whereas earlier models have allowed only for unidirectional influences between PCP and cell mechanics, the simple, phenomenological framework that we introduce here can encompass a broad range of bidirectional feedback interactions among planar polarity, shape, and stresses, our model thus represents a conceptual framework that can address many questions of importance to morphogenesis.'),
(85622, 2012, 'plos', 'Versatility and invariance in the evolution of homologous heteromeric interfaces', 'Andreani, Jessica|Faure, Guilhem|Guerois, Raphaël', 'CEA, iBiTecS, Service de Bioenergetique Biologie Structurale et Mecanismes (SB2SM), Laboratoire de Biologie Structurale et Radiobiologie (LBSR), Gif sur Yvette, France.|CEA, iBiTecS, Service de Bioenergetique Biologie Structurale et Mecanismes (SB2SM), Laboratoire de Biologie Structurale et Radiobiologie (LBSR), Gif sur Yvette, France.|CEA, iBiTecS, Service de Bioenergetique Biologie Structurale et Mecanismes (SB2SM), Laboratoire de Biologie Structurale et Radiobiologie (LBSR), Gif sur Yvette, France.', 'France|France|France', 33, 'Biological Evolution|Models, Theoretical|Proteins', 'Journal Article', '10.1371/journal.pcbi.1002677', '22952442', 'Evolutionary pressures act on protein complex interfaces so that they preserve their complementarity. Nonetheless, the elementary interactions which compose the interface are highly versatile throughout evolution. Understanding and characterizing interface plasticity across evolution is a fundamental issue which could provide new insights into protein-protein interaction prediction. Using a database of 1,024 couples of close and remote heteromeric structural interologs, we studied protein-protein interactions from a structural and evolutionary point of view. We systematically and quantitatively analyzed the conservation of different types of interface contacts. Our study highlights astonishing plasticity regarding polar contacts at complex interfaces. It also reveals that up to a quarter of the residues switch out of the interface when comparing two homologous complexes. Despite such versatility, we identify two important interface descriptors which correlate with an increased conservation in the evolution of interfaces: apolar patches and contacts surrounding anchor residues. These observations hold true even when restricting the dataset to transiently formed complexes. We show that a combination of six features related either to sequence or to geometric properties of interfaces can be used to rank positions likely to share similar contacts between two interologs. Altogether, our analysis provides important tracks for extracting meaningful information from multiple sequence alignments of conserved binding partners and for discriminating near-native interfaces using evolutionary information.'),
(85623, 2012, 'plos', 'The roots of bioinformatics in ISMB', 'Gibson, Todd A', 'Computer Science Department, California State University, Chico, California, USA. tagibson@csuchico.edu', 'United States', 1, 'Computational Biology|Computer Graphics|Societies, Scientific', 'Journal Article', '10.1371/journal.pcbi.1002679', '22952443', '-'),
(85624, 2012, 'plos', 'On genetic specificity in symbiont-mediated host-parasite coevolution', 'Kwiatkowski, Marek|Engelstädter, Jan|Vorburger, Christoph', 'Institute of Integrative Biology, ETH Zürich, Zürich, Switzerland. marek.kwiatkowski@eawag.ch|Institute of Integrative Biology, ETH Zürich, Zürich, Switzerland. marek.kwiatkowski@eawag.ch|Institute of Integrative Biology, ETH Zürich, Zürich, Switzerland. marek.kwiatkowski@eawag.ch', 'Switzerland|Switzerland|Switzerland', 29, 'Alleles|Animals|Bacterial Physiological Phenomena|Biological Evolution|Host-Parasite Interactions|Symbiosis', 'Journal Article', '10.1371/journal.pcbi.1002633', '22956894', 'Existing theory of host-parasite interactions has identified the genetic specificity of interaction as a key variable affecting the outcome of coevolution. The Matching Alleles (MA) and Gene For Gene (GFG) models have been extensively studied as the canonical examples of specific and non-specific interaction. The generality of these models has recently been challenged by uncovering real-world host-parasite systems exhibiting specificity patterns that fit neither MA nor GFG, and by the discovery of symbiotic bacteria protecting insect hosts against parasites. In the present paper we address both challenges, simulating a large number of non-canonical models of host-parasite interactions that explicitly incorporate symbiont-based host resistance. To assess the genetic specialisation in these hybrid models, we develop a quantitative index of specificity applicable to any coevolutionary model based on a fitness matrix. We find qualitative and quantitative effects of host-parasite and symbiont-parasite specificities on genotype frequency dynamics, allele survival, and mean host and parasite fitnesses.'),
(85625, 2012, 'plos', 'Design and implementation of a genomics field trip program aimed at secondary school students', 'McQueen, Jennifer|Wright, Jody J|Fox, Joanne A', 'Genetics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.|Genetics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.|Genetics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.', 'Canada|Canada|Canada', 12, 'Adolescent|Education|Genomics|Humans|Students', 'Journal Article', '10.1371/journal.pcbi.1002636', '22956895', 'With the rapid pace of advancements in biological research brought about by the application of computer science and information technology, we believe the time is right for introducing genomics and bioinformatics tools and concepts to secondary school students. Our approach has been to offer a full-day field trip in our research facility where secondary school students carry out experiments at the laboratory bench and on a laptop computer. This experience offers benefits for students, teachers, and field trip instructors. In delivering a wide variety of science outreach and education programs, we have learned that a number of factors contribute to designing a successful experience for secondary school students. First, it is important to engage students with authentic and fun activities that are linked to real-world applications and/or research questions. Second, connecting with a local high school teacher to pilot programs and linking to curricula taught in secondary schools will enrich the field trip experience. Whether or not programs are linked directly to local teachers, it is important to be flexible and build in mechanisms for collecting feedback in field trip programs. Finally, graduate students can be very powerful mentors for students and should be encouraged to share their enthusiasm for science and to talk about career paths. Our experiences suggest a real need for effective science outreach programs at the secondary school level and that genomics and bioinformatics are ideal areas to explore.'),
(85626, 2012, 'plos', 'Teasing apart translational and transcriptional components of stochastic variations in eukaryotic gene expression', 'Salari, Raheleh|Wojtowicz, Damian|Zheng, Jie|Levens, David|Pilpel, Yitzhak|Przytycka, Teresa M', 'National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland, USA.|National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland, USA.|National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland, USA.|National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland, USA.|National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland, USA.|National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland, USA.', 'United States|United States|United States|United States|United States|United States', 16, 'Eukaryotic Cells|Gene Expression|Nucleic Acid Conformation|Protein Biosynthesis|RNA, Messenger|Stochastic Processes|TATA Box|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002644', '22956896', 'The intrinsic stochasticity of gene expression leads to cell-to-cell variations, noise, in protein abundance. Several processes, including transcription, translation, and degradation of mRNA and proteins, can contribute to these variations. Recent single cell analyses of gene expression in yeast have uncovered a general trend where expression noise scales with protein abundance. This trend is consistent with a stochastic model of gene expression where mRNA copy number follows the random birth and death process. However, some deviations from this basic trend have also been observed, prompting questions about the contribution of gene-specific features to such deviations. For example, recent studies have pointed to the TATA box as a sequence feature that can influence expression noise by facilitating expression bursts. Transcription-originated noise can be potentially further amplified in translation. Therefore, we asked the question of to what extent sequence features known or postulated to accompany translation efficiency can also be associated with increase in noise strength and, on average, how such increase compares to the amplification associated with the TATA box. Untangling different components of expression noise is highly nontrivial, as they may be gene or gene-module specific. In particular, focusing on codon usage as one of the sequence features associated with efficient translation, we found that ribosomal genes display a different relationship between expression noise and codon usage as compared to other genes. Within nonribosomal genes we found that sequence high codon usage is correlated with increased noise relative to the average noise of proteins with the same abundance. Interestingly, by projecting the data on a theoretical model of gene expression, we found that the amplification of noise strength associated with codon usage is comparable to that of the TATA box, suggesting that the effect of translation on noise in eukaryotic gene expression might be more prominent than previously appreciated.'),
(85627, 2012, 'plos', 'Mutual repression enhances the steepness and precision of gene expression boundaries', 'Sokolowski, Thomas R|Erdmann, Thorsten|ten Wolde, Pieter Rein', 'FOM Institute AMOLF, Amsterdam, The Netherlands.|FOM Institute AMOLF, Amsterdam, The Netherlands.|FOM Institute AMOLF, Amsterdam, The Netherlands.', 'Netherlands|Netherlands|Netherlands', 27, 'Animals|Drosophila|Embryonic Development|Gene Expression|Regression Analysis|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002654', '22956897', 'Embryonic development is driven by spatial patterns of gene expression that determine the fate of each cell in the embryo. While gene expression is often highly erratic, embryonic development is usually exceedingly precise. In particular, gene expression boundaries are robust not only against intra-embryonic fluctuations such as noise in gene expression and protein diffusion, but also against embryo-to-embryo variations in the morphogen gradients, which provide positional information to the differentiating cells. How development is robust against intra- and inter-embryonic variations is not understood. A common motif in the gene regulation networks that control embryonic development is mutual repression between pairs of genes. To assess the role of mutual repression in the robust formation of gene expression patterns, we have performed large-scale stochastic simulations of a minimal model of two mutually repressing gap genes in Drosophila, hunchback (hb) and knirps (kni). Our model includes not only mutual repression between hb and kni, but also the stochastic and cooperative activation of hb by the anterior morphogen Bicoid (Bcd) and of kni by the posterior morphogen Caudal (Cad), as well as the diffusion of Hb and Kni between neighboring nuclei. Our analysis reveals that mutual repression can markedly increase the steepness and precision of the gap gene expression boundaries. In contrast to other mechanisms such as spatial averaging and cooperative gene activation, mutual repression thus allows for gene-expression boundaries that are both steep and precise. Moreover, mutual repression dramatically enhances their robustness against embryo-to-embryo variations in the morphogen levels. Finally, our simulations reveal that diffusion of the gap proteins plays a critical role not only in reducing the width of the gap gene expression boundaries via the mechanism of spatial averaging, but also in repairing patterning errors that could arise because of the bistability induced by mutual repression.'),
(85628, 2012, 'plos', 'Weighted frequent gene co-expression network mining to identify genes involved in genome stability', 'Zhang, Jie|Lu, Kewei|Xiang, Yang|Islam, Muhtadi|Kotian, Shweta|Kais, Zeina|Lee, Cindy|Arora, Mansi|Liu, Hui-Wen|Parvin, Jeffrey D|Huang, Kun', 'Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.|Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.|Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.|Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.|Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.|Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.|Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.|Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.|Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.|Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.|Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States', 53, 'Algorithms|Gene Expression|Gene Regulatory Networks|Genomic Instability|Humans|Oligonucleotide Array Sequence Analysis|RNA Interference', 'Journal Article', '10.1371/journal.pcbi.1002656', '22956898', 'Gene co-expression network analysis is an effective method for predicting gene functions and disease biomarkers. However, few studies have systematically identified co-expressed genes involved in the molecular origin and development of various types of tumors. In this study, we used a network mining algorithm to identify tightly connected gene co-expression networks that are frequently present in microarray datasets from 33 types of cancer which were derived from 16 organs/tissues. We compared the results with networks found in multiple normal tissue types and discovered 18 tightly connected frequent networks in cancers, with highly enriched functions on cancer-related activities. Most networks identified also formed physically interacting networks. In contrast, only 6 networks were found in normal tissues, which were highly enriched for housekeeping functions. The largest cancer network contained many genes with genome stability maintenance functions. We tested 13 selected genes from this network for their involvement in genome maintenance using two cell-based assays. Among them, 10 were shown to be involved in either homology-directed DNA repair or centrosome duplication control including the well-known cancer marker MKI67. Our results suggest that the commonly recognized characteristics of cancers are supported by highly coordinated transcriptomic activities. This study also demonstrated that the co-expression network directed approach provides a powerful tool for understanding cancer physiology, predicting new gene functions, as well as providing new target candidates for cancer therapeutics.'),
(85629, 2012, 'plos', 'Shrinking the metabolic solution space using experimental datasets', 'Reed, Jennifer L', 'Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA. reed@engr.wisc.edu', 'United States', 63, 'Gene Expression Regulation|Kinetics|Metabolism|Models, Biological|Thermodynamics|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002662', '22956899', 'Constraint-based models of metabolism have been used in a variety of studies on drug discovery, metabolic engineering, evolution, and multi-species interactions. These genome-scale models can be generated for any sequenced organism since their main parameters (i.e., reaction stoichiometry) are highly conserved. Their relatively low parameter requirement makes these models easy to develop, however, these models often result in a solution space with multiple possible flux distributions, making it difficult to determine the precise flux state in the cell. Recent research efforts in this modeling field have investigated how additional experimental data, including gene expression, protein expression, metabolite concentrations, and kinetic parameters, can be used to reduce the solution space. This mini-review provides a summary of the data-driven computational approaches that are available for reducing the solution space and thereby improve predictions of intracellular fluxes by constraint-based models.'),
(85630, 2012, 'plos', 'Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase', 'Ripoll, Daniel R|Khavrutskii, Ilja V|Chaudhury, Sidhartha|Liu, Jin|Kuschner, Robert A|Wallqvist, Anders|Reifman, Jaques', 'Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, Frederick, Maryland, USA.|Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, Frederick, Maryland, USA.|Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, Frederick, Maryland, USA.|Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, Frederick, Maryland, USA.|Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, Frederick, Maryland, USA.|Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, Frederick, Maryland, USA.|Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, Frederick, Maryland, USA.', 'United States|United States|United States|United States|United States|United States|United States', 13, 'Antiviral Agents|Drug Resistance, Viral|Models, Molecular|Molecular Dynamics Simulation|Neuraminidase|Orthomyxoviridae|Oseltamivir|Thermodynamics|Zanamivir', 'Journal Article', '10.1371/journal.pcbi.1002665', '22956900', 'Quantitatively predicting changes in drug sensitivity associated with residue mutations is a major challenge in structural biology. By expanding the limits of free energy calculations, we successfully identified mutations in influenza neuraminidase (NA) that confer drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD) with Hamiltonian Replica Exchange and calculated binding free energy changes for H274Y, N294S, and Y252H mutants. Based on experimental data, our calculations achieved high accuracy and precision compared with results from established computational methods. Analysis of 15 micros of aggregated MD trajectories provided insights into the molecular mechanisms underlying drug resistance that are at odds with current interpretations of the crystallographic data. Contrary to the notion that resistance is caused by mutant-induced changes in hydrophobicity of the binding pocket, our simulations showed that drug resistance mutations in NA led to subtle rearrangements in the protein structure and its dynamics that together alter the active-site electrostatic environment and modulate inhibitor binding. Importantly, different mutations confer resistance through different conformational changes, suggesting that a generalized mechanism for NA drug resistance is unlikely.'),
(85631, 2012, 'plos', 'External drive to inhibitory cells induces alternating episodes of high- and low-amplitude oscillations', 'Avella Gonzalez, Oscar J|van Aerde, Karlijn I|van Elburg, Ronald A J|Poil, Simon-Shlomo|Mansvelder, Huibert D|Linkenkaer-Hansen, Klaus|van Pelt, Jaap|van Ooyen, Arjen', 'Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam, The Netherlands.|Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam, The Netherlands.|Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam, The Netherlands.|Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam, The Netherlands.|Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam, The Netherlands.|Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam, The Netherlands.|Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam, The Netherlands.|Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 0, 'Brain|Carbachol|Electroencephalography|Hippocampus|Models, Theoretical|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.1002666', '22956901', 'Electrical oscillations in neuronal network activity are ubiquitous in the brain and have been associated with cognition and behavior. Intriguingly, the amplitude of ongoing oscillations, such as measured in EEG recordings, fluctuates irregularly, with episodes of high amplitude alternating with episodes of low amplitude. Despite the widespread occurrence of amplitude fluctuations in many frequency bands and brain regions, the mechanisms by which they are generated are poorly understood. Here, we show that irregular transitions between sub-second episodes of high- and low-amplitude oscillations in the alpha/beta frequency band occur in a generic neuronal network model consisting of interconnected inhibitory and excitatory cells that are externally driven by sustained cholinergic input and trains of action potentials that activate excitatory synapses. In the model, we identify the action potential drive onto inhibitory cells, which represents input from other brain areas and is shown to desynchronize network activity, to be crucial for the emergence of amplitude fluctuations. We show that the duration distributions of high-amplitude episodes in the model match those observed in rat prefrontal cortex for oscillations induced by the cholinergic agonist carbachol. Furthermore, the mean duration of high-amplitude episodes varies in a bell-shaped manner with carbachol concentration, just as in mouse hippocampus. Our results suggest that amplitude fluctuations are a general property of oscillatory neuronal networks that can arise through background input from areas external to the network.'),
(85632, 2012, 'plos', 'Sub-diffraction limit localization of proteins in volumetric space using Bayesian restoration of fluorescence images from ultrathin specimens', 'Wang, Gordon|Smith, Stephen J', 'Department of Molecular and Cellular Physiology, Beckman Center, Stanford University, Palo Alto, California, USA. drwonder@stanford.edu|Department of Molecular and Cellular Physiology, Beckman Center, Stanford University, Palo Alto, California, USA. drwonder@stanford.edu', 'United States|United States', 22, 'Bayes Theorem|Microscopy, Fluorescence|Proteomics|Tomography', 'Journal Article', '10.1371/journal.pcbi.1002671', '22956902', 'Photon diffraction limits the resolution of conventional light microscopy at the lateral focal plane to 0.61xcexbb/NA (xcexbbxe2x80x8a=xe2x80x8awavelength of light, NAxe2x80x8a=xe2x80x8anumerical aperture of the objective) and at the axial plane to 1.4nxcexbb/NA(2) (nxe2x80x8a=xe2x80x8arefractive index of the imaging medium, 1.51 for oil immersion), which with visible wavelengths and a 1.4NA oil immersion objective is -220 nm and -600 nm in the lateral plane and axial plane respectively. This volumetric resolution is too large for the proper localization of protein clustering in subcellular structures. Here we combine the newly developed proteomic imaging technique, Array Tomography (AT), with its native 50-100 nm axial resolution achieved by physical sectioning of resin embedded tissue, and a 2D maximum likelihood deconvolution method, based on Bayes rule, which significantly improves the resolution of protein puncta in the lateral plane to allow accurate and fast computational segmentation and analysis of labeled proteins. The physical sectioning of AT allows tissue specimens to be imaged at the physical optimum of modern high NA plan-apochormatic objectives. This translates to images that have little out of focus light, minimal aberrations and wave-front distortions. Thus, AT is able to provide images with truly invariant point spread functions (PSF), a property critical for accurate deconvolution. We show that AT with deconvolution increases the volumetric analytical fidelity of protein localization by significantly improving the modulation of high spatial frequencies up to and potentially beyond the spatial frequency cut-off of the objective. Moreover, we are able to achieve this improvement with no noticeable introduction of noise or artifacts and arrive at object segmentation and localization accuracies on par with image volumes captured using commercial implementations of super-resolution microscopes.'),
(85633, 2012, 'plos', 'Interplay of gene expression noise and ultrasensitive dynamics affects bacterial operon organization', 'Ray, J Christian J|Igoshin, Oleg A', 'Department of Bioengineering, Rice University, Houston, Texas, USA.|Department of Bioengineering, Rice University, Houston, Texas, USA.', 'United States|United States', 0, 'Gene Expression|Models, Theoretical|Operon|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002672', '22956903', 'Bacterial chromosomes are organized into polycistronic cotranscribed operons, but the evolutionary pressures maintaining them are unclear. We hypothesized that operons alter gene expression noise characteristics, resulting in selection for or against maintaining operons depending on network architecture. Mathematical models for 6 functional classes of network modules showed that three classes exhibited decreased noise and 3 exhibited increased noise with same-operon cotranscription of interacting proteins. Noise reduction was often associated with a decreased chance of reaching an ultrasensitive threshold. Stochastic simulations of the lac operon demonstrated that the predicted effects of transcriptional coupling hold for a complex network module. We employed bioinformatic analysis to find overrepresentation of noise-minimizing operon organization compared with randomized controls. Among constitutively expressed physically interacting protein pairs, higher coupling frequencies appeared at lower expression levels, where noise effects are expected to be dominant. Our results thereby suggest an important role for gene expression noise, in many cases interacting with an ultrasensitive switch, in maintaining or selecting for operons in bacterial chromosomes.'),
(85634, 2012, 'plos', 'Molecular dynamics simulations reveal proton transfer pathways in cytochrome C-dependent nitric oxide reductase', 'Pisliakov, Andrei V|Hino, Tomoya|Shiro, Yoshitsugu|Sugita, Yuji', 'Theoretical Molecular Science Laboratory, RIKEN Advanced Science Institute, Wako-shi, Saitama, Japan. apisliakov@riken.jp|Theoretical Molecular Science Laboratory, RIKEN Advanced Science Institute, Wako-shi, Saitama, Japan. apisliakov@riken.jp|Theoretical Molecular Science Laboratory, RIKEN Advanced Science Institute, Wako-shi, Saitama, Japan. apisliakov@riken.jp|Theoretical Molecular Science Laboratory, RIKEN Advanced Science Institute, Wako-shi, Saitama, Japan. apisliakov@riken.jp', 'Japan|Japan|Japan|Japan', 24, 'Catalytic Domain|Cytochromes c|Hydrogen Bonding|Models, Molecular|Molecular Dynamics Simulation|Oxidoreductases|Protons', 'Journal Article', '10.1371/journal.pcbi.1002674', '22956904', 'Nitric oxide reductases (NORs) are membrane proteins that catalyze the reduction of nitric oxide (NO) to nitrous oxide (N(2)O), which is a critical step of the nitrate respiration process in denitrifying bacteria. Using the recently determined first crystal structure of the cytochrome c-dependent NOR (cNOR) [Hino T, Matsumoto Y, Nagano S, Sugimoto H, Fukumori Y, et al. (2010) Structural basis of biological N2O generation by bacterial nitric oxide reductase. Science 330: 1666-70.], we performed extensive all-atom molecular dynamics (MD) simulations of cNOR within an explicit membrane/solvent environment to fully characterize water distribution and dynamics as well as hydrogen-bonded networks inside the protein, yielding the atomic details of functionally important proton channels. Simulations reveal two possible proton transfer pathways leading from the periplasm to the active site, while no pathways from the cytoplasmic side were found, consistently with the experimental observations that cNOR is not a proton pump. One of the pathways, which was newly identified in the MD simulation, is blocked in the crystal structure and requires small structural rearrangements to allow for water channel formation. That pathway is equivalent to the functional periplasmic cavity postulated in cbb(3) oxidase, which illustrates that the two enzymes share some elements of the proton transfer mechanisms and confirms a close evolutionary relation between NORs and C-type oxidases. Several mechanisms of the critical proton transfer steps near the catalytic center are proposed.'),
(85635, 2012, 'plos', 'Correction: quantifying and analyzing the network basis of genetic complexity', 'Thompson, Ethan G|Galitski, Timothy', 'Theoretical Molecular Science Laboratory, RIKEN Advanced Science Institute, Wako-shi, Saitama, Japan. apisliakov@riken.jp|Theoretical Molecular Science Laboratory, RIKEN Advanced Science Institute, Wako-shi, Saitama, Japan. apisliakov@riken.jp', 'Japan|Japan', 0, 'Animals|Cell Cycle Checkpoints|Gene Regulatory Networks|Genetic Association Studies|Humans', 'Journal Article', '10.1371/annotation/a4b94e99-6f8a-433e-9a13-17a9f206eb68', '22969414', '[This corrects the article on p. e1002583 in vol. 8.].'),
(85636, 2012, 'plos', 'Correction: ensemble models of neutrophil trafficking in severe sepsis', 'Song, Sang Ok|Hogg, Justin|Peng, Zhi-Yong|Parker, Robert|Kellum, John A|Clermont, Gilles', 'Theoretical Molecular Science Laboratory, RIKEN Advanced Science Institute, Wako-shi, Saitama, Japan. apisliakov@riken.jp|Theoretical Molecular Science Laboratory, RIKEN Advanced Science Institute, Wako-shi, Saitama, Japan. apisliakov@riken.jp|Theoretical Molecular Science Laboratory, RIKEN Advanced Science Institute, Wako-shi, Saitama, Japan. apisliakov@riken.jp|Theoretical Molecular Science Laboratory, RIKEN Advanced Science Institute, Wako-shi, Saitama, Japan. apisliakov@riken.jp|Theoretical Molecular Science Laboratory, RIKEN Advanced Science Institute, Wako-shi, Saitama, Japan. apisliakov@riken.jp|Theoretical Molecular Science Laboratory, RIKEN Advanced Science Institute, Wako-shi, Saitama, Japan. apisliakov@riken.jp', 'Japan|Japan|Japan|Japan|Japan|Japan', 0, 'Animals|Cell Movement|Humans|Multivariate Analysis|Neutrophils|Principal Component Analysis|Rats|Sepsis', 'Journal Article', '10.1371/annotation/4ca315e7-1219-46fd-af5c-c29b8e6ecf93', '22969415', '[This corrects the article on p. e1002422 in vol. 8.].'),
(85637, 2012, 'plos', 'Human motor cortical activity is selectively phase-entrained on underlying rhythms', 'Miller, Kai J|Hermes, Dora|Honey, Christopher J|Hebb, Adam O|Ramsey, Nick F|Knight, Robert T|Ojemann, Jeffrey G|Fetz, Eberhard E', 'Department of Neurosurgery, Stanford University, Stanford, California, United States of America. kai.miller@stanford.edu|Department of Neurosurgery, Stanford University, Stanford, California, United States of America. kai.miller@stanford.edu|Department of Neurosurgery, Stanford University, Stanford, California, United States of America. kai.miller@stanford.edu|Department of Neurosurgery, Stanford University, Stanford, California, United States of America. kai.miller@stanford.edu|Department of Neurosurgery, Stanford University, Stanford, California, United States of America. kai.miller@stanford.edu|Department of Neurosurgery, Stanford University, Stanford, California, United States of America. kai.miller@stanford.edu|Department of Neurosurgery, Stanford University, Stanford, California, United States of America. kai.miller@stanford.edu|Department of Neurosurgery, Stanford University, Stanford, California, United States of America. kai.miller@stanford.edu', 'United States|United States|United States|United States|United States|United States|United States|Un', 101, 'Adolescent|Adult|Biological Clocks|Electroencephalography|Evoked Potentials, Motor|Female|Fingers|Humans|Male|Middle Aged|Motor Cortex|Movement|Nerve Net|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1002655', '22969416', 'The functional significance of electrical rhythms in the mammalian brain remains uncertain. In the motor cortex, the 12-20 Hz beta rhythm is known to transiently decrease in amplitude during movement, and to be altered in many motor diseases. Here we show that the activity of neuronal populations is phase-coupled with the beta rhythm on rapid timescales, and describe how the strength of this relation changes with movement. To investigate the relationship of the beta rhythm to neuronal dynamics, we measured local cortical activity using arrays of subdural electrocorticographic (ECoG) electrodes in human patients performing simple movement tasks. In addition to rhythmic brain processes, ECoG potentials also reveal a spectrally broadband motif that reflects the aggregate neural population activity beneath each electrode. During movement, the amplitude of this broadband motif follows the dynamics of individual fingers, with somatotopically specific responses for different fingers at different sites on the pre-central gyrus. The 12-20 Hz beta rhythm, in contrast, is widespread as well as spatially coherent within sulcal boundaries and decreases in amplitude across the pre- and post-central gyri in a diffuse manner that is not finger-specific. We find that the amplitude of this broadband motif is entrained on the phase of the beta rhythm, as well as rhythms at other frequencies, in peri-central cortex during fixation. During finger movement, the beta phase-entrainment is diminished or eliminated. We suggest that the beta rhythm may be more than a resting rhythm, and that this entrainment may reflect a suppressive mechanism for actively gating motor function.'),
(85638, 2012, 'plos', 'Dependencies among editing sites in serotonin 2C receptor mRNA', 'Carmel, Liran|Koonin, Eugene V|Dracheva, Stella', 'Department of Genetics, The Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, Israel.|Department of Genetics, The Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, Israel.|Department of Genetics, The Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, Israel.', 'Israel|Israel|Israel', 6, 'Base Sequence|Molecular Sequence Data|RNA Editing|RNA, Messenger|Receptor, Serotonin, 5-HT2C|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1002663', '22969417', 'The serotonin 2C receptor (5-HT(2C)R)-a key regulator of diverse neurological processes-exhibits functional variability derived from editing of its pre-mRNA by site-specific adenosine deamination (A-to-I pre-mRNA editing) in five distinct sites. Here we describe a statistical technique that was developed for analysis of the dependencies among the editing states of the five sites. The statistical significance of the observed correlations was estimated by comparing editing patterns in multiple individuals. For both human and rat 5-HT(2C)R, the editing states of the physically proximal sites A and B were found to be strongly dependent. In contrast, the editing states of sites C and D, which are also physically close, seem not to be directly dependent but instead are linked through the dependencies on sites A and B, respectively. We observed pronounced differences between the editing patterns in humans and rats: in humans site A is the key determinant of the editing state of the other sites, whereas in rats this role belongs to site B. The structure of the dependencies among the editing sites is notably simpler in rats than it is in humans implying more complex regulation of 5-HT(2C)R editing and, by inference, function in the human brain. Thus, exhaustive statistical analysis of the 5-HT(2C)R editing patterns indicates that the editing state of sites A and B is the primary determinant of the editing states of the other three sites, and hence the overall editing pattern. Taken together, these findings allow us to propose a mechanistic model of concerted action of ADAR1 and ADAR2 in 5-HT(2C)R editing. Statistical approach developed here can be applied to other cases of interdependencies among modification sites in RNA and proteins.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85639, 2012, 'plos', 'A novel computational method identifies intra- and inter-species recombination events in Staphylococcus aureus and Streptococcus pneumoniae', 'Sanguinetti, Lisa|Toti, Simona|Reguzzi, Valerio|Bagnoli, Fabio|Donati, Claudio', 'Novartis Vaccines and Diagnostics, Siena, Italy.|Novartis Vaccines and Diagnostics, Siena, Italy.|Novartis Vaccines and Diagnostics, Siena, Italy.|Novartis Vaccines and Diagnostics, Siena, Italy.|Novartis Vaccines and Diagnostics, Siena, Italy.', 'Italy|Italy|Italy|Italy|Italy', 0, 'Algorithms|Base Sequence|Chromosome Mapping|Computer Simulation|Conserved Sequence|Gene Transfer, Horizontal|Genome, Bacterial|Models, Genetic|Molecular Sequence Data|Sequence Analysis, DNA|Species Specificity|Staphylococcus aureus|Streptococcus pneumoniae', 'Journal Article', '10.1371/journal.pcbi.1002668', '22969418', 'Advances in high-throughput DNA sequencing technologies have determined an explosion in the number of sequenced bacterial genomes. Comparative sequence analysis frequently reveals evidences of homologous recombination occurring with different mechanisms and rates in different species, but the large-scale use of computational methods to identify recombination events is hampered by their high computational costs. Here, we propose a new method to identify recombination events in large datasets of whole genome sequences. Using a filtering procedure of the gene conservation profiles of a test genome against a panel of strains, this algorithm identifies sets of contiguous genes acquired by homologous recombination. The locations of the recombination breakpoints are determined using a statistical test that is able to account for the differences in the natural rate of evolution between different genes. The algorithm was tested on a dataset of 75 genomes of Staphylococcus aureus and 50 genomes comprising different streptococcal species, and was able to detect intra-species recombination events in S. aureus and in Streptococcus pneumoniae. Furthermore, we found evidences of an inter-species exchange of genetic material between S. pneumoniae and Streptococcus mitis, a closely related commensal species that colonizes the same ecological niche. The method has been implemented in an R package, Reco, which is freely available from supplementary material, and provides a rapid screening tool to investigate recombination on a genome-wide scale from sequence data.'),
(85640, 2012, 'plos', 'Criticality is an emergent property of genetic networks that exhibit evolvability', 'Torres-Sosa, Christian|Huang, Sui|Aldana, Maximino', 'Instituto de Biotecnología Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México.|Instituto de Biotecnología Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México.|Instituto de Biotecnología Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México.', '-|-|-', 0, 'Animals|Biological Evolution|Computer Simulation|Evolution, Molecular|Gene Expression Regulation|Genetics, Population|Humans|Models, Genetic|Mutation|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002669', '22969419', 'Accumulating experimental evidence suggests that the gene regulatory networks of living organisms operate in the critical phase, namely, at the transition between ordered and chaotic dynamics. Such critical dynamics of the network permits the coexistence of robustness and flexibility which are necessary to ensure homeostatic stability (of a given phenotype) while allowing for switching between multiple phenotypes (network states) as occurs in development and in response to environmental change. However, the mechanisms through which genetic networks evolve such critical behavior have remained elusive. Here we present an evolutionary model in which criticality naturally emerges from the need to balance between the two essential components of evolvability: phenotype conservation and phenotype innovation under mutations. We simulated the Darwinian evolution of random Boolean networks that mutate gene regulatory interactions and grow by gene duplication. The mutating networks were subjected to selection for networks that both (i) preserve all the already acquired phenotypes (dynamical attractor states) and (ii) generate new ones. Our results show that this interplay between extending the phenotypic landscape (innovation) while conserving the existing phenotypes (conservation) suffices to cause the evolution of all the networks in a population towards criticality. Furthermore, the networks produced by this evolutionary process exhibit structures with hubs (global regulators) similar to the observed topology of real gene regulatory networks. Thus, dynamical criticality and certain elementary topological properties of gene regulatory networks can emerge as a byproduct of the evolvability of the phenotypic landscape.'),
(85641, 2012, 'plos', 'Correlated electrostatic mutations provide a reservoir of stability in HIV protease', 'Haq, Omar|Andrec, Michael|Morozov, Alexandre V|Levy, Ronald M', 'BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, New Jersey, United States America.|BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, New Jersey, United States America.|BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, New Jersey, United States America.|BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, New Jersey, United States America.', 'Jersey|Jersey|Jersey|Jersey', 21, 'Amino Acid Sequence|Computer Simulation|Enzyme Stability|HIV Protease|Models, Chemical|Models, Genetic|Models, Molecular|Molecular Sequence Data|Mutation|Static Electricity|Statistics as Topic|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1002675', '22969420', 'HIV protease, an aspartyl protease crucial to the life cycle of HIV, is the target of many drug development programs. Though many protease inhibitors are on the market, protease eventually evades these drugs by mutating at a rapid pace and building drug resistance. The drug resistance mutations, called primary mutations, are often destabilizing to the enzyme and this loss of stability has to be compensated for. Using a coarse-grained biophysical energy model together with statistical inference methods, we observe that accessory mutations of charged residues increase protein stability, playing a key role in compensating for destabilizing primary drug resistance mutations. Increased stability is intimately related to correlations between electrostatic mutations - uncorrelated mutations would strongly destabilize the enzyme. Additionally, statistical modeling indicates that the network of correlated electrostatic mutations has a simple topology and has evolved to minimize frustrated interactions. The models statistical coupling parameters reflect this lack of frustration and strongly distinguish like-charge electrostatic interactions from unlike-charge interactions for [Formula: see text] of the most significantly correlated double mutants. Finally, we demonstrate that our model has considerable predictive power and can be used to predict complex mutation patterns, that have not yet been observed due to finite sample size effects, and which are likely to exist within the larger patient population whose virus has not yet been sequenced.'),
(85642, 2012, 'plos', 'Performance limitations of relay neurons', 'Agarwal, Rahul|Sarma, Sridevi V', 'Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA. rahul.jhu@gmail.com|Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA. rahul.jhu@gmail.com', 'United States|United States', 0, 'Action Potentials|Animals|Geniculate Bodies|Humans|Models, Neurological|Neurons|Thalamus', 'Journal Article', '10.1371/journal.pcbi.1002626', '22973184', 'Relay cells are prevalent throughout sensory systems and receive two types of inputs: driving and modulating. The driving input contains receptive field properties that must be transmitted while the modulating input alters the specifics of transmission. For example, the visual thalamus contains relay neurons that receive driving inputs from the retina that encode a visual image, and modulating inputs from reticular activating system and layer 6 of visual cortex that control what aspects of the image will be relayed back to visual cortex for perception. What gets relayed depends on several factors such as attentional demands and a subjects goals. In this paper, we analyze a biophysical based model of a relay cell and use systems theoretic tools to construct analytic bounds on how well the cell transmits a driving input as a function of the neurons electrophysiological properties, the modulating input, and the driving signal parameters. We assume that the modulating input belongs to a class of sinusoidal signals and that the driving input is an irregular train of pulses with inter-pulse intervals obeying an exponential distribution. Our analysis applies to any [Formula: see text] order model as long as the neuron does not spike without a driving input pulse and exhibits a refractory period. Our bounds on relay reliability contain performance obtained through simulation of a second and third order model, and suggest, for instance, that if the frequency of the modulating input increases or the DC offset decreases, then relay increases. Our analysis also shows, for the first time, how the biophysical properties of the neuron (e.g. ion channel dynamics) define the oscillatory patterns needed in the modulating input for appropriately timed relay of sensory information. In our discussion, we describe how our bounds predict experimentally observed neural activity in the basal ganglia in (i) health, (ii) in Parkinsons disease (PD), and (iii) in PD during therapeutic deep brain stimulation. Our bounds also predict different rhythms that emerge in the lateral geniculate nucleus in the thalamus during different attentional states.'),
(85643, 2012, 'plos', 'Predicting the extension of biomedical ontologies', 'Pesquita, Catia|Couto, Francisco M', 'Faculty of Sciences, University of Lisboa, Lisboa, Portugal. cpesquita@xldb.di.fc.ul.pt|Faculty of Sciences, University of Lisboa, Lisboa, Portugal. cpesquita@xldb.di.fc.ul.pt', 'Portugal|Portugal', 0, 'Algorithms|Artificial Intelligence|Computational Biology|Database Management Systems|Evolution, Molecular|Humans|Information Storage and Retrieval|Natural Language Processing|Vocabulary, Controlled', 'Journal Article', '10.1371/journal.pcbi.1002630', '23028267', 'Developing and extending a biomedical ontology is a very demanding task that can never be considered complete given our ever-evolving understanding of the life sciences. Extension in particular can benefit from the automation of some of its steps, thus releasing experts to focus on harder tasks. Here we present a strategy to support the automation of change capturing within ontology extension where the need for new concepts or relations is identified. Our strategy is based on predicting areas of an ontology that will undergo extension in a future version by applying supervised learning over features of previous ontology versions. We used the Gene Ontology as our test bed and obtained encouraging results with average f-measure reaching 0.79 for a subset of biological process terms. Our strategy was also able to outperform state of the art change capturing methods. In addition we have identified several issues concerning prediction of ontology evolution, and have delineated a general framework for ontology extension prediction. Our strategy can be applied to any biomedical ontology with versioning, to help focus either manual or semi-automated extension methods on areas of the ontology that need extension.'),
(85644, 2012, 'plos', 'Ten simple rules for online learning', 'Searls, David B', 'Faculty of Sciences, University of Lisboa, Lisboa, Portugal. cpesquita@xldb.di.fc.ul.pt', 'Portugal', 14, 'Algorithms|Computational Biology|Computer-Assisted Instruction|Curriculum|Internet|Online Systems|Teaching', 'Editorial', '10.1371/journal.pcbi.1002631', '23028268', '-'),
(85645, 2012, 'plos', 'An online bioinformatics curriculum', 'Searls, David B', 'david.b.searls@gmail.com', '-', 0, 'Algorithms|Computational Biology|Computer-Assisted Instruction|Curriculum|Internet|Online Systems|Teaching|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1002632', '23028269', 'Online learning initiatives over the past decade have become increasingly comprehensive in their selection of courses and sophisticated in their presentation, culminating in the recent announcement of a number of consortium and startup activities that promise to make a university education on the internet, free of charge, a real possibility. At this pivotal moment it is appropriate to explore the potential for obtaining comprehensive bioinformatics training with currently existing free video resources. This article presents such a bioinformatics curriculum in the form of a virtual course catalog, together with editorial commentary, and an assessment of strengths, weaknesses, and likely future directions for open online learning in this field.'),
(85646, 2012, 'plos', 'What evidence is there for the homology of protein-protein interactions?', 'Lewis, Anna C F|Jones, Nick S|Porter, Mason A|Deane, Charlotte M', 'Department of Statistics, University of Oxford, Oxford, United Kingdom.|Department of Statistics, University of Oxford, Oxford, United Kingdom.|Department of Statistics, University of Oxford, Oxford, United Kingdom.|Department of Statistics, University of Oxford, Oxford, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 24, 'Algorithms|Amino Acid Sequence|Databases, Protein|Molecular Sequence Data|Protein Interaction Mapping|Proteins|Sequence Alignment|Sequence Homology, Amino Acid', 'Journal Article', '10.1371/journal.pcbi.1002645', '23028270', 'The notion that sequence homology implies functional similarity underlies much of computational biology. In the case of protein-protein interactions, an interaction can be inferred between two proteins on the basis that sequence-similar proteins have been observed to interact. The use of transferred interactions is common, but the legitimacy of such inferred interactions is not clear. Here we investigate transferred interactions and whether data incompleteness explains the lack of evidence found for them. Using definitions of homology associated with functional annotation transfer, we estimate that conservation rates of interactions are low even after taking interactome incompleteness into account. For example, at a blastp E-value threshold of 10(-70), we estimate the conservation rate to be about 11 % between S. cerevisiae and H. sapiens. Our method also produces estimates of interactome sizes (which are similar to those previously proposed). Using our estimates of interaction conservation we estimate the rate at which protein-protein interactions are lost across species. To our knowledge, this is the first such study based on large-scale data. Previous work has suggested that interactions transferred within species are more reliable than interactions transferred across species. By controlling for factors that are specific to within-species interaction prediction, we propose that the transfer of interactions within species might be less reliable than transfers between species. Protein-protein interactions appear to be very rarely conserved unless very high sequence similarity is observed. Consequently, inferred interactions should be used with care.'),
(85647, 2012, 'plos', 'High-throughput computer method for 3D neuronal structure reconstruction from the image stack of the Drosophila brain and its applications', 'Lee, Ping-Chang|Chuang, Chao-Chun|Chiang, Ann-Shyn|Ching, Yu-Tai', 'Department of Computer Science, National Chiao Tung University, HsinChu, Taiwan.|Department of Computer Science, National Chiao Tung University, HsinChu, Taiwan.|Department of Computer Science, National Chiao Tung University, HsinChu, Taiwan.|Department of Computer Science, National Chiao Tung University, HsinChu, Taiwan.', '-|-|-|-', 17, 'Animals|Brain|Computer Simulation|Drosophila melanogaster|Image Interpretation, Computer-Assisted|Imaging, Three-Dimensional|Models, Anatomic|Models, Neurological|Nerve Net|Neurons', 'Journal Article', '10.1371/journal.pcbi.1002658', '23028271', 'Drosophila melanogaster is a well-studied model organism, especially in the field of neurophysiology and neural circuits. The brain of the Drosophila is small but complex, and the image of a single neuron in the brain can be acquired using confocal microscopy. Analyzing the Drosophila brain is an ideal start to understanding the neural structure. The most fundamental task in studying the neural network of Drosophila is to reconstruct neuronal structures from image stacks. Although the fruit fly brain is small, it contains approximately 100,000 neurons. It is impossible to trace all the neurons manually. This study presents a high-throughput algorithm for reconstructing the neuronal structures from 3D image stacks collected by a laser scanning confocal microscope. The proposed method reconstructs the neuronal structure by applying the shortest path graph algorithm. The vertices in the graph are certain points on the 2D skeletons of the neuron in the slices. These points are close to the 3D centerlines of the neuron branches. The accuracy of the algorithm was verified using the DIADEM data set. This method has been adopted as part of the protocol of the FlyCircuit Database, and was successfully applied to process more than 16,000 neurons. This study also shows that further analysis based on the reconstruction results can be performed to gather more information on the neural network.'),
(85648, 2012, 'plos', 'Evolutionary dynamics on protein bi-stability landscapes can potentially resolve adaptive conflicts', 'Sikosek, Tobias|Bornberg-Bauer, Erich|Chan, Hue Sun', 'Evolutionary Bioinformatics Group, Institute for Evolution and Biodiversity, University of Münster, Münster, Germany. sikosek@wwu.de|Evolutionary Bioinformatics Group, Institute for Evolution and Biodiversity, University of Münster, Münster, Germany. sikosek@wwu.de|Evolutionary Bioinformatics Group, Institute for Evolution and Biodiversity, University of Münster, Münster, Germany. sikosek@wwu.de', 'Germany|Germany|Germany', 0, 'Adaptation, Physiological|Amino Acid Sequence|Computer Simulation|Evolution, Molecular|Genetic Variation|Models, Chemical|Models, Genetic|Molecular Sequence Data|Proteins|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1002659', '23028272', 'Experimental studies have shown that some proteins exist in two alternative native-state conformations. It has been proposed that such bi-stable proteins can potentially function as evolutionary bridges at the interface between two neutral networks of protein sequences that fold uniquely into the two different native conformations. Under adaptive conflict scenarios, bi-stable proteins may be of particular advantage if they simultaneously provide two beneficial biological functions. However, computational models that simulate protein structure evolution do not yet recognize the importance of bi-stability. Here we use a biophysical model to analyze sequence space to identify bi-stable or multi-stable proteins with two or more equally stable native-state structures. The inclusion of such proteins enhances phenotype connectivity between neutral networks in sequence space. Consideration of the sequence space neighborhood of bridge proteins revealed that bi-stability decreases gradually with each mutation that takes the sequence further away from an exactly bi-stable protein. With relaxed selection pressures, we found that bi-stable proteins in our model are highly successful under simulated adaptive conflict. Inspired by these model predictions, we developed a method to identify real proteins in the PDB with bridge-like properties, and have verified a clear bi-stability gradient for a series of mutants studied by Alexander et al. (Proc Nat Acad Sci USA 2009, 106:21149-21154) that connect two sequences that fold uniquely into two different native structures via a bridge-like intermediate mutant sequence. Based on these findings, new testable predictions for future studies on protein bi-stability and evolution are discussed.'),
(85649, 2012, 'plos', 'Spontaneous excitation patterns computed for axons with injury-like impairments of sodium channels and Na/K pumps', 'Yu, Na|Morris, Catherine E|Joós, Béla|Longtin, André', 'Department of Physics, University of Ottawa, Ottawa, Ontario, Canada.|Department of Physics, University of Ottawa, Ottawa, Ontario, Canada.|Department of Physics, University of Ottawa, Ottawa, Ontario, Canada.|Department of Physics, University of Ottawa, Ottawa, Ontario, Canada.', 'Canada|Canada|Canada|Canada', 0, 'Animals|Axons|Computer Simulation|Diffuse Axonal Injury|Humans|Ion Channel Gating|Membrane Potentials|Models, Neurological|Neural Conduction|Sodium Channels|Sodium-Potassium-Exchanging ATPase', 'Journal Article', '10.1371/journal.pcbi.1002664', '23028273', 'In injured neurons, leaky voltage-gated sodium channels (Nav) underlie dysfunctional excitability that ranges from spontaneous subthreshold oscillations (STO), to ectopic (sometimes paroxysmal) excitation, to depolarizing block. In recombinant systems, mechanical injury to Nav1.6-rich membranes causes cytoplasmic Na(+)-loading and Nav-CLS, i.e., coupled left-(hyperpolarizing)-shift of Nav activation and availability. Metabolic injury of hippocampal neurons (epileptic discharge) results in comparable impairment: left-shifted activation and availability and hence left-shifted I(Na-window). A recent computation study revealed that CLS-based I(Na-window) left-shift dissipates ion gradients and impairs excitability. Here, via dynamical analyses, we focus on sustained excitability patterns in mildly damaged nodes, in particular with more realistic Gaussian-distributed Nav-CLS to mimic smeared injury intensity. Since our interest is axons that might survive injury, pumps (sine qua non for live axons) are included. In some simulations, pump efficacy and system volumes are varied. Impacts of current noise inputs are also characterized. The diverse modes of spontaneous rhythmic activity evident in these scenarios are studied using bifurcation analysis. For mild CLS injury, a prominent feature is slow pump/leak-mediated E(Ion) oscillations. These slow oscillations yield dynamic firing thresholds that underlie complex voltage STO and bursting behaviors. Thus, Nav-CLS, a biophysically justified mode of injury, in parallel with functioning pumps, robustly engenders an emergent slow process that triggers a plethora of pathological excitability patterns. This minimalist device could have physiological analogs. At first nodes of Ranvier and at nociceptors, e.g., localized lipid-tuning that modulated Nav midpoints could produce Nav-CLS, as could co-expression of appropriately differing Nav isoforms.'),
(85650, 2012, 'plos', 'The spatial structure of stimuli shapes the timescale of correlations in population spiking activity', 'Litwin-Kumar, Ashok|Chacron, Maurice J|Doiron, Brent', 'Program for Neural Computation, Carnegie Mellon University and University of Pittsburgh, Pittsburgh, Pennsylvania, USA. alk@cmu.edu|Program for Neural Computation, Carnegie Mellon University and University of Pittsburgh, Pittsburgh, Pennsylvania, USA. alk@cmu.edu|Program for Neural Computation, Carnegie Mellon University and University of Pittsburgh, Pittsburgh, Pennsylvania, USA. alk@cmu.edu', 'United States|United States|United States', 25, 'Action Potentials|Animals|Computer Simulation|Electric Fish|Electric Organ|Electric Stimulation|Models, Neurological|Models, Statistical|Nerve Net|Neuronal Plasticity|Neurons, Afferent|Statistics as Topic', 'Journal Article', '10.1371/journal.pcbi.1002667', '23028274', 'Throughout the central nervous system, the timescale over which pairs of neural spike trains are correlated is shaped by stimulus structure and behavioral context. Such shaping is thought to underlie important changes in the neural code, but the neural circuitry responsible is largely unknown. In this study, we investigate a stimulus-induced shaping of pairwise spike train correlations in the electrosensory system of weakly electric fish. Simultaneous single unit recordings of principal electrosensory cells show that an increase in the spatial extent of stimuli increases correlations at short (xe2x89x88 10 ms) timescales while simultaneously reducing correlations at long (xe2x89x88 100 ms) timescales. A spiking network model of the first two stages of electrosensory processing replicates this correlation shaping, under the assumptions that spatially broad stimuli both saturate feedforward afferent input and recruit an open-loop inhibitory feedback pathway. Our model predictions are experimentally verified using both the natural heterogeneity of the electrosensory system and pharmacological blockade of descending feedback projections. For weak stimuli, linear response analysis of the spiking network shows that the reduction of long timescale correlation for spatially broad stimuli is similar to correlation cancellation mechanisms previously suggested to be operative in mammalian cortex. The mechanism for correlation shaping supports population-level filtering of irrelevant distractor stimuli, thereby enhancing the population response to relevant prey and conspecific communication inputs.'),
(85651, 2012, 'plos', 'Inferring the structure of social contacts from demographic data in the analysis of infectious diseases spread', 'Fumanelli, Laura|Ajelli, Marco|Manfredi, Piero|Vespignani, Alessandro|Merler, Stefano', 'Bruno Kessler Foundation, Trento, Italy. lfumanelli@fbk.eu|Bruno Kessler Foundation, Trento, Italy. lfumanelli@fbk.eu|Bruno Kessler Foundation, Trento, Italy. lfumanelli@fbk.eu|Bruno Kessler Foundation, Trento, Italy. lfumanelli@fbk.eu|Bruno Kessler Foundation, Trento, Italy. lfumanelli@fbk.eu', 'Italy|Italy|Italy|Italy|Italy', 0, 'Computer Simulation|Contact Tracing|Data Interpretation, Statistical|Disease Outbreaks|Disease Transmission, Infectious|Europe|Humans|Incidence|Interpersonal Relations|Models, Statistical|Population Surveillance|Proportional Hazards Models|Risk Assessment|Risk Factors', 'Journal Article', '10.1371/journal.pcbi.1002673', '23028275', 'Social contact patterns among individuals encode the transmission route of infectious diseases and are a key ingredient in the realistic characterization and modeling of epidemics. Unfortunately, the gathering of high quality experimental data on contact patterns in human populations is a very difficult task even at the coarse level of mixing patterns among age groups. Here we propose an alternative route to the estimation of mixing patterns that relies on the construction of virtual populations parametrized with highly detailed census and demographic data. We present the modeling of the population of 26 European countries and the generation of the corresponding synthetic contact matrices among the population age groups. The method is validated by a detailed comparison with the matrices obtained in six European countries by the most extensive survey study on mixing patterns. The methodology presented here allows a large scale comparison of mixing patterns in Europe, highlighting general common features as well as country-specific differences. We find clear relations between epidemiologically relevant quantities (reproduction number and attack rate) and socio-demographic characteristics of the populations, such as the average age of the population and the duration of primary school cycle. This study provides a numerical approach for the generation of human mixing patterns that can be used to improve the accuracy of mathematical models in the absence of specific experimental data.'),
(85652, 2012, 'plos', 'Speeded reaching movements around invisible obstacles', 'Hudson, Todd E|Wolfe, Uta|Maloney, Laurence T', 'Department of Psychology, New York University, New York, New York, USA. hudson@cns.nyu.edu|Department of Psychology, New York University, New York, New York, USA. hudson@cns.nyu.edu|Department of Psychology, New York University, New York, New York, USA. hudson@cns.nyu.edu', 'United States|United States|United States', 13, 'Arm|Artificial Intelligence|Bayes Theorem|Computer Simulation|Humans|Models, Biological|Movement|Pattern Recognition, Automated|Psychomotor Performance|Reward', 'Comparative Study', '10.1371/journal.pcbi.1002676', '23028276', 'We analyze the problem of obstacle avoidance from a Bayesian decision-theoretic perspective using an experimental task in which reaches around a virtual obstacle were made toward targets on an upright monitor. Subjects received monetary rewards for touching the target and incurred losses for accidentally touching the intervening obstacle. The locations of target-obstacle pairs within the workspace were varied from trial to trial. We compared human performance to that of a Bayesian ideal movement planner (who chooses motor strategies maximizing expected gain) using the Dominance Test employed in Hudson et al. (2007). The ideal movement planner suffers from the same sources of noise as the human, but selects movement plans that maximize expected gain in the presence of that noise. We find good agreement between the predictions of the model and actual performance in most but not all experimental conditions.'),
(85653, 2012, 'plos', 'Deciphering interactions in moving animal groups', 'Gautrais, Jacques|Ginelli, Francesco|Fournier, Richard|Blanco, Stéphane|Soria, Marc|Chaté, Hugues|Theraulaz, Guy', 'Centre de Recherches sur la Cognition Animale, UMR-CNRS 5169, Université Paul Sabatier, Toulouse, France. jacques.gautrais@univ-tlse3.fr|Centre de Recherches sur la Cognition Animale, UMR-CNRS 5169, Université Paul Sabatier, Toulouse, France. jacques.gautrais@univ-tlse3.fr|Centre de Recherches sur la Cognition Animale, UMR-CNRS 5169, Université Paul Sabatier, Toulouse, France. jacques.gautrais@univ-tlse3.fr|Centre de Recherches sur la Cognition Animale, UMR-CNRS 5169, Université Paul Sabatier, Toulouse, France. jacques.gautrais@univ-tlse3.fr|Centre de Recherches sur la Cognition Animale, UMR-CNRS 5169, Université Paul Sabatier, Toulouse, France. jacques.gautrais@univ-tlse3.fr|Centre de Recherches sur la Cognition Animale, UMR-CNRS 5169, Université Paul Sabatier, Toulouse, France. jacques.gautrais@univ-tlse3.fr|Centre de Recherches sur la Cognition Animale, UMR-CNRS 5169, Université Paul Sabatier, Toulouse, France. jacques.gautrais@univ-tlse3.fr', 'France|France|France|France|France|France|France', 0, 'Animals|Behavior, Animal|Computer Simulation|Decision Making|Fishes|Models, Biological|Orientation|Spatial Behavior|Swimming', 'Journal Article', '10.1371/journal.pcbi.1002678', '23028277', 'Collective motion phenomena in large groups of social organisms have long fascinated the observer, especially in cases, such as bird flocks or fish schools, where large-scale highly coordinated actions emerge in the absence of obvious leaders. However, the mechanisms involved in this self-organized behavior are still poorly understood, because the individual-level interactions underlying them remain elusive. Here, we demonstrate the power of a bottom-up methodology to build models for animal group motion from data gathered at the individual scale. Using video tracks of fish shoal in a tank, we show how a careful, incremental analysis at the local scale allows for the determination of the stimulus/response function governing an individuals moving decisions. We find in particular that both positional and orientational effects are present, act upon the fish turning speed, and depend on the swimming speed, yielding a novel schooling model whose parameters are all estimated from data. Our approach also leads to identify a density-dependent effect that results in a behavioral change for the largest groups considered. This suggests that, in confined environment, the behavioral state of fish and their reaction patterns change with group size. We debate the applicability, beyond the particular case studied here, of this novel framework for deciphering interactions in moving animal groups.'),
(85654, 2012, 'plos', 'Analysis of surface protein expression reveals the growth pattern of the gram-negative outer membrane', 'Ursell, Tristan S|Trepagnier, Eliane H|Huang, Kerwyn Casey|Theriot, Julie A', 'Department of Bioengineering, Stanford University, Stanford, California, USA.|Department of Bioengineering, Stanford University, Stanford, California, USA.|Department of Bioengineering, Stanford University, Stanford, California, USA.|Department of Bioengineering, Stanford University, Stanford, California, USA.', 'United States|United States|United States|United States', 0, 'Bacterial Outer Membrane Proteins|Cell Enlargement|Cell Membrane|Computer Simulation|Escherichia coli|Gene Expression Regulation|Gene Expression Regulation, Bacterial|Membrane Fluidity|Models, Biological|Porins|Receptors, Virus', 'Journal Article', '10.1371/journal.pcbi.1002680', '23028278', 'The outer membrane (OM) of Gram-negative bacteria is a complex bilayer composed of proteins, phospholipids, lipoproteins, and lipopolysaccharides. Despite recent advances revealing the molecular pathways underlying protein and lipopolysaccharide incorporation into the OM, the spatial distribution and dynamic regulation of these processes remain poorly understood. Here, we used sequence-specific fluorescent labeling to map the incorporation patterns of an OM-porin protein, LamB, by labeling proteins only after epitope exposure on the cell surface. Newly synthesized LamB appeared in discrete puncta, rather than evenly distributed over the cell surface. Further growth of bacteria after labeling resulted in divergence of labeled LamB puncta, consistent with a spatial pattern of OM growth in which new, unlabeled material was also inserted in patches. At the poles, puncta remained relatively stationary through several rounds of division, a salient characteristic of the OM protein population as a whole. We propose a biophysical model of growth in which patches of new OM material are added in discrete bursts that evolve in time according to Stokes flow and are randomly distributed over the cell surface. Simulations based on this model demonstrate that our experimental observations are consistent with a bursty insertion pattern without spatial bias across the cylindrical cell surface, with approximately one burst of xe2x89x88 10(-2) xc2xb5m(2) of OM material per two minutes per xc2xb5m(2). Growth by insertion of discrete patches suggests that stochasticity plays a major role in patterning and material organization in the OM.'),
(85655, 2012, 'plos', 'Stress-induced impairment of a working memory task: role of spiking rate and spiking history predicted discharge', 'Devilbiss, David M|Jenison, Rick L|Berridge, Craig W', 'University of Wisconsin-Madison, Madison, Wisconsin, USA. ddevilbiss@wisc.edu|University of Wisconsin-Madison, Madison, Wisconsin, USA. ddevilbiss@wisc.edu|University of Wisconsin-Madison, Madison, Wisconsin, USA. ddevilbiss@wisc.edu', 'United States|United States|United States', 25, 'Action Potentials|Animals|Maze Learning|Memory Disorders|Memory, Short-Term|Mental Recall|Neurons|Prefrontal Cortex|Rats|Stress, Psychological|Task Performance and Analysis', 'Journal Article', '10.1371/journal.pcbi.1002681', '23028279', 'Stress, pervasive in society, contributes to over half of all work place accidents a year and over time can contribute to a variety of psychiatric disorders including depression, schizophrenia, and post-traumatic stress disorder. Stress impairs higher cognitive processes, dependent on the prefrontal cortex (PFC) and that involve maintenance and integration of information over extended periods, including working memory and attention. Substantial evidence has demonstrated a relationship between patterns of PFC neuron spiking activity (action-potential discharge) and components of delayed-response tasks used to probe PFC-dependent cognitive function in rats and monkeys. During delay periods of these tasks, persistent spiking activity is posited to be essential for the maintenance of information for working memory and attention. However, the degree to which stress-induced impairment in PFC-dependent cognition involves changes in task-related spiking rates or the ability for PFC neurons to retain information over time remains unknown. In the current study, spiking activity was recorded from the medial PFC of rats performing a delayed-response task of working memory during acute noise stress (93 db). Spike history-predicted discharge (SHPD) for PFC neurons was quantified as a measure of the degree to which ongoing neuronal discharge can be predicted by past spiking activity and reflects the degree to which past information is retained by these neurons over time. We found that PFC neuron discharge is predicted by their past spiking patterns for nearly one second. Acute stress impaired SHPD, selectively during delay intervals of the task, and simultaneously impaired task performance. Despite the reduction in delay-related SHPD, stress increased delay-related spiking rates. These findings suggest that neural codes utilizing SHPD within PFC networks likely reflects an additional important neurophysiological mechanism for maintenance of past information over time. Stress-related impairment of this mechanism is posited to contribute to the cognition-impairing actions of stress.'),
(85656, 2012, 'plos', 'Binding of two intrinsically disordered peptides to a multi-specific protein: a combined Monte Carlo and molecular dynamics study', 'Staneva, Iskra|Huang, Yongqi|Liu, Zhirong|Wallin, Stefan', 'Department of Astronomy and Theoretical Physics, Computational Biology and Biological Physics group, Lund University, Lund, Sweden.|Department of Astronomy and Theoretical Physics, Computational Biology and Biological Physics group, Lund University, Lund, Sweden.|Department of Astronomy and Theoretical Physics, Computational Biology and Biological Physics group, Lund University, Lund, Sweden.|Department of Astronomy and Theoretical Physics, Computational Biology and Biological Physics group, Lund University, Lund, Sweden.', 'Sweden|Sweden|Sweden|Sweden', 0, 'Amino Acid Sequence|Binding Sites|CapZ Actin Capping Protein|Computer Simulation|Models, Chemical|Models, Statistical|Molecular Dynamics Simulation|Molecular Sequence Data|Monte Carlo Method|Nerve Growth Factors|Oligopeptides|Peptide Fragments|Protein Binding|Protein Conformation|S100 Calcium Binding Protein beta Subunit|S100 Proteins|Tumor Suppressor Protein p53', 'Journal Article', '10.1371/journal.pcbi.1002682', '23028280', 'The unique ability of intrinsically disordered proteins (IDPs) to fold upon binding to partner molecules makes them functionally well-suited for cellular communication networks. For example, the folding-binding of different IDP sequences onto the same surface of an ordered protein provides a mechanism for signaling in a many-to-one manner. Here, we study the molecular details of this signaling mechanism by applying both Molecular Dynamics and Monte Carlo methods to S100B, a calcium-modulated homodimeric protein, and two of its IDP targets, p53 and TRTK-12. Despite adopting somewhat different conformations in complex with S100B and showing no apparent sequence similarity, the two IDP targets associate in virtually the same manner. As free chains, both target sequences remain flexible and sample their respective bound, natively [Formula: see text]-helical states to a small extent. Association occurs through an intermediate state in the periphery of the S100B binding pocket, stabilized by nonnative interactions which are either hydrophobic or electrostatic in nature. Our results highlight the importance of overall physical properties of IDP segments, such as net charge or presence of strongly hydrophobic amino acids, for molecular recognition via coupled folding-binding.'),
(85657, 2012, 'plos', 'Structural investigation of MscL gating using experimental data and coarse grained MD simulations', 'Deplazes, Evelyne|Louhivuori, Martti|Jayatilaka, Dylan|Marrink, Siewert J|Corry, Ben', 'School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Perth, Australia.|School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Perth, Australia.|School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Perth, Australia.|School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Perth, Australia.|School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Perth, Australia.', 'Australia|Australia|Australia|Australia|Australia', 32, 'Computer Simulation|Escherichia coli Proteins|Ion Channel Gating|Ion Channels|Mechanotransduction, Cellular|Models, Chemical|Molecular Dynamics Simulation|Porosity|Protein Conformation|Stress, Mechanical|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1002683', '23028281', 'The mechanosensitive channel of large conductance (MscL) has become a model system in which to understand mechanosensation, a process involved in osmoregulation and many other physiological functions. While a high resolution closed state structure is available, details of the open structure and the gating mechanism remain unknown. In this study we combine coarse grained simulations with restraints from EPR and FRET experiments to study the structural changes involved in gating with much greater level of conformational sampling than has previously been possible. We generated a set of plausible open pore structures that agree well with existing open pore structures and gating models. Most interestingly, we found that membrane thinning induces a kink in the upper part of TM1 that causes an outward motion of the periplasmic loop away from the pore centre. This previously unobserved structural change might present a new mechanism of tension sensing and might be related to a functional role in osmoregulation.'),
(85658, 2012, 'plos', 'Stochastic simulations suggest that HIV-1 survives close to its error threshold', 'Tripathi, Kushal|Balagam, Rajesh|Vishnoi, Nisheeth K|Dixit, Narendra M', 'Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.|Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.|Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.|Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.', 'India|India|India|India', 0, 'Cell Survival|Computer Simulation|Differential Threshold|Genetics, Population|HIV-1|Models, Genetic|Models, Statistical|Mutation|Recombination, Genetic|Stochastic Processes|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.1002684', '23028282', 'The use of mutagenic drugs to drive HIV-1 past its error threshold presents a novel intervention strategy, as suggested by the quasispecies theory, that may be less susceptible to failure via viral mutation-induced emergence of drug resistance than current strategies. The error threshold of HIV-1, xcexbc c, however, is not known. Application of the quasispecies theory to determine xcexbc c poses significant challenges: Whereas the quasispecies theory considers the asexual reproduction of an infinitely large population of haploid individuals, HIV-1 is diploid, undergoes recombination, and is estimated to have a small effective population size in vivo. We performed population genetics-based stochastic simulations of the within-host evolution of HIV-1 and estimated the structure of the HIV-1 quasispecies and xcexbc c. We found that with small mutation rates, the quasispecies was dominated by genomes with few mutations. Upon increasing the mutation rate, a sharp error catastrophe occurred where the quasispecies became delocalized in sequence space. Using parameter values that quantitatively captured data of viral diversification in HIV-1 patients, we estimated xcexbc c to be 7 x 10(-5)-1 x 10(-4) substitutions/site/replication, xe2x89x88 2-6 fold higher than the natural mutation rate of HIV-1, suggesting that HIV-1 survives close to its error threshold and may be readily susceptible to mutagenic drugs. The latter estimate was weakly dependent on the within-host effective population size of HIV-1. With large population sizes and in the absence of recombination, our simulations converged to the quasispecies theory, bridging the gap between quasispecies theory and population genetics-based approaches to describing HIV-1 evolution. Further, xcexbc c increased with the recombination rate, rendering HIV-1 less susceptible to error catastrophe, thus elucidating an added benefit of recombination to HIV-1. Our estimate of xcexbc c may serve as a quantitative guideline for the use of mutagenic drugs against HIV-1.'),
(85659, 2012, 'plos', 'Mechanism of bacterial signal transduction revealed by molecular dynamics of Tsr dimers and trimers of dimers in lipid vesicles', 'Hall, Benjamin A|Armitage, Judith P|Sansom, Mark S P', 'Oxford Centre for Integrative Systems Biology, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.|Oxford Centre for Integrative Systems Biology, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.|Oxford Centre for Integrative Systems Biology, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 32, 'Bacterial Proteins|Binding Sites|Cell Membrane|Computer Simulation|Membrane Fluidity|Membrane Microdomains|Membrane Proteins|Models, Chemical|Models, Molecular|Protein Binding|Protein Conformation|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002685', '23028283', 'Bacterial chemoreceptors provide an important model for understanding signalling processes. In the serine receptor Tsr from E. coli, a binding event in the periplasmic domain of the receptor dimer causes a shift in a single transmembrane helix of roughly 0.15 nm towards the cytoplasm. This small change is propagated through the xe2x89x88 22 nm length of the receptor, causing downstream inhibition of the kinase CheA. This requires interactions within a trimer of receptor dimers. Additionally, the signal is amplified across a 53,000 nm(2) array of chemoreceptor proteins, including xe2x89x88 5,200 receptor trimers-of-dimers, at the cell pole. Despite a wealth of experimental data on the system, including high resolution structures of individual domains and extensive mutagenesis data, it remains uncertain how information is communicated across the receptor from the binding event to the downstream effectors. We present a molecular model of the entire Tsr dimer, and examine its behaviour using coarse-grained molecular dynamics and elastic network modelling. We observe a large bending in dimer models between the linker domain HAMP and coiled-coil domains, which is supported by experimental data. Models of the trimer of dimers, built from the dimer models, are more constrained and likely represent the signalling state. Simulations of the models in a 70 nm diameter vesicle with a biologically realistic lipid mixture reveal specific lipid interactions and oligomerisation of the trimer of dimers. The results indicate a mechanism whereby small motions of a single helix can be amplified through HAMP domain packing, to initiate large changes in the whole receptor structure.');
