INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85314, 2012, 'plos', 'Network model of immune responses reveals key effectors to single and co-infection dynamics by a respiratory bacterium and a gastrointestinal helminth', 'Thakar, Juilee|Pathak, Ashutosh K|Murphy, Lisa|Albert, Réka|Cattadori, Isabella M', 'Center for Infectious Disease Dynamics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Center for Infectious Disease Dynamics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Center for Infectious Disease Dynamics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Center for Infectious Disease Dynamics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Center for Infectious Disease Dynamics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Animals|Bordetella Infections|Bordetella bronchiseptica|Coinfection|Helminths|Models, Theoretical|Respiratory System|Trichostrongylus', 'Journal Article', '10.1371/journal.pcbi.1002345', '22253585', 'Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology, the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations.'),
(85315, 2012, 'plos', 'Maximization of learning speed in the motor cortex due to neuronal redundancy', 'Takiyama, Ken|Okada, Masato', 'Graduate School of Frontier Sciences, The University of Tokyo, Complex Science and Engineering, Chiba, Japan.|Graduate School of Frontier Sciences, The University of Tokyo, Complex Science and Engineering, Chiba, Japan.', 'Japan|Japan', 11, 'Learning|Motor Cortex|Neural Networks (Computer)|Neurons', 'Journal Article', '10.1371/journal.pcbi.1002348', '22253586', 'Many redundancies play functional roles in motor control and motor learning. For example, kinematic and muscle redundancies contribute to stabilizing posture and impedance control, respectively. Another redundancy is the number of neurons themselves, there are overwhelmingly more neurons than muscles, and many combinations of neural activation can generate identical muscle activity. The functional roles of this neuronal redundancy remains unknown. Analysis of a redundant neural network model makes it possible to investigate these functional roles while varying the number of model neurons and holding constant the number of output units. Our analysis reveals that learning speed reaches its maximum value if and only if the model includes sufficient neuronal redundancy. This analytical result does not depend on whether the distribution of the preferred direction is uniform or a skewed bimodal, both of which have been reported in neurophysiological studies. Neuronal redundancy maximizes learning speed, even if the neural network model includes recurrent connections, a nonlinear activation function, or nonlinear muscle units. Furthermore, our results do not rely on the shape of the generalization function. The results of this study suggest that one of the functional roles of neuronal redundancy is to maximize learning speed.'),
(85316, 2012, 'plos', 'Kinetic rate constant prediction supports the conformational selection mechanism of protein binding', 'Moal, Iain H|Bates, Paul A', 'Protein Interactions and Docking Laboratory, Life Sciences Department, Barcelona Supercomputing Center, Barcelona, Spain. imoal@bsc.es|Protein Interactions and Docking Laboratory, Life Sciences Department, Barcelona Supercomputing Center, Barcelona, Spain. imoal@bsc.es', 'Spain|Spain', 41, 'Algorithms|Binding Sites|Kinetics|Models, Molecular|Protein Conformation|Proteins|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002351', '22253587', 'The prediction of protein-protein kinetic rate constants provides a fundamental test of our understanding of molecular recognition, and will play an important role in the modeling of complex biological systems. In this paper, a feature selection and regression algorithm is applied to mine a large set of molecular descriptors and construct simple models for association and dissociation rate constants using empirical data. Using separate test data for validation, the predicted rate constants can be combined to calculate binding affinity with accuracy matching that of state of the art empirical free energy functions. The models show that the rate of association is linearly related to the proportion of unbound proteins in the bound conformational ensemble relative to the unbound conformational ensemble, indicating that the binding partners must adopt a geometry near to that of the bound prior to binding. Mirroring the conformational selection and population shift mechanism of protein binding, the models provide a strong separate line of evidence for the preponderance of this mechanism in protein-protein binding, complementing structural and theoretical studies.'),
(85317, 2012, 'plos', 'Residual structures, conformational fluctuations, and electrostatic interactions in the synergistic folding of two intrinsically disordered proteins', 'Zhang, Weihong|Ganguly, Debabani|Chen, Jianhan', 'Department of Biochemistry, Kansas State University, Manhattan, Kansas, United States of America.|Department of Biochemistry, Kansas State University, Manhattan, Kansas, United States of America.|Department of Biochemistry, Kansas State University, Manhattan, Kansas, United States of America.', 'United States|United States|United States', 0, 'Binding Sites|Computer Simulation|Models, Molecular|Protein Folding|Protein Structure, Tertiary|Proteins', 'Journal Article', '10.1371/journal.pcbi.1002353', '22253588', 'To understand the interplay of residual structures and conformational fluctuations in the interaction of intrinsically disordered proteins (IDPs), we first combined implicit solvent and replica exchange sampling to calculate atomistic disordered ensembles of the nuclear co-activator binding domain (NCBD) of transcription coactivator CBP and the activation domain of the p160 steroid receptor coactivator ACTR. The calculated ensembles are in quantitative agreement with NMR-derived residue helicity and recapitulate the experimental observation that, while free ACTR largely lacks residual secondary structures, free NCBD is a molten globule with a helical content similar to that in the folded complex. Detailed conformational analysis reveals that free NCBD has an inherent ability to substantially sample all the helix configurations that have been previously observed either unbound or in complexes. Intriguingly, further high-temperature unbinding and unfolding simulations in implicit and explicit solvents emphasize the importance of conformational fluctuations in synergistic folding of NCBD with ACTR. A balance between preformed elements and conformational fluctuations appears necessary to allow NCBD to interact with different targets and fold into alternative conformations. Together with previous topology-based modeling and existing experimental data, the current simulations strongly support an extended conformational selection synergistic folding mechanism that involves a key intermediate state stabilized by interaction between the C-terminal helices of NCBD and ACTR. In addition, the atomistic simulations reveal the role of long-range as well as short-range electrostatic interactions in cooperating with readily fluctuating residual structures, which might enhance the encounter rate and promote efficient folding upon encounter for facile binding and folding interactions of IDPs. Thus, the current study not only provides a consistent mechanistic understanding of the NCBD/ACTR interaction, but also helps establish a multi-scale molecular modeling framework for understanding the structure, interaction, and regulation of IDPs in general.'),
(85318, 2012, 'plos', 'Senescent cells in growing tumors: population dynamics and cancer stem cells', 'La Porta, Caterina A M|Zapperi, Stefano|Sethna, James P', 'Department of Biomolecular Science and Biotechnology, University of Milano, Milano, Italy.|Department of Biomolecular Science and Biotechnology, University of Milano, Milano, Italy.|Department of Biomolecular Science and Biotechnology, University of Milano, Milano, Italy.', 'Italy|Italy|Italy', 0, 'ATP Binding Cassette Transporter, Subfamily G, Member 2|ATP-Binding Cassette Transporters|Cell Growth Processes|Cell Hypoxia|Cell Line, Tumor|Cellular Senescence|Cluster Analysis|Computational Biology|Computer Simulation|Humans|Inhibitor of Apoptosis Proteins|Melanoma|Mesenchymal Stem Cells|Models, Biological|Neoplasm Proteins|Neoplastic Stem Cells|Stochastic Processes|Survivin|Transfection|Transplantation, Heterologous', 'Journal Article', '10.1371/journal.pcbi.1002316', '22275856', 'Tumors are defined by their intense proliferation, but sometimes cancer cells turn senescent and stop replicating. In the stochastic cancer model in which all cells are tumorigenic, senescence is seen as the result of random mutations, suggesting that it could represent a barrier to tumor growth. In the hierarchical cancer model a subset of the cells, the cancer stem cells, divide indefinitely while other cells eventually turn senescent. Here we formulate cancer growth in mathematical terms and obtain predictions for the evolution of senescence. We perform experiments in human melanoma cells which are compatible with the hierarchical model and show that senescence is a reversible process controlled by survivin. We conclude that enhancing senescence is unlikely to provide a useful therapeutic strategy to fight cancer, unless the cancer stem cells are specifically targeted.'),
(85319, 2012, 'plos', 'Learning and generalization under ambiguity: an fMRI study', 'Chumbley, J R|Flandin, G|Bach, D R|Daunizeau, J|Fehr, E|Dolan, R J|Friston, K J', 'The Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. j.chumbley@fil.ion.ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. j.chumbley@fil.ion.ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. j.chumbley@fil.ion.ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. j.chumbley@fil.ion.ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. j.chumbley@fil.ion.ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. j.chumbley@fil.ion.ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. j.chumbley@fil.ion.ucl.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 14, 'Adult|Bayes Theorem|Choice Behavior|Computational Biology|Female|Generalization (Psychology)|Hippocampus|Humans|Learning|Logistic Models|Magnetic Resonance Imaging|Male|Reinforcement (Psychology)|Reward', 'Journal Article', '10.1371/journal.pcbi.1002346', '22275857', 'Adaptive behavior often exploits generalizations from past experience by applying them judiciously in new situations. This requires a means of quantifying the relative importance of prior experience and current information, so they can be balanced optimally. In this study, we ask whether the brain generalizes in an optimal way. Specifically, we used Bayesian learning theory and fMRI to test whether neuronal responses reflect context-sensitive changes in ambiguity or uncertainty about experience-dependent beliefs. We found that the hippocampus expresses clear ambiguity-dependent responses that are associated with an augmented rate of learning. These findings suggest candidate neuronal systems that may be involved in aberrations of generalization, such as over-confidence.'),
(85320, 2012, 'plos', 'A theory of rate coding control by intrinsic plasticity effects', 'Naudé, J|Paz, J T|Berry, H|Delord, B', 'Institut des Systèmes Intelligents et de Robotique, CNRS - UMR 7222, Université Pierre et Marie Curie, Paris, France.|Institut des Systèmes Intelligents et de Robotique, CNRS - UMR 7222, Université Pierre et Marie Curie, Paris, France.|Institut des Systèmes Intelligents et de Robotique, CNRS - UMR 7222, Université Pierre et Marie Curie, Paris, France.|Institut des Systèmes Intelligents et de Robotique, CNRS - UMR 7222, Université Pierre et Marie Curie, Paris, France.', 'France|France|France|France', 10, 'Action Potentials|Animals|Computer Simulation|Models, Neurological|Nerve Net|Neuronal Plasticity|Regression Analysis', 'Journal Article', '10.1371/journal.pcbi.1002349', '22275858', 'Intrinsic plasticity (IP) is a ubiquitous activity-dependent process regulating neuronal excitability and a cellular correlate of behavioral learning and neuronal homeostasis. Because IP is induced rapidly and maintained long-term, it likely represents a major determinant of adaptive collective neuronal dynamics. However, assessing the exact impact of IP has remained elusive. Indeed, it is extremely difficult disentangling the complex non-linear interaction between IP effects, by which conductance changes alter neuronal activity, and IP rules, whereby activity modifies conductance via signaling pathways. Moreover, the two major IP effects on firing rate, threshold and gain modulation, remain unknown in their very mechanisms. Here, using extensive simulations and sensitivity analysis of Hodgkin-Huxley models, we show that threshold and gain modulation are accounted for by maximal conductance plasticity of conductance that situate in two separate domains of the parameter space corresponding to sub- and supra-threshold conductance (i.e. activating below or above the spike onset threshold potential). Analyzing equivalent integrate-and-fire models, we provide formal expressions of sensitivities relating to conductance parameters, unraveling unprecedented mechanisms governing IP effects. Our results generalize to the IP of other conductance parameters and allow strong inference for calcium-gated conductance, yielding a general picture that accounts for a large repertoire of experimental observations. The expressions we provide can be combined with IP rules in rate or spiking models, offering a general framework to systematically assess the computational consequences of IP of pharmacologically identified conductance with both fine grain description and mathematical tractability. We provide an example of such IP loop model addressing the important issue of the homeostatic regulation of spontaneous discharge. Because we do not formulate any assumptions on modification rules, the present theory is also relevant to other neural processes involving excitability changes, such as neuromodulation, development, aging and neural disorders.'),
(85321, 2012, 'plos', 'Membrane properties and the balance between excitation and inhibition control gamma-frequency oscillations arising from feedback inhibition', 'Economo, Michael N|White, John A', 'Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America.|Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America.', 'United States|United States', 0, 'Action Potentials|Animals|Brain Waves|Computer Simulation|Feedback, Physiological|Mice|Mice, Transgenic|Models, Neurological|Neurons|Patch-Clamp Techniques|Pyramidal Cells', 'Journal Article', '10.1371/journal.pcbi.1002354', '22275859', 'Computational studies as well as in vivo and in vitro results have shown that many cortical neurons fire in a highly irregular manner and at low average firing rates. These patterns seem to persist even when highly rhythmic signals are recorded by local field potential electrodes or other methods that quantify the summed behavior of a local population. Models of the 30-80 Hz gamma rhythm in which network oscillations arise through stochastic synchrony capture the variability observed in the spike output of single cells while preserving network-level organization. We extend upon these results by constructing model networks constrained by experimental measurements and using them to probe the effect of biophysical parameters on network-level activity. We find in simulations that gamma-frequency oscillations are enabled by a high level of incoherent synaptic conductance input, similar to the barrage of noisy synaptic input that cortical neurons have been shown to receive in vivo. This incoherent synaptic input increases the emergent network frequency by shortening the time scale of the membrane in excitatory neurons and by reducing the temporal separation between excitation and inhibition due to decreased spike latency in inhibitory neurons. These mechanisms are demonstrated in simulations and in vitro current-clamp and dynamic-clamp experiments. Simulation results further indicate that the membrane potential noise amplitude has a large impact on network frequency and that the balance between excitatory and inhibitory currents controls network stability and sensitivity to external inputs.'),
(85322, 2012, 'plos', 'HIV-1 polymerase inhibition by nucleoside analogs: cellular- and kinetic parameters of efficacy, susceptibility and resistance selection', 'von Kleist, Max|Metzner, Philipp|Marquet, Roland|Schütte, Christof', 'Department of Mathematics and Computer Science, Free University Berlin, Berlin, Germany. vkleist@zedat.fu-berlin.de|Department of Mathematics and Computer Science, Free University Berlin, Berlin, Germany. vkleist@zedat.fu-berlin.de|Department of Mathematics and Computer Science, Free University Berlin, Berlin, Germany. vkleist@zedat.fu-berlin.de|Department of Mathematics and Computer Science, Free University Berlin, Berlin, Germany. vkleist@zedat.fu-berlin.de', 'Germany|Germany|Germany|Germany', 20, 'Anti-HIV Agents|Base Sequence|DNA, Viral|Dideoxynucleotides|Drug Resistance, Viral|HIV Infections|HIV Reverse Transcriptase|HIV-1|Humans|Kinetics|Models, Molecular|Molecular Sequence Data|Mutation|Nucleosides|RNA, Viral|Reverse Transcriptase Inhibitors|Thymine Nucleotides|Zidovudine|pol Gene Products, Human Immunodeficiency Virus', 'Journal Article', '10.1371/journal.pcbi.1002359', '22275860', 'Nucleoside analogs (NAs) are used to treat numerous viral infections and cancer. They compete with endogenous nucleotides (dNTP/NTP) for incorporation into nascent DNA/RNA and inhibit replication by preventing subsequent primer extension. To date, an integrated mathematical model that could allow the analysis of their mechanism of action, of the various resistance mechanisms, and their effect on viral fitness is still lacking. We present the first mechanistic mathematical model of polymerase inhibition by NAs that takes into account the reversibility of polymerase inhibition. Analytical solutions for the model point out the cellular- and kinetic aspects of inhibition. Our model correctly predicts for HIV-1 that resistance against nucleoside analog reverse transcriptase inhibitors (NRTIs) can be conferred by decreasing their incorporation rate, increasing their excision rate, or decreasing their affinity for the polymerase enzyme. For all analyzed NRTIs and their combinations, model-predicted macroscopic parameters (efficacy, fitness and toxicity) were consistent with observations. NRTI efficacy was found to greatly vary between distinct target cells. Surprisingly, target cells with low dNTP/NTP levels may not confer hyper-susceptibility to inhibition, whereas cells with high dNTP/NTP contents are likely to confer natural resistance. Our model also allows quantification of the selective advantage of mutations by integrating their effects on viral fitness and drug susceptibility. For zidovudine triphosphate (AZT-TP), we predict that this selective advantage, as well as the minimal concentration required to select thymidine-associated mutations (TAMs) are highly cell-dependent. The developed model allows studying various resistance mechanisms, inherent fitness effects, selection forces and epistasis based on microscopic kinetic data. It can readily be embedded in extended models of the complete HIV-1 reverse transcription process, or analogous processes in other viruses and help to guide drug development and improve our understanding of the mechanisms of resistance development during treatment.'),
(85323, 2012, 'plos', 'Prediction by promoter logic in bacterial quorum sensing', 'Rai, Navneet|Anand, Rajat|Ramkumar, Krishna|Sreenivasan, Varun|Dabholkar, Sugat|Venkatesh, K V|Thattai, Mukund', 'National Centre for Biological Sciences, Tata Institute of Fundamental Research, UAS/GKVK Campus, Bangalore, India.|National Centre for Biological Sciences, Tata Institute of Fundamental Research, UAS/GKVK Campus, Bangalore, India.|National Centre for Biological Sciences, Tata Institute of Fundamental Research, UAS/GKVK Campus, Bangalore, India.|National Centre for Biological Sciences, Tata Institute of Fundamental Research, UAS/GKVK Campus, Bangalore, India.|National Centre for Biological Sciences, Tata Institute of Fundamental Research, UAS/GKVK Campus, Bangalore, India.|National Centre for Biological Sciences, Tata Institute of Fundamental Research, UAS/GKVK Campus, Bangalore, India.|National Centre for Biological Sciences, Tata Institute of Fundamental Research, UAS/GKVK Campus, Bangalore, India.', 'India|India|India|India|India|India|India', 13, 'Aliivibrio fischeri|Escherichia coli|Feedback, Physiological|Gene Expression Regulation, Bacterial|Models, Genetic|Models, Statistical|Promoter Regions, Genetic|Quorum Sensing|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002361', '22275861', 'Quorum-sensing systems mediate chemical communication between bacterial cells, coordinating cell-density-dependent processes like biofilm formation and virulence-factor expression. In the proteobacterial LuxI/LuxR quorum sensing paradigm, a signaling molecule generated by an enzyme (LuxI) diffuses between cells and allosterically stimulates a transcriptional regulator (LuxR) to activate its cognate promoter (pR). By expressing either LuxI or LuxR in positive feedback from pR, these versatile systems can generate smooth (monostable) or abrupt (bistable) density-dependent responses to suit the ecological context. Here we combine theory and experiment to demonstrate that the promoter logic of pR - its measured activity as a function of LuxI and LuxR levels - contains all the biochemical information required to quantitatively predict the responses of such feedback loops. The interplay of promoter logic with feedback topology underlies the versatility of the LuxI/LuxR paradigm: LuxR and LuxI positive-feedback systems show dramatically different responses, while a dual positive/negative-feedback system displays synchronized oscillations. These results highlight the dual utility of promoter logic: to probe microscopic parameters and predict macroscopic phenotype.'),
(85324, 2012, 'plos', 'Protein design using continuous rotamers', 'Gainza, Pablo|Roberts, Kyle E|Donald, Bruce R', 'Department of Computer Science, Duke University, Durham, North Carolina, United States of America.|Department of Computer Science, Duke University, Durham, North Carolina, United States of America.|Department of Computer Science, Duke University, Durham, North Carolina, United States of America.', 'United States|United States|United States', 71, 'Algorithms|Amino Acids|Computational Biology|Computer Simulation|Databases, Protein|Models, Molecular|Protein Conformation|Protein Engineering|Proteins|Software|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002335', '22279426', 'Optimizing amino acid conformation and identity is a central problem in computational protein design. Protein design algorithms must allow realistic protein flexibility to occur during this optimization, or they may fail to find the best sequence with the lowest energy. Most design algorithms implement side-chain flexibility by allowing the side chains to move between a small set of discrete, low-energy states, which we call rigid rotamers. In this work we show that allowing continuous side-chain flexibility (which we call continuous rotamers) greatly improves protein flexibility modeling. We present a large-scale study that compares the sequences and best energy conformations in 69 protein-core redesigns using a rigid-rotamer model versus a continuous-rotamer model. We show that in nearly all of our redesigns the sequence found by the continuous-rotamer model is different and has a lower energy than the one found by the rigid-rotamer model. Moreover, the sequences found by the continuous-rotamer model are more similar to the native sequences. We then show that the seemingly easy solution of sampling more rigid rotamers within the continuous region is not a practical alternative to a continuous-rotamer model: at computationally feasible resolutions, using more rigid rotamers was never better than a continuous-rotamer model and almost always resulted in higher energies. Finally, we present a new protein design algorithm based on the dead-end elimination (DEE) algorithm, which we call iMinDEE, that makes the use of continuous rotamers feasible in larger systems. iMinDEE guarantees finding the optimal answer while pruning the search space with close to the same efficiency of DEE.'),
(85325, 2012, 'plos', 'Computational and statistical analysis of protein mass spectrometry data', 'Noble, William Stafford|MacCoss, Michael J', 'Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America. william-noble@uw.edu|Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America. william-noble@uw.edu', 'United States|United States', 0, 'Computational Biology|Mass Spectrometry|Proteins|Proteomics', 'Journal Article', '10.1371/journal.pcbi.1002296', '22291580', 'High-throughput proteomics experiments involving tandem mass spectrometry produce large volumes of complex data that require sophisticated computational analyses. As such, the field offers many challenges for computational biologists. In this article, we briefly introduce some of the core computational and statistical problems in the field and then describe a variety of outstanding problems that readers of PLoS Computational Biology might be able to help solve.'),
(85326, 2012, 'plos', 'Beyond statistical significance: implications of network structure on neuronal activity', 'Vlachos, Ioannis|Aertsen, Ad|Kumar, Arvind', 'Bernstein Center Freiburg, Neurobiology & Biophysics, Faculty of Biology, University of Freiburg, Freiburg, Germany. vlachos@bcf.uni-freiburg.de|Bernstein Center Freiburg, Neurobiology & Biophysics, Faculty of Biology, University of Freiburg, Freiburg, Germany. vlachos@bcf.uni-freiburg.de|Bernstein Center Freiburg, Neurobiology & Biophysics, Faculty of Biology, University of Freiburg, Freiburg, Germany. vlachos@bcf.uni-freiburg.de', 'Germany|Germany|Germany', 19, 'Models, Theoretical|Motor Activity|Neurons', 'Journal Article', '10.1371/journal.pcbi.1002311', '22291581', 'It is a common and good practice in experimental sciences to assess the statistical significance of measured outcomes. For this, the probability of obtaining the actual results is estimated under the assumption of an appropriately chosen null-hypothesis. If this probability is smaller than some threshold, the results are deemed statistically significant and the researchers are content in having revealed, within their own experimental domain, a surprising anomaly, possibly indicative of a hitherto hidden fragment of the underlying ground-truth. What is often neglected, though, is the actual importance of these experimental outcomes for understanding the system under investigation. We illustrate this point by giving practical and intuitive examples from the field of systems neuroscience. Specifically, we use the notion of embeddedness to quantify the impact of a neurons activity on its downstream neurons in the network. We show that the network response strongly depends on the embeddedness of stimulated neurons and that embeddedness is a key determinant of the importance of neuronal activity on local and downstream processing. We extrapolate these results to other fields in which networks are used as a theoretical framework.'),
(85327, 2012, 'plos', 'A feedback quenched oscillator produces turing patterning with one diffuser', 'Hsia, Justin|Holtz, William J|Huang, Daniel C|Arcak, Murat|Maharbiz, Michel M', 'Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, California, United States of America. jhsia@eecs.berkeley.edu|Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, California, United States of America. jhsia@eecs.berkeley.edu|Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, California, United States of America. jhsia@eecs.berkeley.edu|Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, California, United States of America. jhsia@eecs.berkeley.edu|Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, California, United States of America. jhsia@eecs.berkeley.edu', 'United States|United States|United States|United States|United States', 0, 'Computer Simulation|Feedback|Gene Regulatory Networks', 'Journal Article', '10.1371/journal.pcbi.1002331', '22291582', 'Efforts to engineer synthetic gene networks that spontaneously produce patterning in multicellular ensembles have focused on Turings original model and the activator-inhibitor models of Meinhardt and Gierer. Systems based on this model are notoriously difficult to engineer. We present the first demonstration that Turing pattern formation can arise in a new family of oscillator-driven gene network topologies, specifically when a second feedback loop is introduced which quenches oscillations and incorporates a diffusible molecule. We provide an analysis of the system that predicts the range of kinetic parameters over which patterning should emerge and demonstrate the systems viability using stochastic simulations of a field of cells using realistic parameters. The primary goal of this paper is to provide a circuit architecture which can be implemented with relative ease by practitioners and which could serve as a model system for pattern generation in synthetic multicellular systems. Given the wide range of oscillatory circuits in natural systems, our system supports the tantalizing possibility that Turing pattern formation in natural multicellular systems can arise from oscillator-driven mechanisms.'),
(85328, 2012, 'plos', 'Balancing feed-forward excitation and inhibition via Hebbian inhibitory synaptic plasticity', 'Luz, Yotam|Shamir, Maoz', 'Department of Physiology and Neurobiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Department of Physiology and Neurobiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.', 'Israel|Israel', 44, 'Excitatory Postsynaptic Potentials|Models, Neurological|Neuronal Plasticity|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002334', '22291583', 'It has been suggested that excitatory and inhibitory inputs to cortical cells are balanced, and that this balance is important for the highly irregular firing observed in the cortex. There are two hypotheses as to the origin of this balance. One assumes that it results from a stable solution of the recurrent neuronal dynamics. This model can account for a balance of steady state excitation and inhibition without fine tuning of parameters, but not for transient inputs. The second hypothesis suggests that the feed forward excitatory and inhibitory inputs to a postsynaptic cell are already balanced. This latter hypothesis thus does account for the balance of transient inputs. However, it remains unclear what mechanism underlies the fine tuning required for balancing feed forward excitatory and inhibitory inputs. Here we investigated whether inhibitory synaptic plasticity is responsible for the balance of transient feed forward excitation and inhibition. We address this issue in the framework of a model characterizing the stochastic dynamics of temporally anti-symmetric Hebbian spike timing dependent plasticity of feed forward excitatory and inhibitory synaptic inputs to a single post-synaptic cell. Our analysis shows that inhibitory Hebbian plasticity generates negative feedback that balances excitation and inhibition, which contrasts with the positive feedback of excitatory Hebbian synaptic plasticity. As a result, this balance may increase the sensitivity of the learning dynamics to the correlation structure of the excitatory inputs.'),
(85329, 2012, 'plos', 'Macro-level modeling of the response of C elegans reproduction to chronic heat stress', 'McMullen, Patrick D|Aprison, Erin Z|Winter, Peter B|Amaral, Luis A N|Morimoto, Richard I|Ruvinsky, Ilya', 'Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, United States of America.|Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, United States of America.|Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, United States of America.|Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, United States of America.|Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, United States of America.|Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, United States of America.', 'United States|United States|United States|United States|United States|United States', 22, 'Animals|Caenorhabditis elegans|Reproduction|Stress, Physiological|Temperature', 'Journal Article', '10.1371/journal.pcbi.1002338', '22291584', 'A major goal of systems biology is to understand how organism-level behavior arises from a myriad of molecular interactions. Often this involves complex sets of rules describing interactions among a large number of components. As an alternative, we have developed a simple, macro-level model to describe how chronic temperature stress affects reproduction in C. elegans. Our approach uses fundamental engineering principles, together with a limited set of experimentally derived facts, and provides quantitatively accurate predictions of performance under a range of physiologically relevant conditions. We generated detailed time-resolved experimental data to evaluate the ability of our model to describe the dynamics of C. elegans reproduction. We find considerable heterogeneity in responses of individual animals to heat stress, which can be understood as modulation of a few processes and may represent a strategy for coping with the ever-changing environment. Our experimental results and model provide quantitative insight into the breakdown of a robust biological system under stress and suggest, surprisingly, that the behavior of complex biological systems may be determined by a small number of key components.'),
(85330, 2012, 'plos', 'Single sample expression-anchored mechanisms predict survival in head and neck cancer', 'Yang, Xinan|Regan, Kelly|Huang, Yong|Zhang, Qingbei|Li, Jianrong|Seiwert, Tanguy Y|Cohen, Ezra E W|Xing, H Rosie|Lussier, Yves A', 'Center for Biomedical Informatics, The University of Chicago, Chicago, Illinois, United States of America.|Center for Biomedical Informatics, The University of Chicago, Chicago, Illinois, United States of America.|Center for Biomedical Informatics, The University of Chicago, Chicago, Illinois, United States of America.|Center for Biomedical Informatics, The University of Chicago, Chicago, Illinois, United States of America.|Center for Biomedical Informatics, The University of Chicago, Chicago, Illinois, United States of America.|Center for Biomedical Informatics, The University of Chicago, Chicago, Illinois, United States of America.|Center for Biomedical Informatics, The University of Chicago, Chicago, Illinois, United States of America.|Center for Biomedical Informatics, The University of Chicago, Chicago, Illinois, United States of America.|Center for Biomedical Informatics, The University of Chicago, Chicago, Illinois, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Carcinoma, Squamous Cell|Cohort Studies|Gene Expression Profiling|Head and Neck Neoplasms|Humans|ROC Curve', 'Journal Article', '10.1371/journal.pcbi.1002350', '22291585', 'Gene expression signatures that are predictive of therapeutic response or prognosis are increasingly useful in clinical care, however, mechanistic (and intuitive) interpretation of expression arrays remains an unmet challenge. Additionally, there is surprisingly little gene overlap among distinct clinically validated expression signatures. These causality challenges hinder the adoption of signatures as compared to functionally well-characterized single gene biomarkers. To increase the utility of multi-gene signatures in survival studies, we developed a novel approach to generate personal mechanism signatures of molecular pathways and functions from gene expression arrays. FAIME, the Functional Analysis of Individual Microarray Expression, computes mechanism scores using rank-weighted gene expression of an individual sample. By comparing head and neck squamous cell carcinoma (HNSCC) samples with non-tumor control tissues, the precision and recall of deregulated FAIME-derived mechanisms of pathways and molecular functions are comparable to those produced by conventional cohort-wide methods (e.g. GSEA). The overlap of Oncogenic FAIME Features of HNSCC (statistically significant and differentially regulated FAIME-derived genesets representing GO functions or KEGG pathways derived from HNSCC tissue) among three distinct HNSCC datasets (pathways:46%, p<0.001) is more significant than the gene overlap (genes:4%). These Oncogenic FAIME Features of HNSCC can accurately discriminate tumors from control tissues in two additional HNSCC datasets (nxe2x80x8a=xe2x80x8a35 and 91, F-accuracyxe2x80x8a=xe2x80x8a100% and 97%, empirical p<0.001, area under the receiver operating characteristic curvesxe2x80x8a=xe2x80x8a99% and 92%), and stratify recurrence-free survival in patients from two independent studies (pxe2x80x8a=xe2x80x8a0.0018 and pxe2x80x8a=xe2x80x8a0.032, log-rank). Previous approaches depending on group assignment of individual samples before selecting features or learning a classifier are limited by design to discrete-class prediction. In contrast, FAIME calculates mechanism profiles for individual patients without requiring group assignment in validation sets. FAIME is more amenable for clinical deployment since it translates the gene-level measurements of each given sample into pathways and molecular function profiles that can be applied to analyze continuous phenotypes in clinical outcome studies (e.g. survival time, tumor volume).'),
(85331, 2012, 'plos', 'Human visual search does not maximize the post-saccadic probability of identifying targets', 'Morvan, Camille|Maloney, Laurence T', 'Department of Psychology, New York University, New York, New York, USA. morvan@fas.harvard.edu|Department of Psychology, New York University, New York, New York, USA. morvan@fas.harvard.edu', 'United States|United States', 0, 'Computational Biology|Female|Fixation, Ocular|Humans|Male|Models, Biological|Photic Stimulation|Psychomotor Performance|Retina|Saccades', 'Journal Article', '10.1371/journal.pcbi.1002342', '22319428', 'Researchers have conjectured that eye movements during visual search are selected to minimize the number of saccades. The optimal Bayesian eye movement strategy minimizing saccades does not simply direct the eye to whichever location is judged most likely to contain the target but makes use of the entire retina as an information gathering device during each fixation. Here we show that human observers do not minimize the expected number of saccades in planning saccades in a simple visual search task composed of three tokens. In this task, the optimal eye movement strategy varied, depending on the spacing between tokens (in the first experiment) or the size of tokens (in the second experiment), and changed abruptly once the separation or size surpassed a critical value. None of our observers changed strategy as a function of separation or size. Human performance fell far short of ideal, both qualitatively and quantitatively.'),
(85332, 2012, 'plos', 'In silico experimentation of glioma microenvironment development and anti-tumor therapy', 'Wu, Yu|Lu, Yao|Chen, Weiqiang|Fu, Jianping|Fan, Rong', 'Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA.|Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA.|Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA.|Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA.|Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA.', 'United States|United States|United States|United States|United States', 0, 'Antineoplastic Agents|Antineoplastic Combined Chemotherapy Protocols|Astrocytes|Computer Simulation|Cytokines|Glioma|Humans|Microglia|Models, Biological|Signal Transduction|Tumor Microenvironment', 'Journal Article', '10.1371/journal.pcbi.1002355', '22319429', 'Tumor cells do not develop in isolation, but co-evolve with stromal cells and tumor-associated immune cells in a tumor microenvironment mediated by an array of soluble factors, forming a complex intercellular signaling network. Herein, we report an unbiased, generic model to integrate prior biochemical data and the constructed brain tumor microenvironment in silico as characterized by an intercellular signaling network comprising 5 types of cells, 15 cytokines, and 69 signaling pathways. The results show that glioma develops through three distinct phases: pre-tumor, rapid expansion, and saturation. We designed a microglia depletion therapy and observed significant benefit for virtual patients treated at the early stages but strikingly no therapeutic efficacy at all when therapy was given at a slightly later stage. Cytokine combination therapy exhibits more focused and enhanced therapeutic response even when microglia depletion therapy already fails. It was further revealed that the optimal combination depends on the molecular profile of individual patients, suggesting the need for patient stratification and personalized treatment. These results, obtained solely by observing the in silico dynamics of the glioma microenvironment with no fitting to experimental/clinical data, reflect many characteristics of human glioma development and imply new venues for treating tumors via selective targeting of microenvironmental components.'),
(85333, 2012, 'plos', 'Positive evolutionary selection of an HD motif on Alzheimer precursor protein orthologues suggests a functional role', 'Miklxc3xb3s, Istvxc3xa1n|Zxc3xa1dori, Zoltxc3xa1n', 'Rxc3xa9nyi Institute, Budapest, Hungary.|Rxc3xa9nyi Institute, Budapest, Hungary.', 'Hungary|Hungary', 3, 'Amino Acid Motifs|Amino Acid Sequence|Amyloid beta-Protein Precursor|Animals|Computational Biology|Consensus Sequence|Evolution, Molecular|Humans|Metals|Molecular Sequence Data|Mutation|Sequence Alignment', 'Journal Article', '10.1371/journal.pcbi.1002356', '22319430', 'HD amino acid duplex has been found in the active center of many different enzymes. The dyad plays remarkably different roles in their catalytic processes that usually involve metal coordination. An HD motif is positioned directly on the amyloid beta fragment (Axcexb2) and on the carboxy-terminal region of the extracellular domain (CAED) of the human amyloid precursor protein (APP) and a taxonomically well defined group of APP orthologues (APPOs). In human Axcexb2 HD is part of a presumed, RGD-like integrin-binding motif RHD, however, neither RHD nor RXD demonstrates reasonable conservation in APPOs. The sequences of CAEDs and the position of the HD are not particularly conserved either, yet we show with a novel statistical method using evolutionary modeling that the presence of HD on CAEDs cannot be the result of neutral evolutionary forces (p<0.0001). The motif is positively selected along the evolutionary process in the majority of APPOs, despite the fact that HD motif is underrepresented in the proteomes of all species of the animal kingdom. Position migration can be explained by high probability occurrence of multiple copies of HD on intermediate sequences, from which only one is kept by selective evolutionary forces, in a similar way as in the case of the transcription binding site turnover. CAED of all APP orthologues and homologues are predicted to bind metal ions including Amyloid-like protein 1 (APLP1) and Amyloid-like protein 2 (APLP2). Our results suggest that HDs on the CAEDs are most probably key components of metal-binding domains, which facilitate and/or regulate inter- or intra-molecular interactions in a metal ion-dependent or metal ion concentration-dependent manner. The involvement of naturally occurring mutations of HD (Tottori (D7N) and English (H6R) mutations) in early onset Alzheimers disease gives additional support to our finding that HD has an evolutionary preserved function on APPOs.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85334, 2012, 'plos', 'Stochastic de-repression of Rhodopsins in single photoreceptors of the fly retina', 'Sood, Pranidhi|Johnston, Robert J|Kussell, Edo', 'Center for Genomics and Systems Biology, Department of Biology, New York University, New York, New York, USA.|Center for Genomics and Systems Biology, Department of Biology, New York University, New York, New York, USA.|Center for Genomics and Systems Biology, Department of Biology, New York University, New York, New York, USA.', 'United States|United States|United States', 0, 'Animals|Drosophila|Drosophila Proteins|Homeodomain Proteins|Image Processing, Computer-Assisted|Microscopy, Confocal|Models, Genetic|Photoreceptor Cells, Invertebrate|Reproducibility of Results|Retina|Sensory Rhodopsins|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002357', '22319431', 'The photoreceptors of the Drosophila compound eye are a classical model for studying cell fate specification. Photoreceptors (PRs) are organized in bundles of eight cells with two major types - inner PRs involved in color vision and outer PRs involved in motion detection. In wild type flies, most PRs express a single type of Rhodopsin (Rh): inner PRs express either Rh3, Rh4, Rh5 or Rh6 and outer PRs express Rh1. In outer PRs, the K(50) homeodomain protein Dve is a key repressor that acts to ensure exclusive Rh expression. Loss of Dve results in de-repression of Rhodopsins in outer PRs, and leads to a wide distribution of expression levels. To quantify these effects, we introduce an automated image analysis method to measure Rhodopsin levels at the single cell level in 3D confocal stacks. Our sensitive methodology reveals cell-specific differences in Rhodopsin distributions among the outer PRs, observed over a developmental time course. We show that Rhodopsin distributions are consistent with a two-state model of gene expression, in which cells can be in either high or basal states of Rhodopsin production. Our model identifies a significant role of post-transcriptional regulation in establishing the two distinct states. The timescale for interconversion between basal and high states is shown to be on the order of days. Our results indicate that even in the absence of Dve, the Rhodopsin regulatory network can maintain highly stable states. We propose that the role of Dve in outer PRs is to buffer against rare fluctuations in this network.'),
(85335, 2012, 'plos', 'Early warning signals for critical transitions: a generalized modeling approach', 'Lade, Steven J|Gross, Thilo', 'Max Planck Institute for the Physics of Complex Systems, Dresden, Germany. slade@pks.mpg.de|Max Planck Institute for the Physics of Complex Systems, Dresden, Germany. slade@pks.mpg.de', 'Germany|Germany', 62, 'Animals|Computer Simulation|Environment|Fisheries|Fishes|Food Chain|Models, Theoretical|Population Dynamics|Signal Processing, Computer-Assisted|Systems Theory', 'Journal Article', '10.1371/journal.pcbi.1002360', '22319432', 'Critical transitions are sudden, often irreversible, changes that can occur in a large variety of complex systems, signals that warn of critical transitions are therefore highly desirable. We propose a new method for early warning signals that integrates multiple sources of information and data about the system through the framework of a generalized model. We demonstrate our proposed approach through several examples, including a previously published fisheries model. We regard our method as complementary to existing early warning signals, taking an approach of intermediate complexity between model-free approaches and fully parameterized simulations. One potential advantage of our approach is that, under appropriate conditions, it may reduce the amount of time series data required for a robust early warning signal.'),
(85336, 2012, 'plos', 'OptCom: a multi-level optimization framework for the metabolic modeling and analysis of microbial communities', 'Zomorrodi, Ali R|Maranas, Costas D', 'Department of Chemical Engineering, The Pennsylvania State University, University Park, Pennsylvania, USA.|Department of Chemical Engineering, The Pennsylvania State University, University Park, Pennsylvania, USA.', 'United States|United States', 0, 'Acids, Acyclic|Bacterial Physiological Phenomena|Biomass|Carbon Dioxide|Electron Transport|Hydrogen|Metabolic Networks and Pathways|Microbial Interactions|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002363', '22319433', 'Microorganisms rarely live isolated in their natural environments but rather function in consolidated and socializing communities. Despite the growing availability of high-throughput sequencing and metagenomic data, we still know very little about the metabolic contributions of individual microbial players within an ecological niche and the extent and directionality of interactions among them. This calls for development of efficient modeling frameworks to shed light on less understood aspects of metabolism in microbial communities. Here, we introduce OptCom, a comprehensive flux balance analysis framework for microbial communities, which relies on a multi-level and multi-objective optimization formulation to properly describe trade-offs between individual vs. community level fitness criteria. In contrast to earlier approaches that rely on a single objective function, here, we consider species-level fitness criteria for the inner problems while relying on community-level objective maximization for the outer problem. OptCom is general enough to capture any type of interactions (positive, negative or combinations thereof) and is capable of accommodating any number of microbial species (or guilds) involved. We applied OptCom to quantify the syntrophic association in a well-characterized two-species microbial system, assess the level of sub-optimal growth in phototrophic microbial mats, and elucidate the extent and direction of inter-species metabolite and electron transfer in a model microbial community. We also used OptCom to examine addition of a new member to an existing community. Our study demonstrates the importance of trade-offs between species- and community-level fitness driving forces and lays the foundation for metabolic-driven analysis of various types of interactions in multi-species microbial systems using genome-scale metabolic models.'),
(85337, 2012, 'plos', 'Viral proteins acquired from a host converge to simplified domain architectures', 'Rappoport, Nadav|Linial, Michal', 'School of Computer Science and Engineering, Hebrew University of Jerusalem, Jerusalem, Israel.|School of Computer Science and Engineering, Hebrew University of Jerusalem, Jerusalem, Israel.', 'Israel|Israel', 0, 'Amino Acid Sequence|Animals|Cluster Analysis|Conserved Sequence|DNA, Viral|Gene Transfer, Horizontal|Host-Pathogen Interactions|Humans|Mammals|Models, Genetic|Molecular Sequence Data|Mutagenesis, Insertional|Protein Structure, Tertiary|RNA, Viral|Sequence Alignment|Viral Proteins|Viruses', 'Journal Article', '10.1371/journal.pcbi.1002364', '22319434', 'The infection cycle of viruses creates many opportunities for the exchange of genetic material with the host. Many viruses integrate their sequences into the genome of their host for replication. These processes may lead to the virus acquisition of host sequences. Such sequences are prone to accumulation of mutations and deletions. However, in rare instances, sequences acquired from a host become beneficial for the virus. We searched for unexpected sequence similarity among the 900,000 viral proteins and all proteins from cellular organisms. Here, we focus on viruses that infect metazoa. The high-conservation analysis yielded 187 instances of highly similar viral-host sequences. Only a small number of them represent viruses that hijacked host sequences. The low-conservation sequence analysis utilizes the Pfam family collection. About 5% of the 12,000 statistical models archived in Pfam are composed of viral-metazoan proteins. In about half of Pfam families, we provide indirect support for the directionality from the host to the virus. The other families are either wrongly annotated or reflect an extensive sequence exchange between the viruses and their hosts. In about 75% of cross-taxa Pfam families, the viral proteins are significantly shorter than their metazoan counterparts. The tendency for shorter viral proteins relative to their related host proteins accounts for the acquisition of only a fragment of the host gene, the elimination of an internal domain and shortening of the linkers between domains. We conclude that, along viral evolution, the host-originated sequences accommodate simplified domain compositions. We postulate that the trimmed proteins act by interfering with the fundamental function of the host including intracellular signaling, post-translational modification, protein-protein interaction networks and cellular trafficking. We compiled a collection of hijacked protein sequences. These sequences are attractive targets for manipulation of viral infection.'),
(85338, 2012, 'plos', 'Novel approach to meta-analysis of microarray datasets reveals muscle remodeling-related drug targets and biomarkers in Duchenne muscular dystrophy', 'Kotelnikova, Ekaterina|Shkrob, Maria A|Pyatnitskiy, Mikhail A|Ferlini, Alessandra|Daraselia, Nikolai', 'Ariadne Genomics Inc., Rockville, Maryland, USA. ekotelnikova@ariadnegenomics.com|Ariadne Genomics Inc., Rockville, Maryland, USA. ekotelnikova@ariadnegenomics.com|Ariadne Genomics Inc., Rockville, Maryland, USA. ekotelnikova@ariadnegenomics.com|Ariadne Genomics Inc., Rockville, Maryland, USA. ekotelnikova@ariadnegenomics.com|Ariadne Genomics Inc., Rockville, Maryland, USA. ekotelnikova@ariadnegenomics.com', 'United States|United States|United States|United States|United States', 50, 'Algorithms|Biomarkers|Computational Biology|Databases, Genetic|Drug Discovery|Gene Expression Profiling|Humans|Male|Meta-Analysis as Topic|Muscular Dystrophy, Duchenne|Oligonucleotide Array Sequence Analysis', 'Journal Article', '10.1371/journal.pcbi.1002365', '22319435', 'Elucidation of new biomarkers and potential drug targets from high-throughput profiling data is a challenging task due to a limited number of available biological samples and questionable reproducibility of differential changes in cross-dataset comparisons. In this paper we propose a novel computational approach for drug and biomarkers discovery using comprehensive analysis of multiple expression profiling datasets.The new method relies on aggregation of individual profiling experiments combined with leave-one-dataset-out validation approach. Aggregated datasets were studied using Sub-Network Enrichment Analysis algorithm (SNEA) to find consistent statistically significant key regulators within the global literature-extracted expression regulation network. These regulators were linked to the consistent differentially expressed genes.We have applied our approach to several publicly available human muscle gene expression profiling datasets related to Duchenne muscular dystrophy (DMD). In order to detect both enhanced and repressed processes we considered up- and down-regulated genes separately. Applying the proposed approach to the regulators search we discovered the disturbance in the activity of several muscle-related transcription factors (e.g. MYOG and MYOD1), regulators of inflammation, regeneration, and fibrosis. Almost all SNEA-derived regulators of down-regulated genes (e.g. AMPK, TORC2, PPARGC1A) correspond to a single common pathway important for fast-to-slow twitch fiber type transition. We hypothesize that this process can affect the severity of DMD symptoms, making corresponding regulators and downstream genes valuable candidates for being potential drug targets and exploratory biomarkers.'),
(85339, 2012, 'plos', 'Developmental maturation of dynamic causal control signals in higher-order cognition: a neurocognitive network model', 'Supekar, Kaustubh|Menon, Vinod', 'Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA. ksupekar@stanford.edu|Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA. ksupekar@stanford.edu', 'United States|United States', 0, 'Cerebral Cortex|Child|Child Development|Cognition|Female|Humans|Magnetic Resonance Imaging|Male|Models, Neurological|Nerve Fibers|Neural Pathways|Regression Analysis|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1002374', '22319436', 'Cognitive skills undergo protracted developmental changes resulting in proficiencies that are a hallmark of human cognition. One skill that develops over time is the ability to problem solve, which in turn relies on cognitive control and attention abilities. Here we use a novel multimodal neurocognitive network-based approach combining task-related fMRI, resting-state fMRI and diffusion tensor imaging (DTI) to investigate the maturation of control processes underlying problem solving skills in 7-9 year-old children. Our analysis focused on two key neurocognitive networks implicated in a wide range of cognitive tasks including control: the insula-cingulate salience network, anchored in anterior insula (AI), ventrolateral prefrontal cortex and anterior cingulate cortex, and the fronto-parietal central executive network, anchored in dorsolateral prefrontal cortex and posterior parietal cortex (PPC). We found that, by age 9, the AI node of the salience network is a major causal hub initiating control signals during problem solving. Critically, despite stronger AI activation, the strength of causal regulatory influences from AI to the PPC node of the central executive network was significantly weaker and contributed to lower levels of behavioral performance in children compared to adults. These results were validated using two different analytic methods for estimating causal interactions in fMRI data. In parallel, DTI-based tractography revealed weaker AI-PPC structural connectivity in children. Our findings point to a crucial role of AI connectivity, and its causal cross-network influences, in the maturation of dynamic top-down control signals underlying cognitive development. Overall, our study demonstrates how a unified neurocognitive network model when combined with multimodal imaging enhances our ability to generalize beyond individual task-activated foci and provides a common framework for elucidating key features of brain and cognitive development. The quantitative approach developed is likely to be useful in investigating neurodevelopmental disorders, in which control processes are impaired, such as autism and ADHD.'),
(85340, 2012, 'plos', 'Integrating flux balance analysis into kinetic models to decipher the dynamic metabolism of Shewanella oneidensis MR-1', 'Feng, Xueyang|Xu, You|Chen, Yixin|Tang, Yinjie J', 'Department of Energy, Environmental and Chemical Engineering, Washington University, St. Louis, Missouri, USA.|Department of Energy, Environmental and Chemical Engineering, Washington University, St. Louis, Missouri, USA.|Department of Energy, Environmental and Chemical Engineering, Washington University, St. Louis, Missouri, USA.|Department of Energy, Environmental and Chemical Engineering, Washington University, St. Louis, Missouri, USA.', 'United States|United States|United States|United States', 48, 'Acetates|Carbon Isotopes|Citric Acid Cycle|Gluconeogenesis|Glutamic Acid|Glyoxylates|Kinetics|Lactic Acid|Metabolic Networks and Pathways|Models, Biological|Pentose Phosphate Pathway|Pyruvic Acid|Shewanella|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002376', '22319437', 'Shewanella oneidensis MR-1 sequentially utilizes lactate and its waste products (pyruvate and acetate) during batch culture. To decipher MR-1 metabolism, we integrated genome-scale flux balance analysis (FBA) into a multiple-substrate Monod model to perform the dynamic flux balance analysis (dFBA). The dFBA employed a static optimization approach (SOA) by dividing the batch time into small intervals (i.e., xe2x88xbc400 mini-FBAs), then the Monod model provided time-dependent inflow/outflow fluxes to constrain the mini-FBAs to profile the pseudo-steady-state fluxes in each time interval. The mini-FBAs used a dual-objective function (a weighted combination of maximizing growth rate and minimizing overall flux) to capture trade-offs between optimal growth and minimal enzyme usage. By fitting the experimental data, a bi-level optimization of dFBA revealed that the optimal weight in the dual-objective function was time-dependent: the objective function was constant in the early growth stage, while the functional weight of minimal enzyme usage increased significantly when lactate became scarce. The dFBA profiled biologically meaningful dynamic MR-1 metabolisms: 1. the oxidative TCA cycle fluxes increased initially and then decreased in the late growth stage, 2. fluxes in the pentose phosphate pathway and gluconeogenesis were stable in the exponential growth period, and 3. the glyoxylate shunt was up-regulated when acetate became the main carbon source for MR-1 growth.'),
(85341, 2012, 'plos', 'Using functional signatures to identify repositioned drugs for breast, myelogenous leukemia and prostate cancer', 'Shigemizu, Daichi|Hu, Zhenjun|Hung, Jui-Hung|Huang, Chia-Ling|Wang, Yajie|DeLisi, Charles', 'Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America.|Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America.|Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America.|Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America.|Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America.|Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States|United States', 0, 'Breast Neoplasms|Computational Biology|Databases, Factual|Drug Discovery|Drug Repositioning|Female|Gene Expression Profiling|Humans|Leukemia, Myeloid|Male|Prostatic Neoplasms|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002347', '22346740', 'The cost and time to develop a drug continues to be a major barrier to widespread distribution of medication. Although the genomic revolution appears to have had little impact on this problem, and might even have exacerbated it because of the flood of additional and usually ineffective leads, the emergence of high throughput resources promises the possibility of rapid, reliable and systematic identification of approved drugs for originally unintended uses. In this paper we develop and apply a method for identifying such repositioned drug candidates against breast cancer, myelogenous leukemia and prostate cancer by looking for inverse correlations between the most perturbed gene expression levels in human cancer tissue and the most perturbed expression levels induced by bioactive compounds. The method uses variable gene signatures to identify bioactive compounds that modulate a given disease. This is in contrast to previous methods that use small and fixed signatures. This strategy is based on the observation that diseases stem from failed/modified cellular functions, irrespective of the particular genes that contribute to the function, i.e., this strategy targets the functional signatures for a given cancer. This function-based strategy broadens the search space for the effective drugs with an impressive hit rate. Among the 79, 94 and 88 candidate drugs for breast cancer, myelogenous leukemia and prostate cancer, 32%, 13% and 17% respectively are either FDA-approved/in-clinical-trial drugs, or drugs with suggestive literature evidences, with an FDR of 0.01. These findings indicate that the method presented here could lead to a substantial increase in efficiency in drug discovery and development, and has potential application for the personalized medicine.'),
(85342, 2012, 'plos', 'Minimal size of cell assemblies coordinated by gamma oscillations', 'Börgers, Christoph|Talei Franzesi, Giovanni|Lebeau, Fiona E N|Boyden, Edward S|Kopell, Nancy J', 'Department of Mathematics, Tufts University, Medford, Massachusetts, United States of America. cborgers@tufts.edu|Department of Mathematics, Tufts University, Medford, Massachusetts, United States of America. cborgers@tufts.edu|Department of Mathematics, Tufts University, Medford, Massachusetts, United States of America. cborgers@tufts.edu|Department of Mathematics, Tufts University, Medford, Massachusetts, United States of America. cborgers@tufts.edu|Department of Mathematics, Tufts University, Medford, Massachusetts, United States of America. cborgers@tufts.edu', 'United States|United States|United States|United States|United States', 25, 'Animals|Brain Waves|CA3 Region, Hippocampal|Channelrhodopsins|Computational Biology|Computer Simulation|Kainic Acid|Light|Macaca|Mice|Mice, Inbred C57BL|Models, Neurological|Single-Cell Analysis|Synapses|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1002362', '22346741', 'In networks of excitatory and inhibitory neurons with mutual synaptic coupling, specific drive to sub-ensembles of cells often leads to gamma-frequency (25-100 Hz) oscillations. When the number of driven cells is too small, however, the synaptic interactions may not be strong or homogeneous enough to support the mechanism underlying the rhythm. Using a combination of computational simulation and mathematical analysis, we study the breakdown of gamma rhythms as the driven ensembles become too small, or the synaptic interactions become too weak and heterogeneous. Heterogeneities in drives or synaptic strengths play an important role in the breakdown of the rhythms, nonetheless, we find that the analysis of homogeneous networks yields insight into the breakdown of rhythms in heterogeneous networks. In particular, if parameter values are such that in a homogeneous network, it takes several gamma cycles to converge to synchrony, then in a similar, but realistically heterogeneous network, synchrony breaks down altogether. This leads to the surprising conclusion that in a network with realistic heterogeneity, gamma rhythms based on the interaction of excitatory and inhibitory cell populations must arise either rapidly, or not at all. For given synaptic strengths and heterogeneities, there is a (soft) lower bound on the possible number of cells in an ensemble oscillating at gamma frequency, based simply on the requirement that synaptic interactions between the two cell populations be strong enough. This observation suggests explanations for recent experimental results concerning the modulation of gamma oscillations in macaque primary visual cortex by varying spatial stimulus size or attention level, and for our own experimental results, reported here, concerning the optogenetic modulation of gamma oscillations in kainate-activated hippocampal slices. We make specific predictions about the behavior of pyramidal cells and fast-spiking interneurons in these experiments.'),
(85343, 2012, 'plos', 'Control of whole heart geometry by intramyocardial mechano-feedback: a model study', 'Arts, Theo|Lumens, Joost|Kroon, Wilco|Delhaas, Tammo', 'Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. t.arts@maastrichtuniversity.nl|Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. t.arts@maastrichtuniversity.nl|Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. t.arts@maastrichtuniversity.nl|Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. t.arts@maastrichtuniversity.nl', 'Netherlands|Netherlands|Netherlands|Netherlands', 0, 'Adaptation, Physiological|Animals|Biomechanical Phenomena|Dogs|Feedback, Physiological|Heart|Hemodynamics|Mechanotransduction, Cellular|Models, Cardiovascular|Myocardium|Myocytes, Cardiac|Myofibrils', 'Journal Article', '10.1371/journal.pcbi.1002369', '22346742', 'Geometry of the heart adapts to mechanical load, imposed by pressures and volumes of the cavities. We regarded preservation of cardiac geometry as a homeostatic control system. The control loop was simulated by a chain of models, starting with geometry of the cardiac walls, sequentially simulating circulation hemodynamics, myofiber stress and strain in the walls, transfer of mechano-sensed signals to structural changes of the myocardium, and finalized by calculation of resulting changes in cardiac wall geometry. Instead of modeling detailed mechano-transductive pathways and their interconnections, we used principles of control theory to find optimal transfer functions, representing the overall biological responses to mechanical signals. As biological responses we regarded tissue mass, extent of contractile myocyte structure and extent of the extra-cellular matrix. Mechano-structural stimulus-response characteristics were considered to be the same for atrial and ventricular tissue. Simulation of adaptation to self-generated hemodynamic load rendered physiologic geometry of all cardiac cavities automatically. Adaptation of geometry to chronic hypertension and volume load appeared also physiologic. Different combinations of mechano-sensors satisfied the condition that control of geometry is stable. Thus, we expect that for various species, evolution may have selected different solutions for mechano-adaptation.'),
(85344, 2012, 'plos', 'Multi-scale modeling of HIV infection in vitro and APOBEC3G-based anti-retroviral therapy', 'Hosseini, Iraj|Mac Gabhann, Feilim', 'Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.|Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.', 'United States|United States', 15, 'APOBEC-3G Deaminase|Anti-Retroviral Agents|Cluster Analysis|Computational Biology|Computer Simulation|Cytidine Deaminase|HIV Infections|HIV-1|Host-Pathogen Interactions|Humans|Models, Biological|Mutation|Reproducibility of Results|T-Lymphocytes|Virion|Virus Replication|vif Gene Products, Human Immunodeficiency Virus', 'Journal Article', '10.1371/journal.pcbi.1002371', '22346743', 'The human APOBEC3G is an innate restriction factor that, in the absence of Vif, restricts HIV-1 replication by inducing excessive deamination of cytidine residues in nascent reverse transcripts and inhibiting reverse transcription and integration. To shed light on impact of A3G-Vif interactions on HIV replication, we developed a multi-scale computational system consisting of intracellular (single-cell), cellular and extracellular (multicellular) events by using ordinary differential equations. The single-cell model describes molecular-level events within individual cells (such as production and degradation of host and viral proteins, and assembly and release of new virions), whereas the multicellular model describes the viral dynamics and multiple cycles of infection within a population of cells. We estimated the model parameters either directly from previously published experimental data or by running simulations to find the optimum values. We validated our integrated model by reproducing the results of in vitro T cell culture experiments. Crucially, both downstream effects of A3G (hypermutation and reduction of viral burst size) were necessary to replicate the experimental results in silico. We also used the model to study anti-HIV capability of several possible therapeutic strategies including: an antibody to Vif, upregulation of A3G, and mutated forms of A3G. According to our simulations, A3G with a mutated Vif binding site is predicted to be significantly more effective than other molecules at the same dose. Ultimately, we performed sensitivity analysis to identify important model parameters. The results showed that the timing of particle formation and virus release had the highest impacts on HIV replication. The model also predicted that the degradation of A3G by Vif is not a crucial step in HIV pathogenesis.'),
(85345, 2012, 'plos', 'Subcellular location of PKA controls striatal plasticity: stochastic simulations in spiny dendrites', 'Oliveira, Rodrigo F|Kim, Myungsook|Blackwell, Kim T', 'The Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia, United States of America.|The Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia, United States of America.|The Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia, United States of America.', 'United States|United States|United States', 0, 'Animals|Computational Biology|Computer Simulation|Cyclic AMP|Cyclic AMP-Dependent Protein Kinases|Dendritic Spines|Dopamine|Dopamine and cAMP-Regulated Phosphoprotein 32|Humans|Intracellular Space|Models, Neurological|Monte Carlo Method|Neuronal Plasticity|Reproducibility of Results|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002383', '22346744', 'Dopamine release in the striatum has been implicated in various forms of reward dependent learning. Dopamine leads to production of cAMP and activation of protein kinase A (PKA), which are involved in striatal synaptic plasticity and learning. PKA and its protein targets are not diffusely located throughout the neuron, but are confined to various subcellular compartments by anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Experiments have shown that blocking the interaction of PKA with AKAPs disrupts its subcellular location and prevents LTP in the hippocampus and striatum, however, these experiments have not revealed whether the critical function of anchoring is to locate PKA near the cAMP that activates it or near its targets, such as AMPA receptors located in the post-synaptic density. We have developed a large scale stochastic reaction-diffusion model of signaling pathways in a medium spiny projection neuron dendrite with spines, based on published biochemical measurements, to investigate this question and to evaluate whether dopamine signaling exhibits spatial specificity post-synaptically. The model was stimulated with dopamine pulses mimicking those recorded in response to reward. Simulations show that PKA colocalization with adenylate cyclase, either in the spine head or in the dendrite, leads to greater phosphorylation of DARPP-32 Thr34 and AMPA receptor GluA1 Ser845 than when PKA is anchored away from adenylate cyclase. Simulations further demonstrate that though cAMP exhibits a strong spatial gradient, diffusible DARPP-32 facilitates the spread of PKA activity, suggesting that additional inactivation mechanisms are required to produce spatial specificity of PKA activity.'),
(85346, 2012, 'plos', 'On the effect of thermodynamic equilibrium on the assembly efficiency of complex multi-layered virus-like particles (VLP): the case of rotavirus VLP', 'Roldão, António|Mellado, Maria Candida M|Lima, J C|Carrondo, Manuel J T|Alves, Paula M|Oliveira, R', 'Instituto de Tecnologia Química e Biológica-Universidade Nova de Lisboa (ITQB-UNL), Oeiras, Portugal.|Instituto de Tecnologia Química e Biológica-Universidade Nova de Lisboa (ITQB-UNL), Oeiras, Portugal.|Instituto de Tecnologia Química e Biológica-Universidade Nova de Lisboa (ITQB-UNL), Oeiras, Portugal.|Instituto de Tecnologia Química e Biológica-Universidade Nova de Lisboa (ITQB-UNL), Oeiras, Portugal.|Instituto de Tecnologia Química e Biológica-Universidade Nova de Lisboa (ITQB-UNL), Oeiras, Portugal.|Instituto de Tecnologia Química e Biológica-Universidade Nova de Lisboa (ITQB-UNL), Oeiras, Portugal.', 'Portugal|Portugal|Portugal|Portugal|Portugal|Portugal', 0, 'Animals|Capsid|Computational Biology|Insecta|Kinetics|Light|Models, Statistical|Models, Theoretical|Rotavirus|Scattering, Radiation|Temperature|Thermodynamics|Viral Proteins|Virus Assembly', 'Journal Article', '10.1371/journal.pcbi.1002367', '22359487', 'Previous studies have reported the production of malformed virus-like-particles (VLP) in recombinant host systems. Here we computationally investigate the case of a large triple-layered rotavirus VLP (RLP). In vitro assembly, disassembly and reassembly data provides strong evidence of microscopic reversibility of RLP assembly. Light scattering experimental data also evidences a slow and reversible assembly untypical of kinetic traps, thus further strengthening the fidelity of a thermodynamically controlled assembly. In silico analysis further reveals that under favourable conditions particles distribution is dominated by structural subunits and completely built icosahedra, while other intermediates are present only at residual concentrations. Except for harshly unfavourable conditions, assembly yield is maximised when proteins are provided in the same VLP protein mass composition. The assembly yield decreases abruptly due to thermodynamic equilibrium when the VLP protein mass composition is not obeyed. The latter effect is more pronounced the higher the Gibbs free energy of subunit association is and the more complex the particle is. Overall this study shows that the correct formation of complex multi-layered VLPs is restricted to a narrow range of association energies and protein concentrations, thus the choice of the host system is critical for successful assembly. Likewise, the dynamic control of intracellular protein expression rates becomes very important to minimize wasted proteins.'),
(85347, 2012, 'plos', 'Dynamic energy landscapes of riboswitches help interpret conformational rearrangements and function', 'Quarta, Giulio|Sin, Ken|Schlick, Tamar', 'Department of Chemistry, New York University, New York, New York, United States of America.|Department of Chemistry, New York University, New York, New York, United States of America.|Department of Chemistry, New York University, New York, New York, United States of America.', 'United States|United States|United States', 26, 'Bacterial Proteins|Computational Biology|Gene Expression Regulation|Kinetics|Ligands|Nucleic Acid Conformation|Nucleotides|Protein Binding|Protein Conformation|Protein Structure, Secondary|Protein Structure, Tertiary|RNA|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002368', '22359488', 'Riboswitches are RNAs that modulate gene expression by ligand-induced conformational changes. However, the way in which sequence dictates alternative folding pathways of gene regulation remains unclear. In this study, we compute energy landscapes, which describe the accessible secondary structures for a range of sequence lengths, to analyze the transcriptional process as a given sequence elongates to full length. In line with experimental evidence, we find that most riboswitch landscapes can be characterized by three broad classes as a function of sequence length in terms of the distribution and barrier type of the conformational clusters: low-barrier landscape with an ensemble of different conformations in equilibrium before encountering a substrate, barrier-free landscape in which a direct, dominant downhill pathway to the minimum free energy structure is apparent, and a barrier-dominated landscape with two isolated conformational states, each associated with a different biological function. Sharing concepts with the new view of protein folding energy landscapes, we term the three sequence ranges above as the sensing, downhill folding, and functional windows, respectively. We find that these energy landscape patterns are conserved in various riboswitch classes, though the order of the windows may vary. In fact, the order of the three windows suggests either kinetic or thermodynamic control of ligand binding. These findings help understand riboswitch structure/function relationships and open new avenues to riboswitch design.'),
(85348, 2012, 'plos', 'A race between tumor immunoescape and genome maintenance selects for optimum levels of (epi)genetic instability', 'Iwami, Shingo|Haeno, Hiroshi|Michor, Franziska', 'PRESTO, Japan Science and Technology Agency, Graduate School of Mathematical Sciences, The University of Tokyo, Institute for Virus Research, Kyoto University, Kyoto, Japan.|PRESTO, Japan Science and Technology Agency, Graduate School of Mathematical Sciences, The University of Tokyo, Institute for Virus Research, Kyoto University, Kyoto, Japan.|PRESTO, Japan Science and Technology Agency, Graduate School of Mathematical Sciences, The University of Tokyo, Institute for Virus Research, Kyoto University, Kyoto, Japan.', 'Japan|Japan|Japan', 0, 'Animals|Cell Transformation, Neoplastic|Computational Biology|Disease Progression|Epigenesis, Genetic|Genome, Human|Humans|Immune System|Models, Statistical|Models, Theoretical|Mutation|Neoplasms|Phenotype', 'Journal Article', '10.1371/journal.pcbi.1002370', '22359489', 'The human immune system functions to provide continuous body-wide surveillance to detect and eliminate foreign agents such as bacteria and viruses as well as the bodys own cells that undergo malignant transformation. To counteract this surveillance, tumor cells evolve mechanisms to evade elimination by the immune system, this tumor immunoescape leads to continuous tumor expansion, albeit potentially with a different composition of the tumor cell population (immunoediting). Tumor immunoescape and immunoediting are products of an evolutionary process and are hence driven by mutation and selection. Higher mutation rates allow cells to more rapidly acquire new phenotypes that help evade the immune system, but also harbor the risk of an inability to maintain essential genome structure and functions, thereby leading to an error catastrophe. In this paper, we designed a novel mathematical framework, based upon the quasispecies model, to study the effects of tumor immunoediting and the evolution of (epi)genetic instability on the abundance of tumor and immune system cells. We found that there exists an optimum number of tumor variants and an optimum magnitude of mutation rates that maximize tumor progression despite an active immune response. Our findings provide insights into the dynamics of tumorigenesis during immune system attacks and help guide the choice of treatment strategies that best inhibit diverse tumor cell populations.'),
(85349, 2012, 'plos', 'Joint analysis of multiple metagenomic samples', 'Baran, Yael|Halperin, Eran', 'School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel.|School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel.', 'Israel|Israel', 0, 'Algorithms|Bacterial Proteins|Cluster Analysis|Computational Biology|Genome, Human|Genome-Wide Association Study|Humans|Likelihood Functions|Metagenomics|Models, Statistical|Phenotype|Phylogeny|Principal Component Analysis|Probability|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1002373', '22359490', 'The availability of metagenomic sequencing data, generated by sequencing DNA pooled from multiple microbes living jointly, has increased sharply in the last few years with developments in sequencing technology. Characterizing the contents of metagenomic samples is a challenging task, which has been extensively attempted by both supervised and unsupervised techniques, each with its own limitations. Common to practically all the methods is the processing of single samples only, when multiple samples are sequenced, each is analyzed separately and the results are combined. In this paper we propose to perform a combined analysis of a set of samples in order to obtain a better characterization of each of the samples, and provide two applications of this principle. First, we use an unsupervised probabilistic mixture model to infer hidden components shared across metagenomic samples. We incorporate the model in a novel framework for studying association of microbial sequence elements with phenotypes, analogous to the genome-wide association studies performed on human genomes: We demonstrate that stratification may result in false discoveries of such associations, and that the components inferred by the model can be used to correct for this stratification. Second, we propose a novel read clustering (also termed binning) algorithm which operates on multiple samples simultaneously, leveraging on the assumption that the different samples contain the same microbial species, possibly in different proportions. We show that integrating information across multiple samples yields more precise binning on each of the samples. Moreover, for both applications we demonstrate that given a fixed depth of coverage, the average per-sample performance generally increases with the number of sequenced samples as long as the per-sample coverage is high enough.'),
(85350, 2012, 'plos', 'Branch mode selection during early lung development', 'Menshykau, Denis|Kraemer, Conradin|Iber, Dagmar', 'Department for Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.|Department for Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.|Department for Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.', 'Switzerland|Switzerland|Switzerland', 0, 'Animals|Computational Biology|Diffusion|Fibroblast Growth Factor 10|Hedgehog Proteins|Humans|Kinetics|Lung|Mice|Models, Theoretical|Mutation|Normal Distribution|Patched Receptors|Patched-1 Receptor|Phenotype|Receptors, Cell Surface|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002377', '22359491', 'Many organs of higher organisms, such as the vascular system, lung, kidney, pancreas, liver and glands, are heavily branched structures. The branching process during lung development has been studied in great detail and is remarkably stereotyped. The branched tree is generated by the sequential, non-random use of three geometrically simple modes of branching (domain branching, planar and orthogonal bifurcation). While many regulatory components and local interactions have been defined an integrated understanding of the regulatory network that controls the branching process is lacking. We have developed a deterministic, spatio-temporal differential-equation based model of the core signaling network that governs lung branching morphogenesis. The model focuses on the two key signaling factors that have been identified in experiments, fibroblast growth factor (FGF10) and sonic hedgehog (SHH) as well as the SHH receptor patched (Ptc). We show that the reported biochemical interactions give rise to a Schnakenberg-type Turing patterning mechanisms that allows us to reproduce experimental observations in wildtype and mutant mice. The kinetic parameters as well as the domain shape are based on experimental data where available. The developed model is robust to small absolute and large relative changes in the parameter values. At the same time there is a strong regulatory potential in that the switching between branching modes can be achieved by targeted changes in the parameter values. We note that the sequence of different branching events may also be the result of different growth speeds: fast growth triggers lateral branching while slow growth favours bifurcations in our model. We conclude that the FGF10-SHH-Ptc1 module is sufficient to generate pattern that correspond to the observed branching modes.'),
(85351, 2012, 'plos', 'Modeling cortisol dynamics in the neuro-endocrine axis distinguishes normal, depression, and post-traumatic stress disorder (PTSD) in humans', 'Sriram, K|Rodriguez-Fernandez, Maria|Doyle, Francis J', 'Institute of Collaborative Biotechnologies, University of California, Santa Barbara, California, United States of America.|Institute of Collaborative Biotechnologies, University of California, Santa Barbara, California, United States of America.|Institute of Collaborative Biotechnologies, University of California, Santa Barbara, California, United States of America.', 'United States|United States|United States', 74, 'Biomarkers|Comorbidity|Computational Biology|Depression|Endocrine System|Humans|Hydrocortisone|Kinetics|Models, Biological|Models, Statistical|Neurosecretory Systems|Phenotype|Stress Disorders, Post-Traumatic|Stress, Psychological', 'Journal Article', '10.1371/journal.pcbi.1002379', '22359492', 'Cortisol, secreted in the adrenal cortex in response to stress, is an informative biomarker that distinguishes anxiety disorders such as major depression and post-traumatic stress disorder (PTSD) from normal subjects. Yehuda et al. proposed a hypothesis that, in humans, the hypersensitive hypothalamus-pituitary-adrenal (HPA) axis is responsible for the occurrence of differing levels of cortisol in anxiety disorders. Specifically, PTSD subjects have lower cortisol levels during the late subjective night in comparison to normal subjects, and this was assumed to occur due to strong negative feedback loops in the HPA axis. In the present work, to address this hypothesis, we modeled the cortisol dynamics using nonlinear ordinary differential equations and estimated the kinetic parameters of the model to fit the experimental data of three categories, namely, normal, depressed, and PTSD human subjects. We concatenated the subjects (nxe2x80x8a=xe2x80x8a3) in each category and created a model subject (nxe2x80x8a=xe2x80x8a1) without considering the patient-to-patient variability in each case. The parameters of the model for the three categories were simultaneously obtained through global optimization. Bifurcation analysis carried out with the optimized parameters exhibited two supercritical Hopf points and, for the choice of parameters, the oscillations were found to be circadian in nature. The fitted kinetic parameters indicate that PTSD subjects have a strong negative feedback loop and, as a result, the predicted oscillating cortisol levels are extremely low at the nadir in contrast to normal subjects, albeit within the endocrinologic range. We also simulated the phenotypes for each of the categories and, as observed in the clinical data of PTSD patients, the simulated cortisol levels are consistently low at the nadir, and correspondingly the negative feedback was found to be extremely strong. These results from the model support the hypothesis that high stress intensity and strong negative feedback loop may cause hypersensitive neuro-endocrine axis that results in hypocortisolemia in PTSD.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85352, 2012, 'plos', 'DOGS: reaction-driven de novo design of bioactive compounds', 'Hartenfeller, Markus|Zettl, Heiko|Walter, Miriam|Rupp, Matthias|Reisen, Felix|Proschak, Ewgenij|Weggen, Sascha|Stark, Holger|Schneider, Gisbert', 'Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zxc3xbcrich, Switzerland.|Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zxc3xbcrich, Switzerland.|Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zxc3xbcrich, Switzerland.|Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zxc3xbcrich, Switzerland.|Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zxc3xbcrich, Switzerland.|Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zxc3xbcrich, Switzerland.|Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zxc3xbcrich, Switzerland.|Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zxc3xbcrich, Switzerland.|Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zxc3xbcrich, Switzerland.', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Swit', 110, 'Algorithms|Amyloid Precursor Protein Secretases|Automation|Computational Biology|Computers|Drug Design|Humans|Ligands|Models, Chemical|Models, Statistical|Molecular Structure|Receptors, G-Protein-Coupled|Receptors, Histamine|Receptors, Histamine H4|Software|Technology, Pharmaceutical', 'Journal Article', '10.1371/journal.pcbi.1002380', '22359493', 'We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated in silico assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features. We implemented a deterministic compound construction procedure that explicitly considers compound synthesizability, based on a compilation of 25144 readily available synthetic building blocks and 58 established reaction principles. This enables the software to suggest a synthesis route for each designed compound. Two prospective case studies are presented together with details on the algorithm and its implementation. De novo designed ligand candidates for the human histamine Hxe2x82x84 receptor and xcexb3-secretase were synthesized as suggested by the software. The computational approach proved to be suitable for scaffold-hopping from known ligands to novel chemotypes, and for generating bioactive molecules with drug-like properties.'),
(85353, 2012, 'plos', 'Paradoxical evidence integration in rapid decision processes', 'Rüter, Johannes|Marcille, Nicolas|Sprekeler, Henning|Gerstner, Wulfram|Herzog, Michael H', 'Laboratory of Psychophysics, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. johannes.rueter@gmail.com|Laboratory of Psychophysics, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. johannes.rueter@gmail.com|Laboratory of Psychophysics, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. johannes.rueter@gmail.com|Laboratory of Psychophysics, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. johannes.rueter@gmail.com|Laboratory of Psychophysics, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. johannes.rueter@gmail.com', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 13, 'Adult|Algorithms|Computational Biology|Decision Making|Diffusion|Discrimination (Psychology)|Female|Humans|Male|Observer Variation|Reaction Time|Reproducibility of Results|Software|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1002382', '22359494', 'Decisions about noisy stimuli require evidence integration over time. Traditionally, evidence integration and decision making are described as a one-stage process: a decision is made when evidence for the presence of a stimulus crosses a threshold. Here, we show that one-stage models cannot explain psychophysical experiments on feature fusion, where two visual stimuli are presented in rapid succession. Paradoxically, the second stimulus biases decisions more strongly than the first one, contrary to predictions of one-stage models and intuition. We present a two-stage model where sensory information is integrated and buffered before it is fed into a drift diffusion process. The model is tested in a series of psychophysical experiments and explains both accuracy and reaction time distributions.'),
(85354, 2012, 'plos', 'On the Use of Gene Ontology Annotations to Assess Functional Similarity among Orthologs and Paralogs: A Short Report', 'Thomas, Paul D|Wood, Valerie|Mungall, Christopher J|Lewis, Suzanna E|Blake, Judith A|Gene Ontology Consortium', 'Division of Bioinformatics, Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America. go-discuss@lists.stanford.edu|Division of Bioinformatics, Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America. go-discuss@lists.stanford.edu|Division of Bioinformatics, Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America. go-discuss@lists.stanford.edu|Division of Bioinformatics, Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America. go-discuss@lists.stanford.edu|Division of Bioinformatics, Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America. go-discuss@lists.stanford.edu|Division of Bioinformatics, Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America. go-discuss@lists.stanford.edu', 'United States|United States|United States|United States|United States|United States', 62, 'Algorithms|Animals|Cell Nucleus|Computational Biology|Genome|Genome, Human|Genomics|Humans|Mice|Models, Genetic|Models, Statistical|Molecular Biology|Molecular Sequence Annotation|Phosphorylation|Probability|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.1002386', '22359495', 'A recent paper (Nehrt et al., PLoS Comput. Biol. 7:e1002073, 2011) has proposed a metric for the functional similarity between two genes that uses only the Gene Ontology (GO) annotations directly derived from published experimental results. Applying this metric, the authors concluded that paralogous genes within the mouse genome or the human genome are more functionally similar on average than orthologous genes between these genomes, an unexpected result with broad implications if true. We suggest, based on both theoretical and empirical considerations, that this proposed metric should not be interpreted as a functional similarity, and therefore cannot be used to support any conclusions about the ortholog conjecture (or, more properly, the ortholog functional conservation hypothesis). First, we reexamine the case studies presented by Nehrt et al. as examples of orthologs with divergent functions, and come to a very different conclusion: they actually exemplify how GO annotations for orthologous genes provide complementary information about conserved biological functions. We then show that there is a global ascertainment bias in the experiment-based GO annotations for human and mouse genes: particular types of experiments tend to be performed in different model organisms. We conclude that the reported statistical differences in annotations between pairs of orthologous genes do not reflect differences in biological function, but rather complementarity in experimental approaches. Our results underscore two general considerations for researchers proposing novel types of analysis based on the GO: 1) that GO annotations are often incomplete, potentially in a biased manner, and subject to an open world assumption (absence of an annotation does not imply absence of a function), and 2) that conclusions drawn from a novel, large-scale GO analysis should whenever possible be supported by careful, in-depth examination of examples, to help ensure the conclusions have a justifiable biological basis.'),
(85355, 2012, 'plos', 'Noise and robustness in phyllotaxis', 'Mirabet, Vincent|Besnard, Fabrice|Vernoux, Teva|Boudaoud, Arezki', 'Laboratoire Joliot-Curie, CNRS, ENS, Université de Lyon, Lyon, France.|Laboratoire Joliot-Curie, CNRS, ENS, Université de Lyon, Lyon, France.|Laboratoire Joliot-Curie, CNRS, ENS, Université de Lyon, Lyon, France.|Laboratoire Joliot-Curie, CNRS, ENS, Université de Lyon, Lyon, France.', 'France|France|France|France', 36, 'Algorithms|Arabidopsis|Biological Transport|Computational Biology|Diffusion|Flowers|Indoleacetic Acids|Models, Biological|Models, Theoretical|Plant Leaves|Plant Proteins|Plant Shoots|Plant Stems|Reproducibility of Results|Signal Transduction|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002389', '22359496', 'A striking feature of vascular plants is the regular arrangement of lateral organs on the stem, known as phyllotaxis. The most common phyllotactic patterns can be described using spirals, numbers from the Fibonacci sequence and the golden angle. This rich mathematical structure, along with the experimental reproduction of phyllotactic spirals in physical systems, has led to a view of phyllotaxis focusing on regularity. However all organisms are affected by natural stochastic variability, raising questions about the effect of this variability on phyllotaxis and the achievement of such regular patterns. Here we address these questions theoretically using a dynamical system of interacting sources of inhibitory field. Previous work has shown that phyllotaxis can emerge deterministically from the self-organization of such sources and that inhibition is primarily mediated by the depletion of the plant hormone auxin through polarized transport. We incorporated stochasticity in the model and found three main classes of defects in spiral phyllotaxis--the reversal of the handedness of spirals, the concomitant initiation of organs and the occurrence of distichous angles--and we investigated whether a secondary inhibitory field filters out defects. Our results are consistent with available experimental data and yield a prediction of the main source of stochasticity during organogenesis. Our model can be related to cellular parameters and thus provides a framework for the analysis of phyllotactic mutants at both cellular and tissular levels. We propose that secondary fields associated with organogenesis, such as other biochemical signals or mechanical forces, are important for the robustness of phyllotaxis. More generally, our work sheds light on how a target pattern can be achieved within a noisy background.'),
(85356, 2012, 'plos', 'The role of conserved waters in conformational transitions of Q61H K-ras', 'Prakash, Priyanka|Sayyed-Ahmad, Abdallah|Gorfe, Alemayehu A', 'Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.|Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.|Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.', 'United States|United States|United States', 35, 'Algorithms|Allosteric Site|Binding Sites|Computational Biology|Computer Simulation|Crystallography, X-Ray|GTP-Binding Proteins|Guanosine Triphosphate|Humans|Ligands|Models, Statistical|Molecular Dynamics Simulation|Nucleotides|Protein Conformation|Signal Transduction|Water|ras Proteins', 'Journal Article', '10.1371/journal.pcbi.1002394', '22359497', 'To investigate the stability and functional role of long-residence water molecules in the Q61H variant of the signaling protein K-ras, we analyzed all available Ras crystal structures and conformers derived from a series of independent explicit solvent molecular dynamics (MD) simulations totaling 1.76 xc2xb5s. We show that the protein samples a different region of phase space in the presence and absence of several crystallographically conserved and buried water molecules. The dynamics of these waters is coupled with the local as well as the global motions of the protein, in contrast to less buried waters whose exchange with bulk is only loosely coupled with the motion of loops in their vicinity. Aided by two novel reaction coordinates involving the distance (d) between the C(xcexb1) atoms of G60 at switch 2 and G10 at the P-loop and the N-C(xcexb1)-C-O dihedral (xcexbe) of G60, we further show that three water molecules located in lobe1, at the interface between the lobes and at lobe2, are involved in the relative motion of residues at the two lobes of Q61H K-ras. Moreover, a d/xcexbe plot classifies the available Ras x-ray structures and MD-derived K-ras conformers into active GTP-, intermediate GTP-, inactive GDP-bound, and nucleotide-free conformational states. The population of these states and the transition between them is modulated by water-mediated correlated motions involving the functionally critical switch 2, P-loop and helix 3. These results suggest that water molecules act as allosteric ligands to induce a population shift among distinct switch 2 conformations that differ in effector recognition.'),
(85357, 2012, 'plos', 'Dynamic modelling under uncertainty: the case of Trypanosoma brucei energy metabolism', 'Achcar, Fiona|Kerkhoven, Eduard J|SilicoTryp Consortium|Bakker, Barbara M|Barrett, Michael P|Breitling, Rainer', 'Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.|Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.|Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.|Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.|Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.|Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 26, 'Bayes Theorem|Energy Metabolism|Glyceric Acids|Glycolysis|Models, Biological|Models, Statistical|Pyruvic Acid|Trypanosoma brucei brucei|Uncertainty', 'Journal Article', '10.1371/journal.pcbi.1002352', '22379410', 'Kinetic models of metabolism require detailed knowledge of kinetic parameters. However, due to measurement errors or lack of data this knowledge is often uncertain. The model of glycolysis in the parasitic protozoan Trypanosoma brucei is a particularly well analysed example of a quantitative metabolic model, but so far it has been studied with a fixed set of parameters only. Here we evaluate the effect of parameter uncertainty. In order to define probability distributions for each parameter, information about the experimental sources and confidence intervals for all parameters were collected. We created a wiki-based website dedicated to the detailed documentation of this information: the SilicoTryp wiki (http://silicotryp.ibls.gla.ac.uk/wiki/Glycolysis). Using information collected in the wiki, we then assigned probability distributions to all parameters of the model. This allowed us to sample sets of alternative models, accurately representing our degree of uncertainty. Some properties of the model, such as the repartition of the glycolytic flux between the glycerol and pyruvate producing branches, are robust to these uncertainties. However, our analysis also allowed us to identify fragilities of the model leading to the accumulation of 3-phosphoglycerate and/or pyruvate. The analysis of the control coefficients revealed the importance of taking into account the uncertainties about the parameters, as the ranking of the reactions can be greatly affected. This work will now form the basis for a comprehensive Bayesian analysis and extension of the model considering alternative topologies.'),
(85358, 2012, 'plos', 'Ten years of pathway analysis: current approaches and outstanding challenges', 'Khatri, Purvesh|Sirota, Marina|Butte, Atul J', 'Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America. pkhatri@stanford.edu|Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America. pkhatri@stanford.edu|Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America. pkhatri@stanford.edu', 'United States|United States|United States', 803, 'Algorithms|Animals|Computational Biology|Gene Expression Profiling|Gene Expression Regulation|Genomics|Humans|Models, Biological|Models, Genetic|Models, Statistical|Multivariate Analysis|Reproducibility of Results|Sensitivity and Specificity|Software', 'Journal Article', '10.1371/journal.pcbi.1002375', '22383865', 'Pathway analysis has become the first choice for gaining insight into the underlying biology of differentially expressed genes and proteins, as it reduces complexity and has increased explanatory power. We discuss the evolution of knowledge base-driven pathway analysis over its first decade, distinctly divided into three generations. We also discuss the limitations that are specific to each generation, and how they are addressed by successive generations of methods. We identify a number of annotation challenges that must be addressed to enable development of the next generation of pathway analysis methods. Furthermore, we identify a number of methodological challenges that the next generation of methods must tackle to take advantage of the technological advances in genomics and proteomics in order to improve specificity, sensitivity, and relevance of pathway analysis.'),
(85359, 2012, 'plos', 'A cell-based computational modeling approach for developing site-directed molecular probes', 'Yu, Jing-Yu|Zheng, Nan|Mane, Gerta|Min, Kyoung Ah|Hinestroza, Juan P|Zhu, Huaning|Stringer, Kathleen A|Rosania, Gus R', 'Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, United States of America.|Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, United States of America.|Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, United States of America.|Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, United States of America.|Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, United States of America.|Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, United States of America.|Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, United States of America.|Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 6, 'Absorption|Animals|Biological Transport|Bronchi|Cations|Cell Differentiation|Computational Biology|Computer Simulation|Epithelial Cells|Fluorescent Dyes|Humans|Lung|Mice|Microscopy, Confocal|Mitochondria|Molecular Probes|Software|Trachea', 'Journal Article', '10.1371/journal.pcbi.1002378', '22383866', 'Modeling the local absorption and retention patterns of membrane-permeant small molecules in a cellular context could facilitate development of site-directed chemical agents for bioimaging or therapeutic applications. Here, we present an integrative approach to this problem, combining in silico computational models, in vitro cell based assays and in vivo biodistribution studies. To target small molecule probes to the epithelial cells of the upper airways, a multiscale computational model of the lung was first used as a screening tool, in silico. Following virtual screening, cell monolayers differentiated on microfabricated pore arrays and multilayer cultures of primary human bronchial epithelial cells differentiated in an air-liquid interface were used to test the local absorption and intracellular retention patterns of selected probes, in vitro. Lastly, experiments involving visualization of bioimaging probe distribution in the lungs after local and systemic administration were used to test the relevance of computational models and cell-based assays, in vivo. The results of in vivo experiments were consistent with the results of in silico simulations, indicating that mitochondrial accumulation of membrane permeant, hydrophilic cations can be used to maximize local exposure and retention, specifically in the upper airways after intratracheal administration.'),
(85360, 2012, 'plos', 'The efficiency of the human CD8+ T cell response: how should we quantify it, what determines it, and does it matter?', 'Elemans, Marjet|Seich Al Basatena, Nafisa-Katrin|Asquith, Becca', 'Section of Immunology, Imperial College School of Medicine, London, United Kingdom.|Section of Immunology, Imperial College School of Medicine, London, United Kingdom.|Section of Immunology, Imperial College School of Medicine, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 13, 'CD8-Positive T-Lymphocytes|Computational Biology|Epitopes|Histocompatibility Antigens Class I|Humans|Ligands|Models, Biological|Models, Theoretical|Phenotype|Receptors, Antigen, T-Cell', 'Journal Article', '10.1371/journal.pcbi.1002381', '22383867', 'Multidisciplinary techniques, in particular the combination of theoretical and experimental immunology, can address questions about human immunity that cannot be answered by other means. From the turnover of virus-infected cells in vivo, to rates of thymic production and HLA class I epitope prediction, theoretical techniques provide a unique insight to supplement experimental approaches. Here we present our opinion, with examples, of some of the ways in which mathematics has contributed in our field of interest: the efficiency of the human CD8+ T cell response to persistent viruses.'),
(85361, 2012, 'plos', 'Structural consensus among antibodies defines the antigen binding site', 'Kunik, Vered|Peters, Bjoern|Ofran, Yanay', 'The Goodman Faculty of Life Sciences, Nanotechnology Building, Bar Ilan University, Ramat Gan, Israel.|The Goodman Faculty of Life Sciences, Nanotechnology Building, Bar Ilan University, Ramat Gan, Israel.|The Goodman Faculty of Life Sciences, Nanotechnology Building, Bar Ilan University, Ramat Gan, Israel.', 'Israel|Israel|Israel', 57, 'Alanine|Antibodies|Antigen-Antibody Complex|Antigens|Automation|B-Lymphocytes|Binding Sites|Binding Sites, Antibody|Complementarity Determining Regions|Epitopes|Humans|Molecular Conformation|Mutation|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1002388', '22383868', 'The Complementarity Determining Regions (CDRs) of antibodies are assumed to account for the antigen recognition and binding and thus to contain also the antigen binding site. CDRs are typically discerned by searching for regions that are most different, in sequence or in structure, between different antibodies. Here, we show that ~20% of the antibody residues that actually bind the antigen fall outside the CDRs. However, virtually all antigen binding residues lie in regions of structural consensus across antibodies. Furthermore, we show that these regions of structural consensus which cover the antigen binding site are identifiable from the sequence of the antibody. Analyzing the predicted contribution of antigen binding residues to the stability of the antibody-antigen complex, we show that residues that fall outside of the traditionally defined CDRs are at least as important to antigen binding as residues within the CDRs, and in some cases, they are even more important energetically. Furthermore, antigen binding residues that fall outside of the structural consensus regions but within traditionally defined CDRs show a marginal energetic contribution to antigen binding. These findings allow for systematic and comprehensive identification of antigen binding sites, which can improve the understanding of antigenic interactions and may be useful in antibody engineering and B-cell epitope identification.'),
(85362, 2012, 'plos', 'Effects of electrical and structural remodeling on atrial fibrillation maintenance: a simulation study', 'Krogh-Madsen, Trine|Abbott, Geoffrey W|Christini, David J', 'Greenberg Division of Cardiology, Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America.|Greenberg Division of Cardiology, Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America.|Greenberg Division of Cardiology, Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America.', 'United States|United States|United States', 55, 'Arrhythmias, Cardiac|Atrial Fibrillation|Biophysics|Computational Biology|Computer Simulation|Electrophysiology|Heart Atria|Heart Conduction System|Humans|Ion Channels|Models, Cardiovascular|Models, Theoretical|Muscle Cells', 'Journal Article', '10.1371/journal.pcbi.1002390', '22383869', 'Atrial fibrillation, a common cardiac arrhythmia, often progresses unfavourably: in patients with long-term atrial fibrillation, fibrillatory episodes are typically of increased duration and frequency of occurrence relative to healthy controls. This is due to electrical, structural, and contractile remodeling processes. We investigated mechanisms of how electrical and structural remodeling contribute to perpetuation of simulated atrial fibrillation, using a mathematical model of the human atrial action potential incorporated into an anatomically realistic three-dimensional structural model of the human atria. Electrical and structural remodeling both shortened the atrial wavelength--electrical remodeling primarily through a decrease in action potential duration, while structural remodeling primarily slowed conduction. The decrease in wavelength correlates with an increase in the average duration of atrial fibrillation/flutter episodes. The dependence of reentry duration on wavelength was the same for electrical vs. structural remodeling. However, the dynamics during atrial reentry varied between electrical, structural, and combined electrical and structural remodeling in several ways, including: (i) with structural remodeling there were more occurrences of fragmented wavefronts and hence more filaments than during electrical remodeling, (ii) dominant waves anchored around different anatomical obstacles in electrical vs. structural remodeling, (iii) dominant waves were often not anchored in combined electrical and structural remodeling. We conclude that, in simulated atrial fibrillation, the wavelength dependence of reentry duration is similar for electrical and structural remodeling, despite major differences in overall dynamics, including maximal number of filaments, wave fragmentation, restitution properties, and whether dominant waves are anchored to anatomical obstacles or spiralling freely.'),
(85363, 2012, 'plos', 'Robust detection of hierarchical communities from Escherichia coli gene expression data', 'Treviño, Santiago|Sun, Yudong|Cooper, Tim F|Bassler, Kevin E', 'Department of Physics, University of Houston, Houston, Texas, United States of America.|Department of Physics, University of Houston, Houston, Texas, United States of America.|Department of Physics, University of Houston, Houston, Texas, United States of America.|Department of Physics, University of Houston, Houston, Texas, United States of America.', 'United States|United States|United States|United States', 26, 'Algorithms|Computational Biology|Escherichia coli|Escherichia coli Proteins|Flagella|Gene Expression|Gene Expression Profiling|Gene Expression Regulation, Bacterial|Gene Regulatory Networks|Genes, Bacterial|Models, Genetic|Models, Statistical|Oligonucleotide Array Sequence Analysis|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002391', '22383870', 'Determining the functional structure of biological networks is a central goal of systems biology. One approach is to analyze gene expression data to infer a network of gene interactions on the basis of their correlated responses to environmental and genetic perturbations. The inferred network can then be analyzed to identify functional communities. However, commonly used algorithms can yield unreliable results due to experimental noise, algorithmic stochasticity, and the influence of arbitrarily chosen parameter values. Furthermore, the results obtained typically provide only a simplistic view of the network partitioned into disjoint communities and provide no information of the relationship between communities. Here, we present methods to robustly detect co-regulated and functionally enriched gene communities and demonstrate their application and validity for Escherichia coli gene expression data. Applying a recently developed community detection algorithm to the network of interactions identified with the context likelihood of relatedness (CLR) method, we show that a hierarchy of network communities can be identified. These communities significantly enrich for gene ontology (GO) terms, consistent with them representing biologically meaningful groups. Further, analysis of the most significantly enriched communities identified several candidate new regulatory interactions. The robustness of our methods is demonstrated by showing that a core set of functional communities is reliably found when artificial noise, modeling experimental noise, is added to the data. We find that noise mainly acts conservatively, increasing the relatedness required for a network link to be reliably assigned and decreasing the size of the core communities, rather than causing association of genes into new communities.'),
(85364, 2012, 'plos', 'Comparison of insertional RNA editing in Myxomycetes', 'Chen, Cai|Frankhouser, David|Bundschuh, Ralf', 'Biophysics Graduate Program, The Ohio State University, Columbus, Ohio, United States of America.|Biophysics Graduate Program, The Ohio State University, Columbus, Ohio, United States of America.|Biophysics Graduate Program, The Ohio State University, Columbus, Ohio, United States of America.', 'United States|United States|United States', 0, 'Algorithms|Binding Sites|Codon|Computational Biology|Computers|Conserved Sequence|DNA, Mitochondrial|Genome|Models, Biological|Models, Statistical|Mutation|Myxomycetes|Nucleotides|Physarum|Probability|RNA Editing', 'Comparative Study', '10.1371/journal.pcbi.1002400', '22383871', 'RNA editing describes the process in which individual or short stretches of nucleotides in a messenger or structural RNA are inserted, deleted, or substituted. A high level of RNA editing has been observed in the mitochondrial genome of Physarum polycephalum. The most frequent editing type in Physarum is the insertion of individual Cs. RNA editing is extremely accurate in Physarum, however, little is known about its mechanism. Here, we demonstrate how analyzing two organisms from the Myxomycetes, namely Physarum polycephalum and Didymium iridis, allows us to test hypotheses about the editing mechanism that can not be tested from a single organism alone. First, we show that using the recently determined full transcriptome information of Physarum dramatically improves the accuracy of computational editing site prediction in Didymium. We use this approach to predict genes in the mitochondrial genome of Didymium and identify six new edited genes as well as one new gene that appears unedited. Next we investigate sequence conservation in the vicinity of editing sites between the two organisms in order to identify sites that harbor the information for the location of editing sites based on increased conservation. Our results imply that the information contained within only nine or ten nucleotides on either side of the editing site (a distance previously suggested through experiments) is not enough to locate the editing sites. Finally, we show that the codon position bias in C insertional RNA editing of these two organisms is correlated with the selection pressure on the respective genes thereby directly testing an evolutionary theory on the origin of this codon bias. Beyond revealing interesting properties of insertional RNA editing in Myxomycetes, our work suggests possible approaches to be used when finding sequence motifs for any biological process fails.'),
(85365, 2012, 'plos', 'Efficient sparse coding in early sensory processing: lessons from signal recovery', 'Lörincz, András|Palotai, Zsolt|Szirtes, Gábor', 'Department of Software Technology and Methodology, Eötvös Loránd University, Budapest, Hungary. andras.lorincz@elte.hu|Department of Software Technology and Methodology, Eötvös Loránd University, Budapest, Hungary. andras.lorincz@elte.hu|Department of Software Technology and Methodology, Eötvös Loránd University, Budapest, Hungary. andras.lorincz@elte.hu', 'Hungary|Hungary|Hungary', 9, 'Action Potentials|Animals|Computer Simulation|Humans|Models, Neurological|Nerve Net|Retina|Sensory Receptor Cells|Visual Cortex|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1002372', '22396629', 'Sensory representations are not only sparse, but often overcomplete: coding units significantly outnumber the input units. For models of neural coding this overcompleteness poses a computational challenge for shaping the signal processing channels as well as for using the large and sparse representations in an efficient way. We argue that higher level overcompleteness becomes computationally tractable by imposing sparsity on synaptic activity and we also show that such structural sparsity can be facilitated by statistics based decomposition of the stimuli into typical and atypical parts prior to sparse coding. Typical parts represent large-scale correlations, thus they can be significantly compressed. Atypical parts, on the other hand, represent local features and are the subjects of actual sparse coding. When applied on natural images, our decomposition based sparse coding model can efficiently form overcomplete codes and both center-surround and oriented filters are obtained similar to those observed in the retina and the primary visual cortex, respectively. Therefore we hypothesize that the proposed computational architecture can be seen as a coherent functional model of the first stages of sensory coding in early vision.'),
(85366, 2012, 'plos', 'Depression-biased reverse plasticity rule is required for stable learning at top-down connections', 'Burbank, Kendra S|Kreiman, Gabriel', 'Department of Neurology and Ophthalmology, Childrens Hospital Boston, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Neurology and Ophthalmology, Childrens Hospital Boston, Harvard Medical School, Boston, Massachusetts, United States of America.', 'United States|United States', 0, 'Action Potentials|Computer Simulation|Humans|Long-Term Synaptic Depression|Models, Neurological|Neocortex|Nerve Net|Neural Inhibition|Neuronal Plasticity|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002393', '22396630', 'Top-down synapses are ubiquitous throughout neocortex and play a central role in cognition, yet little is known about their development and specificity. During sensory experience, lower neocortical areas are activated before higher ones, causing top-down synapses to experience a preponderance of post-synaptic activity preceding pre-synaptic activity. This timing pattern is the opposite of that experienced by bottom-up synapses, which suggests that different versions of spike-timing dependent synaptic plasticity (STDP) rules may be required at top-down synapses. We consider a two-layer neural network model and investigate which STDP rules can lead to a distribution of top-down synaptic weights that is stable, diverse and avoids strong loops. We introduce a temporally reversed rule (rSTDP) where top-down synapses are potentiated if post-synaptic activity precedes pre-synaptic activity. Combining analytical work and integrate-and-fire simulations, we show that only depression-biased rSTDP (and not classical STDP) produces stable and diverse top-down weights. The conclusions did not change upon addition of homeostatic mechanisms, multiplicative STDP rules or weak external input to the top neurons. Our prediction for rSTDP at top-down synapses, which are distally located, is supported by recent neurophysiological evidence showing the existence of temporally reversed STDP in synapses that are distal to the post-synaptic cell body.'),
(85367, 2012, 'plos', 'Uncovering the dynamics of cardiac systems using stochastic pacing and frequency domain analyses', 'Lemay, Mathieu|de Lange, Enno|Kucera, Jan P', 'Department of Physiology, University of Bern, Bern, Switzerland.|Department of Physiology, University of Bern, Bern, Switzerland.|Department of Physiology, University of Bern, Bern, Switzerland.', 'Switzerland|Switzerland|Switzerland', 12, 'Action Potentials|Animals|Arrhythmias, Cardiac|Calcium Signaling|Cardiac Pacing, Artificial|Computer Simulation|Heart Conduction System|Heart Rate|Humans|Models, Cardiovascular|Models, Statistical', 'Journal Article', '10.1371/journal.pcbi.1002399', '22396631', 'Alternans of cardiac action potential duration (APD) is a well-known arrhythmogenic mechanism which results from dynamical instabilities. The propensity to alternans is classically investigated by examining APD restitution and by deriving APD restitution slopes as predictive markers. However, experiments have shown that such markers are not always accurate for the prediction of alternans. Using a mathematical ventricular cell model known to exhibit unstable dynamics of both membrane potential and Caxc2xb2xe2x81xba cycling, we demonstrate that an accurate marker can be obtained by pacing at cycle lengths (CLs) varying randomly around a basic CL (BCL) and by evaluating the transfer function between the time series of CLs and APDs using an autoregressive-moving-average (ARMA) model. The first pole of this transfer function corresponds to the eigenvalue (xcexbb(alt)) of the dominant eigenmode of the cardiac system, which predicts that alternans occurs when xcexbb(alt) xe2x89xa4 -1. For different BCLs, control values of xcexbb(alt) were obtained using eigenmode analysis and compared to the first pole of the transfer function estimated using ARMA model fitting in simulations of random pacing protocols. In all versions of the cell model, this pole provided an accurate estimation of xcexbb(alt). Furthermore, during slow ramp decreases of BCL or simulated drug application, this approach predicted the onset of alternans by extrapolating the time course of the estimated xcexbb(alt). In conclusion, stochastic pacing and ARMA model identification represents a novel approach to predict alternans without making any assumptions about its ionic mechanisms. It should therefore be applicable experimentally for any type of myocardial cell.'),
(85368, 2012, 'plos', 'A self-organizing state-space-model approach for parameter estimation in hodgkin-huxley-type models of single neurons', 'Vavoulis, Dimitrios V|Straub, Volko A|Aston, John A D|Feng, Jianfeng', 'Department of Computer Science, University of Warwick, Coventry, United Kingdom. Dimitris.Vavoulis@dcs.warwick.ac.uk|Department of Computer Science, University of Warwick, Coventry, United Kingdom. Dimitris.Vavoulis@dcs.warwick.ac.uk|Department of Computer Science, University of Warwick, Coventry, United Kingdom. Dimitris.Vavoulis@dcs.warwick.ac.uk|Department of Computer Science, University of Warwick, Coventry, United Kingdom. Dimitris.Vavoulis@dcs.warwick.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 21, 'Action Potentials|Algorithms|Animals|Computer Simulation|Humans|Models, Neurological|Models, Statistical|Neurons', 'Journal Article', '10.1371/journal.pcbi.1002401', '22396632', 'Traditional approaches to the problem of parameter estimation in biophysical models of neurons and neural networks usually adopt a global search algorithm (for example, an evolutionary algorithm), often in combination with a local search method (such as gradient descent) in order to minimize the value of a cost function, which measures the discrepancy between various features of the available experimental data and model output. In this study, we approach the problem of parameter estimation in conductance-based models of single neurons from a different perspective. By adopting a hidden-dynamical-systems formalism, we expressed parameter estimation as an inference problem in these systems, which can then be tackled using a range of well-established statistical inference methods. The particular method we used was Kitagawas self-organizing state-space model, which was applied on a number of Hodgkin-Huxley-type models using simulated or actual electrophysiological data. We showed that the algorithm can be used to estimate a large number of parameters, including maximal conductances, reversal potentials, kinetics of ionic currents, measurement and intrinsic noise, based on low-dimensional experimental data and sufficiently informative priors in the form of pre-defined constraints imposed on model parameters. The algorithm remained operational even when very noisy experimental data were used. Importantly, by combining the self-organizing state-space model with an adaptive sampling algorithm akin to the Covariance Matrix Adaptation Evolution Strategy, we achieved a significant reduction in the variance of parameter estimates. The algorithm did not require the explicit formulation of a cost function and it was straightforward to apply on compartmental models and multiple data sets. Overall, the proposed methodology is particularly suitable for resolving high-dimensional inference problems based on noisy electrophysiological data and, therefore, a potentially useful tool in the construction of biophysical neuron models.'),
(85369, 2012, 'plos', 'How cells integrate complex stimuli: the effect of feedback from phosphoinositides and cell shape on cell polarization and motility', 'Marxc3xa9e, Athanasius F M|Grieneisen, Verxc3xb4nica A|Edelstein-Keshet, Leah', 'Computational & Systems Biology, John Innes Centre, Norwich Research Park, Norwich, United Kingdom. stan.maree@jic.ac.uk|Computational & Systems Biology, John Innes Centre, Norwich Research Park, Norwich, United Kingdom. stan.maree@jic.ac.uk|Computational & Systems Biology, John Innes Centre, Norwich Research Park, Norwich, United Kingdom. stan.maree@jic.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Animals|Cell Polarity|Cell Size|Chemotaxis|Computer Simulation|Feedback, Physiological|Humans|Models, Biological|Phosphatidylinositols|rho GTP-Binding Proteins', 'Journal Article', '10.1371/journal.pcbi.1002402', '22396633', 'To regulate shape changes, motility and chemotaxis in eukaryotic cells, signal transduction pathways channel extracellular stimuli to the reorganization of the actin cytoskeleton. The complexity of such networks makes it difficult to understand the roles of individual components, let alone their interactions and multiple feedbacks within a given layer and between layers of signalling. Even more challenging is the question of if and how the shape of the cell affects and is affected by this internal spatiotemporal reorganization. Here we build on our previous 2D cell motility model where signalling from the Rho family GTPases (Cdc42, Rac, and Rho) was shown to organize the cell polarization, actin reorganization, shape change, and motility in simple gradients. We extend this work in two ways: First, we investigate the effects of the feedback between the phosphoinositides (PIs) PIPxe2x82x82, PIPxe2x82x83 and Rho family GTPases. We show how that feedback increases heights and breadths of zones of Cdc42 activity, facilitating global communication between competing cell fronts. This hastens the commitment to a single lamellipodium initiated in response to multiple, complex, or rapidly changing stimuli. Second, we show how cell shape feeds back on internal distribution of GTPases. Constraints on chemical isocline curvature imposed by boundary conditions results in the fact that dynamic cell shape leads to faster biochemical redistribution when the cell is repolarized. Cells with frozen cytoskeleton, and static shapes, consequently respond more slowly to reorienting stimuli than cells with dynamic shape changes, the degree of the shape-induced effects being proportional to the extent of cell deformation. We explain these concepts in the context of several in silico experiments using our 2D computational cell model.'),
(85370, 2012, 'plos', 'Exploring the evolution of novel enzyme functions within structurally defined protein superfamilies', 'Furnham, Nicholas|Sillitoe, Ian|Holliday, Gemma L|Cuff, Alison L|Laskowski, Roman A|Orengo, Christine A|Thornton, Janet M', 'EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom. nickf@ebi.ac.uk|EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom. nickf@ebi.ac.uk|EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom. nickf@ebi.ac.uk|EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom. nickf@ebi.ac.uk|EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom. nickf@ebi.ac.uk|EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom. nickf@ebi.ac.uk|EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom. nickf@ebi.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 61, 'Amino Acid Sequence|Enzymes|Evolution, Molecular|Molecular Sequence Data|Sequence Analysis, Protein|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1002403', '22396634', 'In order to understand the evolution of enzyme reactions and to gain an overview of biological catalysis we have combined sequence and structural data to generate phylogenetic trees in an analysis of 276 structurally defined enzyme superfamilies, and used these to study how enzyme functions have evolved. We describe in detail the analysis of two superfamilies to illustrate different paradigms of enzyme evolution. Gathering together data from all the superfamilies supports and develops the observation that they have all evolved to act on a diverse set of substrates, whilst the evolution of new chemistry is much less common. Despite that, by bringing together so much data, we can provide a comprehensive overview of the most common and rare types of changes in function. Our analysis demonstrates on a larger scale than previously studied, that modifications in overall chemistry still occur, with all possible changes at the primary level of the Enzyme Commission (E.C.) classification observed to a greater or lesser extent. The phylogenetic trees map out the evolutionary route taken within a superfamily, as well as all the possible changes within a superfamily. This has been used to generate a matrix of observed exchanges from one enzyme function to another, revealing the scale and nature of enzyme evolution and that some types of exchanges between and within E.C. classes are more prevalent than others. Surprisingly a large proportion (71%) of all known enzyme functions are performed by this relatively small set of 276 superfamilies. This reinforces the hypothesis that relatively few ancient enzymatic domain superfamilies were progenitors for most of the chemistry required for life.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85371, 2012, 'plos', 'Cortical Surround Interactions and Perceptual Salience via Natural Scene Statistics', 'Coen-Cagli, Ruben|Dayan, Peter|Schwartz, Odelia', 'Dominick Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America. ruben.coencagli@einstein.yu.edu|Dominick Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America. ruben.coencagli@einstein.yu.edu|Dominick Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America. ruben.coencagli@einstein.yu.edu', 'United States|United States|United States', 46, 'Animals|Computer Simulation|Humans|Models, Neurological|Models, Statistical|Nerve Net|Orientation|Space Perception|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1002405', '22396635', 'Spatial context in images induces perceptual phenomena associated with salience and modulates the responses of neurons in primary visual cortex (V1). However, the computational and ecological principles underlying contextual effects are incompletely understood. We introduce a model of natural images that includes grouping and segmentation of neighboring features based on their joint statistics, and we interpret the firing rates of V1 neurons as performing optimal recognition in this model. We show that this leads to a substantial generalization of divisive normalization, a computation that is ubiquitous in many neural areas and systems. A main novelty in our model is that the influence of the context on a target stimulus is determined by their degree of statistical dependence. We optimized the parameters of the model on natural image patches, and then simulated neural and perceptual responses on stimuli used in classical experiments. The model reproduces some rich and complex response patterns observed in V1, such as the contrast dependence, orientation tuning and spatial asymmetry of surround suppression, while also allowing for surround facilitation under conditions of weak stimulation. It also mimics the perceptual salience produced by simple displays, and leads to readily testable predictions. Our results provide a principled account of orientation-based contextual modulation in early vision and its sensitivity to the homogeneity and spatial arrangement of inputs, and lends statistical support to the theory that V1 computes visual salience.'),
(85372, 2012, 'plos', 'Modelling the self-assembly of elastomeric proteins provides insights into the evolution of their domain architectures', 'Song, Hongyan|Parkinson, John', 'Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada.', 'Canada|Canada', 0, 'Amino Acid Sequence|Binding Sites|Computer Simulation|Elastomers|Evolution, Molecular|Models, Chemical|Molecular Sequence Data|Protein Binding|Protein Structure, Tertiary|Proteins', 'Journal Article', '10.1371/journal.pcbi.1002406', '22396636', 'Elastomeric proteins have evolved independently multiple times through evolution. Produced as monomers, they self-assemble into polymeric structures that impart properties of stretch and recoil. They are composed of an alternating domain architecture of elastomeric domains interspersed with cross-linking elements. While the former provide the elasticity as well as help drive the assembly process, the latter serve to stabilise the polymer. Changes in the number and arrangement of the elastomeric and cross-linking regions have been shown to significantly impact their assembly and mechanical properties. However, to date, such studies are relatively limited. Here we present a theoretical study that examines the impact of domain architecture on polymer assembly and integrity. At the core of this study is a novel simulation environment that uses a model of diffusion limited aggregation to simulate the self-assembly of rod-like particles with alternating domain architectures. Applying the model to different domain architectures, we generate a variety of aggregates which are subsequently analysed by graph-theoretic metrics to predict their structural integrity. Our results show that the relative length and number of elastomeric and cross-linking domains can significantly impact the morphology and structural integrity of the resultant polymeric structure. For example, the most highly connected polymers were those constructed from asymmetric rods consisting of relatively large cross-linking elements interspersed with smaller elastomeric domains. In addition to providing insights into the evolution of elastomeric proteins, simulations such as those presented here may prove valuable for the tuneable design of new molecules that may be exploited as useful biomaterials.'),
(85373, 2012, 'plos', 'Changes in Lysozyme Flexibility upon Mutation Are Frequent, Large and Long-Ranged', 'Verma, Deeptak|Jacobs, Donald J|Livesay, Dennis R', 'Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, North Carolina, United States of America.|Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, North Carolina, United States of America.|Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, North Carolina, United States of America.', 'United States|United States|United States', 34, 'Amino Acid Sequence|Binding Sites|Computer Simulation|Genetic Variation|Models, Chemical|Models, Genetic|Molecular Sequence Data|Muramidase|Mutation|Protein Binding|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1002409', '22396637', 'We investigate changes in human c-type lysozyme flexibility upon mutation via a Distance Constraint Model, which gives a statistical mechanical treatment of network rigidity. Specifically, two dynamical metrics are tracked. Changes in flexibility index quantify differences within backbone flexibility, whereas changes in the cooperativity correlation quantify differences within pairwise mechanical couplings. Regardless of metric, the same general conclusions are drawn. That is, small structural perturbations introduced by single point mutations have a frequent and pronounced affect on lysozyme flexibility that can extend over long distances. Specifically, an appreciable change occurs in backbone flexibility for 48% of the residues, and a change in cooperativity occurs in 42% of residue pairs. The average distance from mutation to a site with a change in flexibility is 17-20 xc3x85. Interestingly, the frequency and scale of the changes within single point mutant structures are generally larger than those observed in the hen egg white lysozyme (HEWL) ortholog, which shares 61% sequence identity with human lysozyme. For example, point mutations often lead to substantial flexibility increases within the xcexb2-subdomain, which is consistent with experimental results indicating that it is the nucleation site for amyloid formation. However, xcexb2-subdomain flexibility within the human and HEWL orthologs is more similar despite the lowered sequence identity. These results suggest compensating mutations in HEWL reestablish desired properties.'),
(85374, 2012, 'plos', 'Degenerate T-cell recognition of peptides on MHC molecules creates large holes in the T-cell repertoire', 'Calis, Jorg J A|de Boer, Rob J|Kexc5x9fmir, Can', 'Theoretical Biology & Bioinformatics, Utrecht University, Utrecht, The Netherlands. j.j.a.calis@uu.nl|Theoretical Biology & Bioinformatics, Utrecht University, Utrecht, The Netherlands. j.j.a.calis@uu.nl|Theoretical Biology & Bioinformatics, Utrecht University, Utrecht, The Netherlands. j.j.a.calis@uu.nl', 'Netherlands|Netherlands|Netherlands', 40, 'Bacterial Proteins|Binding Sites|Computer Simulation|Epitope Mapping|HLA Antigens|Models, Chemical|Models, Immunological|Protein Binding|Receptors, Antigen, T-Cell|Viral Proteins', 'Journal Article', '10.1371/journal.pcbi.1002412', '22396638', 'The cellular immune system screens peptides presented by host cells on MHC molecules to assess if the cells are infected. In this study we examined whether the presented peptides contain enough information for a proper self/nonself assessment by comparing the presented human (self) and bacterial or viral (nonself) peptides on a large number of MHC molecules. For all MHC molecules tested, only a small fraction of the presented nonself peptides from 174 species of bacteria and 1000 viral proteomes ([Formula: see text]0.2%) is shown to be identical to a presented self peptide. Next, we use available data on T-cell receptor-peptide-MHC interactions to estimate how well T-cells distinguish between similar peptides. The recognition of a peptide-MHC by the T-cell receptor is flexible, and as a result, about one-third of the presented nonself peptides is expected to be indistinguishable (by T-cells) from presented self peptides. This suggests that T-cells are expected to remain tolerant for a large fraction of the presented nonself peptides, which provides an explanation for the holes in the T-cell repertoire that are found for a large fraction of foreign epitopes. Additionally, this overlap with self increases the need for efficient self tolerance, as many self-similar nonself peptides could initiate an autoimmune response. Degenerate recognition of peptide-MHC-I complexes by T-cells thus creates large and potentially dangerous overlaps between self and nonself.'),
(85375, 2012, 'plos', 'Living on three time scales: the dynamics of plasma cell and antibody populations illustrated for hepatitis a virus', 'Andraud, Mathieu|Lejeune, Olivier|Musoro, Jammbe Z|Ogunjimi, Benson|Beutels, Philippe|Hens, Niel', 'Centre for Health Economics Research and Modelling of Infectious Diseases-CHERMID, Vaccine & Infectious Disease Institute-VAXINFECTIO, University of Antwerp, Antwerp, Belgium. mathieu.andraud@ua.ac.be|Centre for Health Economics Research and Modelling of Infectious Diseases-CHERMID, Vaccine & Infectious Disease Institute-VAXINFECTIO, University of Antwerp, Antwerp, Belgium. mathieu.andraud@ua.ac.be|Centre for Health Economics Research and Modelling of Infectious Diseases-CHERMID, Vaccine & Infectious Disease Institute-VAXINFECTIO, University of Antwerp, Antwerp, Belgium. mathieu.andraud@ua.ac.be|Centre for Health Economics Research and Modelling of Infectious Diseases-CHERMID, Vaccine & Infectious Disease Institute-VAXINFECTIO, University of Antwerp, Antwerp, Belgium. mathieu.andraud@ua.ac.be|Centre for Health Economics Research and Modelling of Infectious Diseases-CHERMID, Vaccine & Infectious Disease Institute-VAXINFECTIO, University of Antwerp, Antwerp, Belgium. mathieu.andraud@ua.ac.be|Centre for Health Economics Research and Modelling of Infectious Diseases-CHERMID, Vaccine & Infectious Disease Institute-VAXINFECTIO, University of Antwerp, Antwerp, Belgium. mathieu.andraud@ua.ac.be', 'Belgium|Belgium|Belgium|Belgium|Belgium|Belgium', 0, 'Antibodies, Viral|Antigens, Viral|Computer Simulation|Hepatitis A Vaccines|Hepatitis A virus|Humans|Immunity, Innate|Models, Immunological|Plasma Cells|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1002418', '22396639', 'Understanding the mechanisms involved in long-term persistence of humoral immunity after natural infection or vaccination is challenging and crucial for further research in immunology, vaccine development as well as health policy. Long-lived plasma cells, which have recently been shown to reside in survival niches in the bone marrow, are instrumental in the process of immunity induction and persistence. We developed a mathematical model, assuming two antibody-secreting cell subpopulations (short- and long-lived plasma cells), to analyze the antibody kinetics after HAV-vaccination using data from two long-term follow-up studies. Model parameters were estimated through a hierarchical nonlinear mixed-effects model analysis. Long-term individual predictions were derived from the individual empirical parameters and were used to estimate the mean time to immunity waning. We show that three life spans are essential to explain the observed antibody kinetics: that of the antibodies (around one month), the short-lived plasma cells (several months) and the long-lived plasma cells (decades). Although our model is a simplified representation of the actual mechanisms that govern individual immune responses, the level of agreement between long-term individual predictions and observed kinetics is reassuringly close. The quantitative assessment of the time scales over which plasma cells and antibodies live and interact provides a basis for further quantitative research on immunology, with direct consequences for understanding the epidemiology of infectious diseases, and for timing serum sampling in clinical trials of vaccines.'),
(85376, 2012, 'plos', 'State-space analysis of time-varying higher-order spike correlation for multiple neural spike train data', 'Shimazaki, Hideaki|Amari, Shun-Ichi|Brown, Emery N|Grün, Sonja', 'RIKEN Brain Science Institute, Wako-shi, Saitama, Japan. shimazaki@brain.riken.jp|RIKEN Brain Science Institute, Wako-shi, Saitama, Japan. shimazaki@brain.riken.jp|RIKEN Brain Science Institute, Wako-shi, Saitama, Japan. shimazaki@brain.riken.jp|RIKEN Brain Science Institute, Wako-shi, Saitama, Japan. shimazaki@brain.riken.jp', 'Japan|Japan|Japan|Japan', 63, 'Action Potentials|Algorithms|Animals|Computer Simulation|Electroencephalography|Haplorhini|Models, Neurological|Motor Cortex|Movement|Nerve Net|Neurons|Statistics as Topic|Task Performance and Analysis', 'Journal Article', '10.1371/journal.pcbi.1002385', '22412358', 'Precise spike coordination between the spiking activities of multiple neurons is suggested as an indication of coordinated network activity in active cell assemblies. Spike correlation analysis aims to identify such cooperative network activity by detecting excess spike synchrony in simultaneously recorded multiple neural spike sequences. Cooperative activity is expected to organize dynamically during behavior and cognition, therefore currently available analysis techniques must be extended to enable the estimation of multiple time-varying spike interactions between neurons simultaneously. In particular, new methods must take advantage of the simultaneous observations of multiple neurons by addressing their higher-order dependencies, which cannot be revealed by pairwise analyses alone. In this paper, we develop a method for estimating time-varying spike interactions by means of a state-space analysis. Discretized parallel spike sequences are modeled as multi-variate binary processes using a log-linear model that provides a well-defined measure of higher-order spike correlation in an information geometry framework. We construct a recursive Bayesian filter/smoother for the extraction of spike interaction parameters. This method can simultaneously estimate the dynamic pairwise spike interactions of multiple single neurons, thereby extending the Ising/spin-glass model analysis of multiple neural spike train data to a nonstationary analysis. Furthermore, the method can estimate dynamic higher-order spike interactions. To validate the inclusion of the higher-order terms in the model, we construct an approximation method to assess the goodness-of-fit to spike data. In addition, we formulate a test method for the presence of higher-order spike correlation even in nonstationary spike data, e.g., data from awake behaving animals. The utility of the proposed methods is tested using simulated spike data with known underlying correlation dynamics. Finally, we apply the methods to neural spike data simultaneously recorded from the motor cortex of an awake monkey and demonstrate that the higher-order spike correlation organizes dynamically in relation to a behavioral demand.'),
(85377, 2012, 'plos', 'Epitope flexibility and dynamic footprint revealed by molecular dynamics of a pMHC-TCR complex', 'Reboul, Cyril F|Meyer, Grischa R|Porebski, Benjamin T|Borg, Natalie A|Buckle, Ashley M', 'Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia.', 'Australia|Australia|Australia|Australia|Australia', 39, 'Binding Sites|Computer Simulation|Epitope Mapping|Histocompatibility Antigens|Major Histocompatibility Complex|Models, Chemical|Models, Molecular|Multiprotein Complexes|Protein Binding|Protein Conformation|Receptors, Antigen, T-Cell', 'Journal Article', '10.1371/journal.pcbi.1002404', '22412359', 'The crystal structures of unliganded and liganded pMHC molecules provide a structural basis for TCR recognition yet they represent snapshots and offer limited insight into dynamics that may be important for interaction and T cell activation. MHC molecules HLA-B*3501 and HLA-B*3508 both bind a 13 mer viral peptide (LPEP) yet only HLA-B*3508-LPEP induces a CTL response characterised by the dominant TCR clonetype SB27. HLA-B*3508-LPEP forms a tight and long-lived complex with SB27, but the relatively weak interaction between HLA-B*3501-LPEP and SB27 fails to trigger an immune response. HLA-B*3501 and HLA-B*3508 differ by only one amino acid (L/R156) located on xcexb12-helix, but this does not alter the MHC or peptide structure nor does this polymorphic residue interact with the peptide or SB27. In the absence of a structural rationalisation for the differences in TCR engagement we performed a molecular dynamics study of both pMHC complexes and HLA-B*3508-LPEP in complex with SB27. This reveals that the high flexibility of the peptide in HLA-B*3501 compared to HLA-B*3508, which was not apparent in the crystal structure alone, may have an under-appreciated role in SB27 recognition. The TCR pivots atop peptide residues 6-9 and makes transient MHC contacts that extend those observed in the crystal structure. Thus MD offers an insight into scanning mechanism of SB27 that extends the role of the germline encoded CDR2xcexb1 and CDR2xcexb2 loops. Our data are consistent with the vast body of experimental observations for the pMHC-LPEP-SB27 interaction and provide additional insights not accessible using crystallography.'),
(85378, 2012, 'plos', 'Bonsai trees in your head: how the pavlovian system sculpts goal-directed choices by pruning decision trees', 'Huys, Quentin J M|Eshel, Neir|ONions, Elizabeth|Sheridan, Luke|Dayan, Peter|Roiser, Jonathan P', 'Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom. qhuys@cantab.net|Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom. qhuys@cantab.net|Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom. qhuys@cantab.net|Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom. qhuys@cantab.net|Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom. qhuys@cantab.net|Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom. qhuys@cantab.net', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Algorithms|Computer Simulation|Decision Making|Goals|Humans|Models, Neurological|Reinforcement (Psychology)|Task Performance and Analysis', 'Journal Article', '10.1371/journal.pcbi.1002410', '22412360', 'When planning a series of actions, it is usually infeasible to consider all potential future sequences, instead, one must prune the decision tree. Provably optimal pruning is, however, still computationally ruinous and the specific approximations humans employ remain unknown. We designed a new sequential reinforcement-based task and showed that human subjects adopted a simple pruning strategy: during mental evaluation of a sequence of choices, they curtailed any further evaluation of a sequence as soon as they encountered a large loss. This pruning strategy was Pavlovian: it was reflexively evoked by large losses and persisted even when overwhelmingly counterproductive. It was also evident above and beyond loss aversion. We found that the tendency towards Pavlovian pruning was selectively predicted by the degree to which subjects exhibited sub-clinical mood disturbance, in accordance with theories that ascribe Pavlovian behavioural inhibition, via serotonin, a role in mood disorders. We conclude that Pavlovian behavioural inhibition shapes highly flexible, goal-directed choices in a manner that may be important for theories of decision-making in mood disorders.'),
(85379, 2012, 'plos', 'Inferring epidemic contact structure from phylogenetic trees', 'Leventhal, Gabriel E|Kouyos, Roger|Stadler, Tanja|Wyl, Viktor von|Yerly, Sabine|Böni, Jürg|Cellerai, Cristina|Klimkait, Thomas|Günthard, Huldrych F|Bonhoeffer, Sebastian', 'Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. gabriel.leventhal@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. gabriel.leventhal@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. gabriel.leventhal@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. gabriel.leventhal@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. gabriel.leventhal@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. gabriel.leventhal@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. gabriel.leventhal@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. gabriel.leventhal@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. gabriel.leventhal@env.ethz.ch|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. gabriel.leventhal@env.ethz.ch', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Swit', 56, 'Contact Tracing|Disease Transmission, Infectious|Female|Genetic Predisposition to Disease|HIV Infections|Humans|Male|Phylogeny|Prevalence|Proportional Hazards Models|Risk Assessment|Risk Factors|Switzerland', 'Journal Article', '10.1371/journal.pcbi.1002413', '22412361', 'Contact structure is believed to have a large impact on epidemic spreading and consequently using networks to model such contact structure continues to gain interest in epidemiology. However, detailed knowledge of the exact contact structure underlying real epidemics is limited. Here we address the question whether the structure of the contact network leaves a detectable genetic fingerprint in the pathogen population. To this end we compare phylogenies generated by disease outbreaks in simulated populations with different types of contact networks. We find that the shape of these phylogenies strongly depends on contact structure. In particular, measures of tree imbalance allow us to quantify to what extent the contact structure underlying an epidemic deviates from a null model contact network and illustrate this in the case of random mixing. Using a phylogeny from the Swiss HIV epidemic, we show that this epidemic has a significantly more unbalanced tree than would be expected from random mixing.'),
(85380, 2012, 'plos', 'Does sex speed up evolutionary rate and increase biodiversity?', 'Melián, Carlos J|Alonso, David|Allesina, Stefano|Condit, Richard S|Etienne, Rampal S', 'National Center for Ecological Analysis and Synthesis, University of California, Santa Barbara, California, United States of America. carlos.melian@eawag.ch|National Center for Ecological Analysis and Synthesis, University of California, Santa Barbara, California, United States of America. carlos.melian@eawag.ch|National Center for Ecological Analysis and Synthesis, University of California, Santa Barbara, California, United States of America. carlos.melian@eawag.ch|National Center for Ecological Analysis and Synthesis, University of California, Santa Barbara, California, United States of America. carlos.melian@eawag.ch|National Center for Ecological Analysis and Synthesis, University of California, Santa Barbara, California, United States of America. carlos.melian@eawag.ch', 'United States|United States|United States|United States|United States', 13, 'Biodiversity|Biological Evolution|Computer Simulation|DNA|DNA Mutational Analysis|Genetics, Population|Humans|Models, Genetic|Models, Statistical|Sexual Behavior', 'Journal Article', '10.1371/journal.pcbi.1002414', '22412362', 'Most empirical and theoretical studies have shown that sex increases the rate of evolution, although evidence of sex constraining genomic and epigenetic variation and slowing down evolution also exists. Faster rates with sex have been attributed to new gene combinations, removal of deleterious mutations, and adaptation to heterogeneous environments. Slower rates with sex have been attributed to removal of major genetic rearrangements, the cost of finding a mate, vulnerability to predation, and exposure to sexually transmitted diseases. Whether sex speeds or slows evolution, the connection between reproductive mode, the evolutionary rate, and species diversity remains largely unexplored. Here we present a spatially explicit model of ecological and evolutionary dynamics based on DNA sequence change to study the connection between mutation, speciation, and the resulting biodiversity in sexual and asexual populations. We show that faster speciation can decrease the abundance of newly formed species and thus decrease long-term biodiversity. In this way, sex can reduce diversity relative to asexual populations, because it leads to a higher rate of production of new species, but with lower abundances. Our results show that reproductive mode and the mechanisms underlying it can alter the link between mutation, evolutionary rate, speciation and biodiversity and we suggest that a high rate of evolution may not be required to yield high biodiversity.'),
(85381, 2012, 'plos', 'Mitochondrial variability as a source of extrinsic cellular noise', 'Johnston, Iain G|Gaal, Bernadett|Neves, Ricardo Pires das|Enver, Tariq|Iborra, Francisco J|Jones, Nick S', 'Department of Physics, Clarendon Laboratory, Oxford, United Kingdom.|Department of Physics, Clarendon Laboratory, Oxford, United Kingdom.|Department of Physics, Clarendon Laboratory, Oxford, United Kingdom.|Department of Physics, Clarendon Laboratory, Oxford, United Kingdom.|Department of Physics, Clarendon Laboratory, Oxford, United Kingdom.|Department of Physics, Clarendon Laboratory, Oxford, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Adaptation, Physiological|Animals|Cell Cycle|Cell Size|Computer Simulation|Humans|Mitochondria|Models, Biological|Models, Statistical|Transcriptional Activation', 'Journal Article', '10.1371/journal.pcbi.1002416', '22412363', 'We present a study investigating the role of mitochondrial variability in generating noise in eukaryotic cells. Noise in cellular physiology plays an important role in many fundamental cellular processes, including transcription, translation, stem cell differentiation and response to medication, but the specific random influences that affect these processes have yet to be clearly elucidated. Here we present a mechanism by which variability in mitochondrial volume and functionality, along with cell cycle dynamics, is linked to variability in transcription rate and hence has a profound effect on downstream cellular processes. Our model mechanism is supported by an appreciable volume of recent experimental evidence, and we present the results of several new experiments with which our model is also consistent. We find that noise due to mitochondrial variability can sometimes dominate over other extrinsic noise sources (such as cell cycle asynchronicity) and can significantly affect large-scale observable properties such as cell cycle length and gene expression levels. We also explore two recent regulatory network-based models for stem cell differentiation, and find that extrinsic noise in transcription rate causes appreciable variability in the behaviour of these model systems. These results suggest that mitochondrial and transcriptional variability may be an important mechanism influencing a large variety of cellular processes and properties.'),
(85382, 2012, 'plos', 'Cytoskeletal signaling: is memory encoded in microtubule lattices by CaMKII phosphorylation?', 'Craddock, Travis J A|Tuszynski, Jack A|Hameroff, Stuart', 'Department of Physics, University of Alberta, Edmonton, Canada. travisc@ualberta.ca|Department of Physics, University of Alberta, Edmonton, Canada. travisc@ualberta.ca|Department of Physics, University of Alberta, Edmonton, Canada. travisc@ualberta.ca', 'Canada|Canada|Canada', 79, 'Calcium-Calmodulin-Dependent Protein Kinase Type 2|Computer Simulation|Cytoskeleton|Humans|Memory|Models, Biological|Models, Chemical|Phosphorylation|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002421', '22412364', 'Memory is attributed to strengthened synaptic connections among particular brain neurons, yet synaptic membrane components are transient, whereas memories can endure. This suggests synaptic information is encoded and hard-wired elsewhere, e.g. at molecular levels within the post-synaptic neuron. In long-term potentiation (LTP), a cellular and molecular model for memory, post-synaptic calcium ion (Caxc2xb2xe2x81xba) flux activates the hexagonal Caxc2xb2xe2x81xba-calmodulin dependent kinase II (CaMKII), a dodacameric holoenzyme containing 2 hexagonal sets of 6 kinase domains. Each kinase domain can either phosphorylate substrate proteins, or not (i.e. encoding one bit). Thus each set of extended CaMKII kinases can potentially encode synaptic Caxc2xb2xe2x81xba information via phosphorylation as ordered arrays of binary bits. Candidate sites for CaMKII phosphorylation-encoded molecular memory include microtubules (MTs), cylindrical organelles whose surfaces represent a regular lattice with a pattern of hexagonal polymers of the protein tubulin. Using molecular mechanics modeling and electrostatic profiling, we find that spatial dimensions and geometry of the extended CaMKII kinase domains precisely match those of MT hexagonal lattices. This suggests sets of six CaMKII kinase domains phosphorylate hexagonal MT lattice neighborhoods collectively, e.g. conveying synaptic information as ordered arrays of six bits, and thus bytes, with 64 to 5,281 possible bit states per CaMKII-MT byte. Signaling and encoding in MTs and other cytoskeletal structures offer rapid, robust solid-state information processing which may reflect a general code for MT-based memory and information processing within neurons and other eukaryotic cells.'),
(85383, 2012, 'plos', 'Ensemble models of neutrophil trafficking in severe sepsis', 'Song, Sang Ok|Song, Sang O K|Hogg, Justin|Peng, Zhi-Yong|Parker, Robert|Kellum, John A|Clermont, Gilles', 'CRISMA Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. sas261@pitt.edu|CRISMA Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. sas261@pitt.edu|CRISMA Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. sas261@pitt.edu|CRISMA Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. sas261@pitt.edu|CRISMA Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. sas261@pitt.edu|CRISMA Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. sas261@pitt.edu|CRISMA Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. sas261@pitt.edu', 'United States|United States|United States|United States|United States|United States|United States', 26, 'Animals|Computer Simulation|Immunologic Factors|Models, Immunological|Neutrophil Activation|Neutrophils|Rats|Sepsis|Systemic Inflammatory Response Syndrome', 'Journal Article', '10.1371/journal.pcbi.1002422', '22412365', 'A hallmark of severe sepsis is systemic inflammation which activates leukocytes and can result in their misdirection. This leads to both impaired migration to the locus of infection and increased infiltration into healthy tissues. In order to better understand the pathophysiologic mechanisms involved, we developed a coarse-grained phenomenological model of the acute inflammatory response in CLP (cecal ligation and puncture)-induced sepsis in rats. This model incorporates distinct neutrophil kinetic responses to the inflammatory stimulus and the dynamic interactions between components of a compartmentalized inflammatory response. Ensembles of model parameter sets consistent with experimental observations were statistically generated using a Markov-Chain Monte Carlo sampling. Prediction uncertainty in the model states was quantified over the resulting ensemble parameter sets. Forward simulation of the parameter ensembles successfully captured experimental features and predicted that systemically activated circulating neutrophils display impaired migration to the tissue and neutrophil sequestration in the lung, consequently contributing to tissue damage and mortality. Principal component and multiple regression analyses of the parameter ensembles estimated from survivor and non-survivor cohorts provide insight into pathologic mechanisms dictating outcome in sepsis. Furthermore, the model was extended to incorporate hypothetical mechanisms by which immune modulation using extracorporeal blood purification results in improved outcome in septic rats. Simulations identified a sub-population (about 18% of the treated population) that benefited from blood purification. Survivors displayed enhanced neutrophil migration to tissue and reduced sequestration of lung neutrophils, contributing to improved outcome. The model ensemble presented herein provides a platform for generating and testing hypotheses in silico, as well as motivating further experimental studies to advance understanding of the complex biological response to severe infection, a problem of growing magnitude in humans.'),
(85384, 2012, 'plos', 'Measured dynamic social contact patterns explain the spread of H1N1v influenza', 'Eames, Ken T D|Tilston, Natasha L|Brooks-Pollock, Ellen|Edmunds, W John', 'Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom. Ken.Eames@lshtm.ac.uk|Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom. Ken.Eames@lshtm.ac.uk|Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom. Ken.Eames@lshtm.ac.uk|Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom. Ken.Eames@lshtm.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 93, 'Contact Tracing|Disease Outbreaks|Holidays|Humans|Influenza A Virus, H1N1 Subtype|Influenza, Human|Prevalence|Proportional Hazards Models|Risk Assessment|Risk Factors|Seasons|Social Behavior|United Kingdom', 'Journal Article', '10.1371/journal.pcbi.1002425', '22412366', 'Patterns of social mixing are key determinants of epidemic spread. Here we present the results of an internet-based social contact survey completed by a cohort of participants over 9,000 times between July 2009 and March 2010, during the 2009 H1N1v influenza epidemic. We quantify the changes in social contact patterns over time, finding that school children make 40% fewer contacts during holiday periods than during term time. We use these dynamically varying contact patterns to parameterise an age-structured model of influenza spread, capturing well the observed patterns of incidence, the changing contact patterns resulted in a fall of approximately 35% in the reproduction number of influenza during the holidays. This work illustrates the importance of including changing mixing patterns in epidemic models. We conclude that changes in contact patterns explain changes in disease incidence, and that the timing of school terms drove the 2009 H1N1v epidemic in the UK. Changes in social mixing patterns can be usefully measured through simple internet-based surveys.'),
(85385, 2012, 'plos', 'A common model for cytokine receptor activation: combined scissor-like rotation and self-rotation of receptor dimer induced by class I cytokine', 'Pang, Xiaodong|Zhou, Huan-Xiang', 'Department of Physics, Florida State University, Tallahassee, Florida, United States of America.|Department of Physics, Florida State University, Tallahassee, Florida, United States of America.', 'United States|United States', 22, 'Binding Sites|Computer Simulation|Cytokines|Dimerization|Models, Chemical|Models, Molecular|Protein Binding|Protein Conformation|Protein Structure, Tertiary|Receptors, Cytokine', 'Journal Article', '10.1371/journal.pcbi.1002427', '22412367', 'The precise mechanism by which the binding of a class I cytokine to the extracellular domain of its corresponding receptor transmits a signal through the cell membrane remains unclear. Receptor activation involves a cytokine-receptor complex with a 1xe2x88xb62 stoichiometry. Previously we used our transient-complex theory to calculate the rate constant of the initial cytokine-receptor binding to form a 1xe2x88xb61 complex. Here we computed the binding pathway leading to the 1xe2x88xb62 activation complex. Three cytokine systems (growth hormone, erythropoietin, and prolactin) were studied, and the focus was on the binding of the extracellular domain of the second receptor molecule after forming the 1xe2x88xb61 complex. According to the transient-complex theory, translational and rotation diffusion of the binding entities bring them together to form a transient complex, which has near-native relative separation and orientation but not the short-range specific native interactions. Subsequently conformational rearrangement leads to the formation of the native complex. We found that the changes in relative orientations between the two receptor molecules from the transient complex to the 1xe2x88xb62 native complex are similar for the three cytokine-receptor systems. We thus propose a common model for receptor activation by class I cytokines, involving combined scissor-like rotation and self-rotation of the two receptor molecules. Both types of rotations seem essential: the scissor-like rotation separates the intracellular domains of the two receptor molecules to make room for the associated Janus kinase molecules, while the self-rotation allows them to orient properly for transphosphorylation. This activation model explains a host of experimental observations. The transient-complex based approach presented here may provide a strategy for designing antagonists and prove useful for elucidating activation mechanisms of other receptors.'),
(85386, 2012, 'plos', 'Beyond the binding site: the role of the xcexb2xe2x82x82-xcexb2xe2x82x83 loop and extra-domain structures in PDZ domains', 'Mostarda, Stefano|Gfeller, David|Rao, Francesco', 'Freiburg Institute for Advanced Studies, School of Soft Matter Research, Freiburg im Breisgau, Germany.|Freiburg Institute for Advanced Studies, School of Soft Matter Research, Freiburg im Breisgau, Germany.|Freiburg Institute for Advanced Studies, School of Soft Matter Research, Freiburg im Breisgau, Germany.', 'Germany|Germany|Germany', 24, 'Adaptor Proteins, Signal Transducing|Amino Acid Sequence|Binding Sites|Computer Simulation|Conserved Sequence|Models, Chemical|Models, Molecular|Molecular Sequence Data|PDZ Domains|Protein Binding|Protein Structure, Secondary|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1002429', '22412368', 'A general paradigm to understand protein function is to look at properties of isolated well conserved domains, such as SH3 or PDZ domains. While common features of domain families are well understood, the role of subtle differences among members of these families is less clear. Here, molecular dynamics simulations indicate that the binding mechanism in PSD95-PDZ3 is critically regulated via interactions outside the canonical binding site, involving both the poorly conserved xcexb2xe2x82x82-xcexb2xe2x82x83 loop and an extra-domain helix. Using the CRIPT peptide as a prototypical ligand, our simulations suggest that a network of salt-bridges between the ligand and this loop is necessary for binding. These contacts interconvert between each other on a time scale of a few tens of nanoseconds, making them elusive to X-ray crystallography. The loop is stabilized by an extra-domain helix. The latter influences the global dynamics of the domain, considerably increasing binding affinity. We found that two key contacts between the helix and the domain, one involving the xcexb2xe2x82x82-xcexb2xe2x82x83 loop, provide an atomistic interpretation of the increased affinity. Our analysis indicates that both extra-domain segments and loosely conserved regions play critical roles in PDZ binding affinity and specificity.'),
(85387, 2012, 'plos', 'System-level insights into yeast metabolism by thermodynamic analysis of elementary flux modes', 'Jol, Stefan J|Kümmel, Anne|Terzer, Marco|Stelling, Jörg|Heinemann, Matthias', 'Life Science Zurich PhD Program on Systems Biology of Complex Diseases, ETH Zurich, Switzerland.|Life Science Zurich PhD Program on Systems Biology of Complex Diseases, ETH Zurich, Switzerland.|Life Science Zurich PhD Program on Systems Biology of Complex Diseases, ETH Zurich, Switzerland.|Life Science Zurich PhD Program on Systems Biology of Complex Diseases, ETH Zurich, Switzerland.|Life Science Zurich PhD Program on Systems Biology of Complex Diseases, ETH Zurich, Switzerland.', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 0, 'Computer Simulation|Energy Metabolism|Models, Biological|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Signal Transduction|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002415', '22416224', 'One of the most obvious phenotypes of a cell is its metabolic activity, which is defined by the fluxes in the metabolic network. Although experimental methods to determine intracellular fluxes are well established, only a limited number of fluxes can be resolved. Especially in eukaryotes such as yeast, compartmentalization and the existence of many parallel routes render exact flux analysis impossible using current methods. To gain more insight into the metabolic operation of S. cerevisiae we developed a new computational approach where we characterize the flux solution space by determining elementary flux modes (EFMs) that are subsequently classified as thermodynamically feasible or infeasible on the basis of experimental metabolome data. This allows us to provably rule out the contribution of certain EFMs to the in vivo flux distribution. From the 71 million EFMs in a medium size metabolic network of S. cerevisiae, we classified 54% as thermodynamically feasible. By comparing the thermodynamically feasible and infeasible EFMs, we could identify reaction combinations that span the cytosol and mitochondrion and, as a system, cannot operate under the investigated glucose batch conditions. Besides conclusions on single reactions, we found that thermodynamic constraints prevent the import of redox cofactor equivalents into the mitochondrion due to limits on compartmental cofactor concentrations. Our novel approach of incorporating quantitative metabolite concentrations into the analysis of the space of all stoichiometrically feasible flux distributions allows generating new insights into the system-level operation of the intracellular fluxes without making assumptions on metabolic objectives of the cell.'),
(85388, 2012, 'plos', 'Effect of network architecture on synchronization and entrainment properties of the circadian oscillations in the suprachiasmatic nucleus', 'Hafner, Marc|Koeppl, Heinz|Gonze, Didier', 'Laboratory of Nonlinear Systems, School of Computer and Communication Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. Marc_Hafner@hms.harvard.edu|Laboratory of Nonlinear Systems, School of Computer and Communication Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. Marc_Hafner@hms.harvard.edu|Laboratory of Nonlinear Systems, School of Computer and Communication Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. Marc_Hafner@hms.harvard.edu', 'Switzerland|Switzerland|Switzerland', 36, 'Action Potentials|Animals|Biological Clocks|Circadian Rhythm|Computer Simulation|Humans|Models, Neurological|Nerve Net|Neurons|Suprachiasmatic Nucleus|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002419', '22423219', 'In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus constitutes the central circadian pacemaker. The SCN receives light signals from the retina and controls peripheral circadian clocks (located in the cortex, the pineal gland, the liver, the kidney, the heart, etc.). This hierarchical organization of the circadian system ensures the proper timing of physiological processes. In each SCN neuron, interconnected transcriptional and translational feedback loops enable the circadian expression of the clock genes. Although all the neurons have the same genotype, the oscillations of individual cells are highly heterogeneous in dispersed cell culture: many cells present damped oscillations and the period of the oscillations varies from cell to cell. In addition, the neurotransmitters that ensure the intercellular coupling, and thereby the synchronization of the cellular rhythms, differ between the two main regions of the SCN. In this work, a mathematical model that accounts for this heterogeneous organization of the SCN is presented and used to study the implication of the SCN network topology on synchronization and entrainment properties. The results show that oscillations with larger amplitude can be obtained with scale-free networks, in contrast to random and local connections. Networks with the small-world property such as the scale-free networks used in this work can adapt faster to a delay or advance in the light/dark cycle (jet lag). Interestingly a certain level of cellular heterogeneity is not detrimental to synchronization performances, but on the contrary helps resynchronization after jet lag. When coupling two networks with different topologies that mimic the two regions of the SCN, efficient filtering of pulse-like perturbations in the entrainment pattern is observed. These results suggest that the complex and heterogeneous architecture of the SCN decreases the sensitivity of the network to short entrainment perturbations while, at the same time, improving its adaptation abilities to long term changes.'),
(85389, 2012, 'plos', 'Mechanistic basis of branch-site selection in filamentous bacteria', 'Richards, David M|Hempel, Antje M|Flärdh, Klas|Buttner, Mark J|Howard, Martin', 'John Innes Centre, Norwich Research Park, Norwich, United Kingdom.|John Innes Centre, Norwich Research Park, Norwich, United Kingdom.|John Innes Centre, Norwich Research Park, Norwich, United Kingdom.|John Innes Centre, Norwich Research Park, Norwich, United Kingdom.|John Innes Centre, Norwich Research Park, Norwich, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 28, 'Bacterial Proteins|Cell Cycle Proteins|Cell Enlargement|Cell Surface Extensions|Computer Simulation|Models, Biological|Streptomyces', 'Journal Article', '10.1371/journal.pcbi.1002423', '22423220', 'Many filamentous organisms, such as fungi, grow by tip-extension and by forming new branches behind the tips. A similar growth mode occurs in filamentous bacteria, including the genus Streptomyces, although here our mechanistic understanding has been very limited. The Streptomyces protein DivIVA is a critical determinant of hyphal growth and localizes in foci at hyphal tips and sites of future branch development. However, how such foci form was previously unknown. Here, we show experimentally that DivIVA focus-formation involves a novel mechanism in which new DivIVA foci break off from existing tip-foci, bypassing the need for initial nucleation or de novo branch-site selection. We develop a mathematical model for DivIVA-dependent growth and branching, involving DivIVA focus-formation by tip-focus splitting, focus growth, and the initiation of new branches at a critical focus size. We quantitatively fit our model to the experimentally-measured tip-to-branch and branch-to-branch length distributions. The model predicts a particular bimodal tip-to-branch distribution results from tip-focus splitting, a prediction we confirm experimentally. Our work provides mechanistic understanding of a novel mode of hyphal growth regulation that may be widely employed.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85390, 2012, 'plos', 'Cell shape dynamics: from waves to migration', 'Driscoll, Meghan K|McCann, Colin|Kopace, Rael|Homan, Tess|Fourkas, John T|Parent, Carole|Losert, Wolfgang', 'Department of Physics, University of Maryland, College Park, Maryland, USA.|Department of Physics, University of Maryland, College Park, Maryland, USA.|Department of Physics, University of Maryland, College Park, Maryland, USA.|Department of Physics, University of Maryland, College Park, Maryland, USA.|Department of Physics, University of Maryland, College Park, Maryland, USA.|Department of Physics, University of Maryland, College Park, Maryland, USA.|Department of Physics, University of Maryland, College Park, Maryland, USA.', 'United States|United States|United States|United States|United States|United States|United States', 0, 'Cell Membrane|Cell Size|Chemotaxis|Computer Simulation|Dictyostelium|Membrane Fluidity|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002392', '22438794', 'We observe and quantify wave-like characteristics of amoeboid migration. Using the amoeba Dictyostelium discoideum, a model system for the study of chemotaxis, we demonstrate that cell shape changes in a wave-like manner. Cells have regions of high boundary curvature that propagate from the leading edge toward the back, usually along alternating sides of the cell. Curvature waves are easily seen in cells that do not adhere to a surface, such as cells that are electrostatically repelled from surfaces or cells that extend over the edge of micro-fabricated cliffs. Without surface contact, curvature waves travel from the leading edge to the back of a cell at -35 µm/min. Non-adherent myosin II null cells do not exhibit these curvature waves. At the leading edge of adherent cells, curvature waves are associated with protrusive activity. Like regions of high curvature, protrusive activity travels along the boundary in a wave-like manner. Upon contact with a surface, the protrusions stop moving relative to the surface, and the boundary shape thus reflects the history of protrusive motion. The wave-like character of protrusions provides a plausible mechanism for the zig-zagging of pseudopods and for the ability of cells both to swim in viscous fluids and to navigate complex three dimensional topography.'),
(85391, 2012, 'plos', 'AutoClickChem: click chemistry in silico', 'Durrant, Jacob D|McCammon, J Andrew', 'Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, California, USA. jdurrant@ucsd.edu|Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, California, USA. jdurrant@ucsd.edu', 'United States|United States', 28, 'Combinatorial Chemistry Techniques|Computer Simulation|Drug Evaluation, Preclinical|Models, Chemical|Models, Molecular|Pharmaceutical Preparations|Software|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1002397', '22438795', 'Academic researchers and many in industry often lack the financial resources available to scientists working in big pharma. High costs include those associated with high-throughput screening and chemical synthesis. In order to address these challenges, many researchers have in part turned to alternate methodologies. Virtual screening, for example, often substitutes for high-throughput screening, and click chemistry ensures that chemical synthesis is fast, cheap, and comparatively easy. Though both in silico screening and click chemistry seek to make drug discovery more feasible, it is not yet routine to couple these two methodologies. We here present a novel computer algorithm, called AutoClickChem, capable of performing many click-chemistry reactions in silico. AutoClickChem can be used to produce large combinatorial libraries of compound models for use in virtual screens. As the compounds of these libraries are constructed according to the reactions of click chemistry, they can be easily synthesized for subsequent testing in biochemical assays. Additionally, in silico modeling of click-chemistry products may prove useful in rational drug design and drug optimization. AutoClickChem is based on the pymolecule toolbox, a framework that may facilitate the development of future python-based programs that require the manipulation of molecular models. Both the pymolecule toolbox and AutoClickChem are released under the GNU General Public License version 3 and are available for download from http://autoclickchem.ucsd.edu.'),
(85392, 2012, 'plos', 'Network evolution: rewiring and signatures of conservation in signaling', 'Sun, Mark G F|Sikora, Martin|Costanzo, Michael|Boone, Charles|Kim, Philip M', 'Department of Computer Science, University of Toronto, Toronto, Canada.|Department of Computer Science, University of Toronto, Toronto, Canada.|Department of Computer Science, University of Toronto, Toronto, Canada.|Department of Computer Science, University of Toronto, Toronto, Canada.|Department of Computer Science, University of Toronto, Toronto, Canada.', 'Canada|Canada|Canada|Canada|Canada', 25, 'Computer Simulation|Conserved Sequence|Evolution, Molecular|Fungal Proteins|Fungi|Models, Genetic|Signal Transduction|src Homology Domains', 'Journal Article', '10.1371/journal.pcbi.1002411', '22438796', 'The analysis of network evolution has been hampered by limited availability of protein interaction data for different organisms. In this study, we investigate evolutionary mechanisms in Src Homology 3 (SH3) domain and kinase interaction networks using high-resolution specificity profiles. We constructed and examined networks for 23 fungal species ranging from Saccharomyces cerevisiae to Schizosaccharomyces pombe. We quantify rates of different rewiring mechanisms and show that interaction change through binding site evolution is faster than through gene gain or loss. We found that SH3 interactions evolve swiftly, at rates similar to those found in phosphoregulation evolution. Importantly, we show that interaction changes are sufficiently rapid to exhibit saturation phenomena at the observed timescales. Finally, focusing on the SH3 interaction network, we observe extensive clustering of binding sites on target proteins by SH3 domains and a strong correlation between the number of domains that bind a target protein (target in-degree) and interaction conservation. The relationship between in-degree and interaction conservation is driven by two different effects, namely the number of clusters that correspond to interaction interfaces and the number of domains that bind to each cluster leads to sequence specific conservation, which in turn results in interaction conservation. In summary, we uncover several network evolution mechanisms likely to generalize across peptide recognition modules.'),
(85393, 2012, 'plos', 'Highly sensitive and specific detection of rare variants in mixed viral populations from massively parallel sequence data', 'Macalalad, Alexander R|Zody, Michael C|Charlebois, Patrick|Lennon, Niall J|Newman, Ruchi M|Malboeuf, Christine M|Ryan, Elizabeth M|Boutwell, Christian L|Power, Karen A|Brackney, Doug E|Pesko, Kendra N|Levin, Joshua Z|Ebel, Gregory D|Allen, Todd M|Birren, Bruce W|Henn, Matthew R', 'Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.|Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.|Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.|Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.|Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.|Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.|Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.|Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.|Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.|Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.|Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.|Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.|Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.|Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.|Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.|Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States', 82, 'Algorithms|Base Sequence|DNA, Viral|Genetic Variation|Molecular Sequence Data|Mutation|Sensitivity and Specificity|Sequence Alignment|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1002417', '22438797', 'Viruses diversify over time within hosts, often undercutting the effectiveness of host defenses and therapeutic interventions. To design successful vaccines and therapeutics, it is critical to better understand viral diversification, including comprehensively characterizing the genetic variants in viral intra-host populations and modeling changes from transmission through the course of infection. Massively parallel sequencing technologies can overcome the cost constraints of older sequencing methods and obtain the high sequence coverage needed to detect rare genetic variants (< 1%) within an infected host, and to assay variants without prior knowledge. Critical to interpreting deep sequence data sets is the ability to distinguish biological variants from process errors with high sensitivity and specificity. To address this challenge, we describe V-Phaser, an algorithm able to recognize rare biological variants in mixed populations. V-Phaser uses covariation (i.e. phasing) between observed variants to increase sensitivity and an expectation maximization algorithm that iteratively recalibrates base quality scores to increase specificity. Overall, V-Phaser achieved > 97% sensitivity and > 97% specificity on control read sets. On data derived from a patient after four years of HIV-1 infection, V-Phaser detected 2,015 variants across the -10 kb genome, including 603 rare variants (< 1% frequency) detected only using phase information. V-Phaser identified variants at frequencies down to 0.2%, comparable to the detection threshold of allele-specific PCR, a method that requires prior knowledge of the variants. The high sensitivity and specificity of V-Phaser enables identifying and tracking changes in low frequency variants in mixed populations such as RNA viruses.'),
(85394, 2012, 'plos', 'Conformational control of the binding of the transactivation domain of the MLL protein and c-Myb to the KIX domain of CREB', 'Korkmaz, Elif Nihal|Nussinov, Ruth|Haliloxc4x9flu, Txc3xbcrkan', 'Polymer Research Center & Chemical Engineering Department, Boxc4x9fazixc3xa7i University, Istanbul, Turkey.|Polymer Research Center & Chemical Engineering Department, Boxc4x9fazixc3xa7i University, Istanbul, Turkey.|Polymer Research Center & Chemical Engineering Department, Boxc4x9fazixc3xa7i University, Istanbul, Turkey.', 'Turkey|Turkey|Turkey', 0, 'Binding Sites|CREB-Binding Protein|Computer Simulation|Histone-Lysine N-Methyltransferase|Models, Chemical|Models, Molecular|Myeloid-Lymphoid Leukemia Protein|Protein Binding|Protein Conformation|Protein Structure, Tertiary|Proto-Oncogene Proteins c-myb|Transcriptional Activation', 'Journal Article', '10.1371/journal.pcbi.1002420', '22438798', 'The KIX domain of CBP is a transcriptional coactivator. Concomitant binding to the activation domain of proto-oncogene protein c-Myb and the transactivation domain of the trithorax group protein mixed lineage leukemia (MLL) transcription factor lead to the biologically active ternary MLLxe2x88xb6KIXxe2x88xb6c-Myb complex which plays a role in Pol II-mediated transcription. The binding of the activation domain of MLL to KIX enhances c-Myb binding. Here we carried out molecular dynamics (MD) simulations for the MLLxe2x88xb6KIXxe2x88xb6c-Myb ternary complex, its binary components and KIX with the goal of providing a mechanistic explanation for the experimental observations. The dynamic behavior revealed that the MLL binding site is allosterically coupled to the c-Myb binding site. MLL binding redistributes the conformational ensemble of KIX, leading to higher populations of states which favor c-Myb binding. The key element in the allosteric communication pathways is the KIX loop, which acts as a control mechanism to enhance subsequent binding events. We tested this conclusion by in silico mutations of loop residues in the KIXxe2x88xb6MLL complex and by comparing wild type and mutant dynamics through MD simulations. The loop assumed MLL binding conformation similar to that observed in the KIXxe2x88xb6c-Myb state which disfavors the allosteric network. The coupling with c-Myb binding site faded, abolishing the positive cooperativity observed in the presence of MLL. Our major conclusion is that by eliciting a loop-mediated allosteric switch between the different states following the binding events, transcriptional activation can be regulated. The KIX system presents an example how nature makes use of conformational control in higher level regulation of transcriptional activity and thus cellular events.'),
(85395, 2012, 'plos', 'Gradients and modulation of K(+) channels optimize temporal accuracy in networks of auditory neurons', 'Kaczmarek, Leonard K', 'Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA. leonard.kaczmarek@yale.edu', 'United States', 6, 'Action Potentials|Animals|Auditory Cortex|Computer Simulation|Humans|Ion Channel Gating|Models, Neurological|Nerve Net|Potassium Channels|Sensory Receptor Cells', 'Journal Article', '10.1371/journal.pcbi.1002424', '22438799', 'Accurate timing of action potentials is required for neurons in auditory brainstem nuclei to encode the frequency and phase of incoming sound stimuli. Many such neurons express high threshold Kv3-family channels that are required for firing at high rates (> -200 Hz). Kv3 channels are expressed in gradients along the medial-lateral tonotopic axis of the nuclei. Numerical simulations of auditory brainstem neurons were used to calculate the input-output relations of ensembles of 1-50 neurons, stimulated at rates between 100-1500 Hz. Individual neurons with different levels of potassium currents differ in their ability to follow specific rates of stimulation but all perform poorly when the stimulus rate is greater than the maximal firing rate of the neurons. The temporal accuracy of the combined synaptic output of an ensemble is, however, enhanced by the presence of gradients in Kv3 channel levels over that measured when neurons express uniform levels of channels. Surprisingly, at high rates of stimulation, temporal accuracy is also enhanced by the occurrence of random spontaneous activity, such as is normally observed in the absence of sound stimulation. For any pattern of stimulation, however, greatest accuracy is observed when, in the presence of spontaneous activity, the levels of potassium conductance in all of the neurons is adjusted to that found in the subset of neurons that respond better than their neighbors. This optimization of response by adjusting the K(+) conductance occurs for stimulus patterns containing either single and or multiple frequencies in the phase-locking range. The findings suggest that gradients of channel expression are required for normal auditory processing and that changes in levels of potassium currents across the nuclei, by mechanisms such as protein phosphorylation and rapid changes in channel synthesis, adapt the nuclei to the ongoing auditory environment.'),
(85396, 2012, 'plos', 'The impact of oxygen on metabolic evolution: a chemoinformatic investigation', 'Jiang, Ying-Ying|Kong, De-Xin|Qin, Tao|Li, Xiao|Caetano-Anollés, Gustavo|Zhang, Hong-Yu', 'National Key Laboratory of Crop Genetic Improvement, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China.|National Key Laboratory of Crop Genetic Improvement, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China.|National Key Laboratory of Crop Genetic Improvement, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China.|National Key Laboratory of Crop Genetic Improvement, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China.|National Key Laboratory of Crop Genetic Improvement, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China.|National Key Laboratory of Crop Genetic Improvement, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China.', 'China|China|China|China|China|China', 16, 'Aerobiosis|Anaerobiosis|Animals|Biological Evolution|Computer Simulation|Energy Metabolism|Humans|Models, Genetic|Oxygen Consumption|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002426', '22438800', 'The appearance of planetary oxygen likely transformed the chemical and biochemical makeup of life and probably triggered episodes of organismal diversification. Here we use chemoinformatic methods to explore the impact of the rise of oxygen on metabolic evolution. We undertake a comprehensive comparative analysis of structures, chemical properties and chemical reactions of anaerobic and aerobic metabolites. The results indicate that aerobic metabolism has expanded the structural and chemical space of metabolites considerably, including the appearance of 130 novel molecular scaffolds. The molecular functions of these metabolites are mainly associated with derived aspects of cellular life, such as signal transfer, defense against biotic factors, and protection of organisms from oxidation. Moreover, aerobic metabolites are more hydrophobic and rigid than anaerobic compounds, suggesting they are better fit to modulate membrane functions and to serve as transmembrane signaling factors. Since higher organisms depend largely on sophisticated membrane-enabled functions and intercellular signaling systems, the metabolic developments brought about by oxygen benefit the diversity of cellular makeup and the complexity of cellular organization as well. These findings enhance our understanding of the molecular link between oxygen and evolution. They also show the significance of chemoinformatics in addressing basic biological questions.'),
(85397, 2012, 'plos', 'Entropic tension in crowded membranes', 'Lindén, Martin|Sens, Pierre|Phillips, Rob', 'Department of Applied Physics, California Institute of Technology, Pasadena, California, USA.|Department of Applied Physics, California Institute of Technology, Pasadena, California, USA.|Department of Applied Physics, California Institute of Technology, Pasadena, California, USA.', 'United States|United States|United States', 0, 'Cell Membrane|Computer Simulation|Membrane Fluidity|Membrane Proteins|Models, Biological|Osmotic Pressure', 'Journal Article', '10.1371/journal.pcbi.1002431', '22438801', 'Unlike their model membrane counterparts, biological membranes are richly decorated with a heterogeneous assembly of membrane proteins. These proteins are so tightly packed that their excluded area interactions can alter the free energy landscape controlling the conformational transitions suffered by such proteins. For membrane channels, this effect can alter the critical membrane tension at which they undergo a transition from a closed to an open state, and therefore influence protein function in vivo. Despite their obvious importance, crowding phenomena in membranes are much less well studied than in the cytoplasm. Using statistical mechanics results for hard disk liquids, we show that crowding induces an entropic tension in the membrane, which influences transitions that alter the projected area and circumference of a membrane protein. As a specific case study in this effect, we consider the impact of crowding on the gating properties of bacterial mechanosensitive membrane channels, which are thought to confer osmoprotection when these cells are subjected to osmotic shock. We find that crowding can alter the gating energies by more than [Formula: see text] in physiological conditions, a substantial fraction of the total gating energies in some cases. Given the ubiquity of membrane crowding, the nonspecific nature of excluded volume interactions, and the fact that the function of many membrane proteins involve significant conformational changes, this specific case study highlights a general aspect in the function of membrane proteins.'),
(85398, 2012, 'plos', 'Neurogenesis drives stimulus decorrelation in a model of the olfactory bulb', 'Chow, Siu-Fai|Wick, Stuart D|Riecke, Hermann', 'Engineering Sciences and Applied Mathematics, Northwestern University, Evanston, Illinois, USA.|Engineering Sciences and Applied Mathematics, Northwestern University, Evanston, Illinois, USA.|Engineering Sciences and Applied Mathematics, Northwestern University, Evanston, Illinois, USA.', 'United States|United States|United States', 18, 'Action Potentials|Computer Simulation|Humans|Models, Neurological|Nerve Net|Neurogenesis|Neuronal Plasticity|Olfactory Bulb|Sensory Receptor Cells|Smell', 'Journal Article', '10.1371/journal.pcbi.1002398', '22442645', 'The reshaping and decorrelation of similar activity patterns by neuronal networks can enhance their discriminability, storage, and retrieval. How can such networks learn to decorrelate new complex patterns, as they arise in the olfactory system? Using a computational network model for the dominant neural populations of the olfactory bulb we show that fundamental aspects of the adult neurogenesis observed in the olfactory bulb--the persistent addition of new inhibitory granule cells to the network, their activity-dependent survival, and the reciprocal character of their synapses with the principal mitral cells--are sufficient to restructure the network and to alter its encoding of odor stimuli adaptively so as to reduce the correlations between the bulbar representations of similar stimuli. The decorrelation is quite robust with respect to various types of perturbations of the reciprocity. The model parsimoniously captures the experimentally observed role of neurogenesis in perceptual learning and the enhanced response of young granule cells to novel stimuli. Moreover, it makes specific predictions for the type of odor enrichment that should be effective in enhancing the ability of animals to discriminate similar odor mixtures.'),
(85399, 2012, 'plos', 'Impact of network structure and cellular response on spike time correlations', 'Trousdale, James|Hu, Yu|Shea-Brown, Eric|Josixc4x87, Krexc5xa1imir', 'Department of Mathematics, University of Houston, Houston, Texas, USA. jrtrousd@math.uh.edu|Department of Mathematics, University of Houston, Houston, Texas, USA. jrtrousd@math.uh.edu|Department of Mathematics, University of Houston, Houston, Texas, USA. jrtrousd@math.uh.edu|Department of Mathematics, University of Houston, Houston, Texas, USA. jrtrousd@math.uh.edu', 'United States|United States|United States|United States', 84, 'Action Potentials|Animals|Computer Simulation|Humans|Models, Anatomic|Models, Neurological|Nerve Net|Neurons', 'Journal Article', '10.1371/journal.pcbi.1002408', '22457608', 'Novel experimental techniques reveal the simultaneous activity of larger and larger numbers of neurons. As a result there is increasing interest in the structure of cooperative--or correlated--activity in neural populations, and in the possible impact of such correlations on the neural code. A fundamental theoretical challenge is to understand how the architecture of network connectivity along with the dynamical properties of single cells shape the magnitude and timescale of correlations. We provide a general approach to this problem by extending prior techniques based on linear response theory. We consider networks of general integrate-and-fire cells with arbitrary architecture, and provide explicit expressions for the approximate cross-correlation between constituent cells. These correlations depend strongly on the operating point (input mean and variance) of the neurons, even when connectivity is fixed. Moreover, the approximations admit an expansion in powers of the matrices that describe the network architecture. This expansion can be readily interpreted in terms of paths between different cells. We apply our results to large excitatory-inhibitory networks, and demonstrate first how precise balance--or lack thereof--between the strengths and timescales of excitatory and inhibitory synapses is reflected in the overall correlation structure of the network. We then derive explicit expressions for the average correlation structure in randomly connected networks. These expressions help to identify the important factors that shape coordinated neural activity in such networks.'),
(85400, 2012, 'plos', 'Implications of behavioral architecture for the evolution of self-organized division of labor', 'Duarte, A|Scholtens, E|Weissing, F J', 'Theoretical Biology, Centre for Ecological and Evolutionary Studies, University of Groningen, Groningen, The Netherlands.|Theoretical Biology, Centre for Ecological and Evolutionary Studies, University of Groningen, Groningen, The Netherlands.|Theoretical Biology, Centre for Ecological and Evolutionary Studies, University of Groningen, Groningen, The Netherlands.', 'Netherlands|Netherlands|Netherlands', 7, 'Animals|Biological Evolution|Computer Simulation|Insecta|Models, Genetic|Motor Activity|Neural Networks (Computer)|Social Behavior|Work', 'Journal Article', '10.1371/journal.pcbi.1002430', '22457609', 'Division of labor has been studied separately from a proximate self-organization and an ultimate evolutionary perspective. We aim to bring together these two perspectives. So far this has been done by choosing a behavioral mechanism a priori and considering the evolution of the properties of this mechanism. Here we use artificial neural networks to allow for a more open architecture. We study whether emergent division of labor can evolve in two different network architectures, a simple feedforward network, and a more complex network that includes the possibility of self-feedback from previous experiences. We focus on two aspects of division of labor, worker specialization and the ratio of work performed for each task. Colony fitness is maximized by both reducing idleness and achieving a predefined optimal work ratio. Our results indicate that architectural constraints play an important role for the outcome of evolution. With the simplest network, only genetically determined specialization is possible. This imposes several limitations on worker specialization. Moreover, in order to minimize idleness, networks evolve a biased work ratio, even when an unbiased work ratio would be optimal. By adding self-feedback to the network we increase the networks flexibility and worker specialization evolves under a wider parameter range. Optimal work ratios are more easily achieved with the self-feedback network, but still provide a challenge when combined with worker specialization.'),
(85401, 2012, 'plos', 'Feedforward inhibition and synaptic scaling--two sides of the same coin?', 'Keck, Christian|Savin, Cristina|Lücke, Jörg', 'Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany.|Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany.|Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany.', 'Germany|Germany|Germany', 18, 'Action Potentials|Animals|Computer Simulation|Feedback, Physiological|Humans|Models, Neurological|Nerve Net|Neural Inhibition|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002432', '22457610', 'Feedforward inhibition and synaptic scaling are important adaptive processes that control the total input a neuron can receive from its afferents. While often studied in isolation, the two have been reported to co-occur in various brain regions. The functional implications of their interactions remain unclear, however. Based on a probabilistic modeling approach, we show here that fast feedforward inhibition and synaptic scaling interact synergistically during unsupervised learning. In technical terms, we model the input to a neural circuit using a normalized mixture model with Poisson noise. We demonstrate analytically and numerically that, in the presence of lateral inhibition introducing competition between different neurons, Hebbian plasticity and synaptic scaling approximate the optimal maximum likelihood solutions for this model. Our results suggest that, beyond its conventional use as a mechanism to remove undesired pattern variations, input normalization can make typical neural interaction and learning rules optimal on the stimulus subspace defined through feedforward inhibition. Furthermore, learning within this subspace is more efficient in practice, as it helps avoid locally optimal solutions. Our results suggest a close connection between feedforward inhibition and synaptic scaling which may have important functional implications for general cortical processing.'),
(85402, 2012, 'plos', 'Corresponding functional dynamics across the Hsp90 Chaperone family: insights from a multiscale analysis of MD simulations', 'Morra, Giulia|Potestio, Raffaello|Micheletti, Cristian|Colombo, Giorgio', 'Istituto di Chimica del Riconoscimento Molecolare, CNR, Milano, Italy.|Istituto di Chimica del Riconoscimento Molecolare, CNR, Milano, Italy.|Istituto di Chimica del Riconoscimento Molecolare, CNR, Milano, Italy.|Istituto di Chimica del Riconoscimento Molecolare, CNR, Milano, Italy.', 'Italy|Italy|Italy|Italy', 65, 'Computer Simulation|HSP90 Heat-Shock Proteins|Models, Chemical|Models, Molecular|Motion|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1002433', '22457611', 'Understanding how local protein modifications, such as binding small-molecule ligands, can trigger and regulate large-scale motions of large protein domains is a major open issue in molecular biology. We address various aspects of this problem by analyzing and comparing atomistic simulations of Hsp90 family representatives for which crystal structures of the full length protein are available: mammalian Grp94, yeast Hsp90 and E.coli HtpG. These chaperones are studied in complex with the natural ligands ATP, ADP and in the Apo state. Common key aspects of their functional dynamics are elucidated with a novel multi-scale comparison of their internal dynamics. Starting from the atomic resolution investigation of internal fluctuations and geometric strain patterns, a novel analysis of domain dynamics is developed. The results reveal that the ligand-dependent structural modulations mostly consist of relative rigid-like movements of a limited number of quasi-rigid domains, shared by the three proteins. Two common primary hinges for such movements are identified. The first hinge, whose functional role has been demonstrated by several experimental approaches, is located at the boundary between the N-terminal and Middle-domains. The second hinge is located at the end of a three-helix bundle in the Middle-domain and unfolds/unpacks going from the ATP- to the ADP-state. This latter site could represent a promising novel druggable allosteric site common to all chaperones.'),
(85403, 2012, 'plos', 'Hemodynamic traveling waves in human visual cortex', 'Aquino, Kevin M|Schira, Mark M|Robinson, P A|Drysdale, Peter M|Breakspear, Michael', 'School of Physics, University of Sydney, New South Wales, Australia. aquino@physics.usyd.edu.au|School of Physics, University of Sydney, New South Wales, Australia. aquino@physics.usyd.edu.au|School of Physics, University of Sydney, New South Wales, Australia. aquino@physics.usyd.edu.au|School of Physics, University of Sydney, New South Wales, Australia. aquino@physics.usyd.edu.au|School of Physics, University of Sydney, New South Wales, Australia. aquino@physics.usyd.edu.au', 'Australia|Australia|Australia|Australia|Australia', 48, 'Biological Clocks|Blood Flow Velocity|Cerebrovascular Circulation|Computer Simulation|Humans|Magnetic Resonance Imaging|Models, Cardiovascular|Models, Neurological|Visual Cortex|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1002435', '22457612', 'Functional MRI (fMRI) experiments rely on precise characterization of the blood oxygen level dependent (BOLD) signal. As the spatial resolution of fMRI reaches the sub-millimeter range, the need for quantitative modelling of spatiotemporal properties of this hemodynamic signal has become pressing. Here, we find that a detailed physiologically-based model of spatiotemporal BOLD responses predicts traveling waves with velocities and spatial ranges in empirically observable ranges. Two measurable parameters, related to physiology, characterize these waves: wave velocity and damping rate. To test these predictions, high-resolution fMRI data are acquired from subjects viewing discrete visual stimuli. Predictions and experiment show strong agreement, in particular confirming BOLD waves propagating for at least 5-10 mm across the cortical surface at speeds of 2-12 mm s-1. These observations enable fundamentally new approaches to fMRI analysis, crucial for fMRI data acquired at high spatial resolution.'),
(85404, 2012, 'plos', 'Influence of the fibroblastic reticular network on cell-cell interactions in lymphoid organs', 'Graw, Frederik|Regoes, Roland R', 'Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. frederik.graw@t-online.de|Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. frederik.graw@t-online.de', 'Switzerland|Switzerland', 0, 'Animals|Cell Communication|Cell Movement|Computer Simulation|Fibroblasts|Humans|Lymphatic System|Models, Biological|Reticulin|T-Lymphocytes', 'Journal Article', '10.1371/journal.pcbi.1002436', '22457613', 'Secondary lymphoid organs (SLO), such as lymph nodes and the spleen, display a complex micro-architecture. In the T cell zone the micro-architecture is provided by a network of fibroblastic reticular cells (FRC) and their filaments. The FRC network is thought to enhance the interaction between immune cells and their cognate antigen. However, the effect of the FRC network on cell interaction cannot be quantified to date because of limitations in immunological methodology. We use computational models to study the influence of different densities of FRC networks on the probability that two cells meet. We developed a 3D cellular automaton model to simulate cell movements and interactions along the FRC network inside lymphatic tissue. We show that the FRC network density has only a small effect on the probability of a cell to come into contact with a static or motile target. However, damage caused by a disruption of the FRC network is greatest at FRC densities corresponding to densities observed in the spleen of naïve mice. Our analysis suggests that the FRC network as a guiding structure for moving T cells has only a minor effect on the probability to find a corresponding dendritic cell. We propose alternative hypotheses by which the FRC network might influence the functionality of immune responses in a more significant way.'),
(85405, 2012, 'plos', 'Dynamic effective connectivity of inter-areal brain circuits', 'Battaglia, Demian|Witt, Annette|Wolf, Fred|Geisel, Theo', 'Max Planck Institute for Dynamics and Self-Organization, Göttingen, Germany. demian@nld.ds.mpg.de|Max Planck Institute for Dynamics and Self-Organization, Göttingen, Germany. demian@nld.ds.mpg.de|Max Planck Institute for Dynamics and Self-Organization, Göttingen, Germany. demian@nld.ds.mpg.de|Max Planck Institute for Dynamics and Self-Organization, Göttingen, Germany. demian@nld.ds.mpg.de', 'Germany|Germany|Germany|Germany', 80, 'Action Potentials|Animals|Brain|Computer Simulation|Humans|Models, Anatomic|Models, Neurological|Nerve Net|Neural Pathways|Neurons', 'Journal Article', '10.1371/journal.pcbi.1002438', '22457614', 'Anatomic connections between brain areas affect information flow between neuronal circuits and the synchronization of neuronal activity. However, such structural connectivity does not coincide with effective connectivity (or, more precisely, causal connectivity), related to the elusive question Which areas cause the present activity of which others?. Effective connectivity is directed and depends flexibly on contexts and tasks. Here we show that dynamic effective connectivity can emerge from transitions in the collective organization of coherent neural activity. Integrating simulation and semi-analytic approaches, we study mesoscale network motifs of interacting cortical areas, modeled as large random networks of spiking neurons or as simple rate units. Through a causal analysis of time-series of model neural activity, we show that different dynamical states generated by a same structural connectivity motif correspond to distinct effective connectivity motifs. Such effective motifs can display a dominant directionality, due to spontaneous symmetry breaking and effective entrainment between local brain rhythms, although all connections in the considered structural motifs are reciprocal. We show then that transitions between effective connectivity configurations (like, for instance, reversal in the direction of inter-areal interactions) can be triggered reliably by brief perturbation inputs, properly timed with respect to an ongoing local oscillation, without the need for plastic synaptic changes. Finally, we analyze how the information encoded in spiking patterns of a local neuronal population is propagated across a fixed structural connectivity motif, demonstrating that changes in the active effective connectivity regulate both the efficiency and the directionality of information transfer. Previous studies stressed the role played by coherent oscillations in establishing efficient communication between distant areas. Going beyond these early proposals, we advance here that dynamic interactions between brain rhythms provide as well the basis for the self-organized control of this communication-through-coherence, making thus possible a fast on-demand reconfiguration of global information routing modalities.'),
(85406, 2012, 'plos', 'Traffic instabilities in self-organized pedestrian crowds', 'Moussaïd, Mehdi|Guillot, Elsa G|Moreau, Mathieu|Fehrenbach, Jérôme|Chabiron, Olivier|Lemercier, Samuel|Pettré, Julien|Appert-Rolland, Cécile|Degond, Pierre|Theraulaz, Guy', 'Centre de Recherches sur la Cognition Animale, Université Paul Sabatier, Toulouse, France. mehdi.moussaid@gmail.com|Centre de Recherches sur la Cognition Animale, Université Paul Sabatier, Toulouse, France. mehdi.moussaid@gmail.com|Centre de Recherches sur la Cognition Animale, Université Paul Sabatier, Toulouse, France. mehdi.moussaid@gmail.com|Centre de Recherches sur la Cognition Animale, Université Paul Sabatier, Toulouse, France. mehdi.moussaid@gmail.com|Centre de Recherches sur la Cognition Animale, Université Paul Sabatier, Toulouse, France. mehdi.moussaid@gmail.com|Centre de Recherches sur la Cognition Animale, Université Paul Sabatier, Toulouse, France. mehdi.moussaid@gmail.com|Centre de Recherches sur la Cognition Animale, Université Paul Sabatier, Toulouse, France. mehdi.moussaid@gmail.com|Centre de Recherches sur la Cognition Animale, Université Paul Sabatier, Toulouse, France. mehdi.moussaid@gmail.com|Centre de Recherches sur la Cognition Animale, Université Paul Sabatier, Toulouse, France. mehdi.moussaid@gmail.com|Centre de Recherches sur la Cognition Animale, Université Paul Sabatier, Toulouse, France. mehdi.moussaid@gmail.com', 'France|France|France|France|France|France|France|France|France|France', 109, 'Computer Simulation|Crowding|Humans|Models, Theoretical|Population Dynamics|Walking', 'Journal Article', '10.1371/journal.pcbi.1002442', '22457615', 'In human crowds as well as in many animal societies, local interactions among individuals often give rise to self-organized collective organizations that offer functional benefits to the group. For instance, flows of pedestrians moving in opposite directions spontaneously segregate into lanes of uniform walking directions. This phenomenon is often referred to as a smart collective pattern, as it increases the traffic efficiency with no need of external control. However, the functional benefits of this emergent organization have never been experimentally measured, and the underlying behavioral mechanisms are poorly understood. In this work, we have studied this phenomenon under controlled laboratory conditions. We found that the traffic segregation exhibits structural instabilities characterized by the alternation of organized and disorganized states, where the lifetime of well-organized clusters of pedestrians follow a stretched exponential relaxation process. Further analysis show that the inter-pedestrian variability of comfortable walking speeds is a key variable at the origin of the observed traffic perturbations. We show that the collective benefit of the emerging pattern is maximized when all pedestrians walk at the average speed of the group. In practice, however, local interactions between slow- and fast-walking pedestrians trigger global breakdowns of organization, which reduce the collective and the individual payoff provided by the traffic segregation. This work is a step ahead toward the understanding of traffic self-organization in crowds, which turns out to be modulated by complex behavioral mechanisms that do not always maximize the groups benefits. The quantitative understanding of crowd behaviors opens the way for designing bottom-up management strategies bound to promote the emergence of efficient collective behaviors in crowds.'),
(85407, 2012, 'plos', 'Neural network mechanisms underlying stimulus driven variability reduction', 'Deco, Gustavo|Hugues, Etienne', 'Theoretical and Computational Neuroscience Group, Center of Brain and Cognition, Universitat Pompeu Fabra, Barcelona, Spain. gustavo.deco@upf.edu|Theoretical and Computational Neuroscience Group, Center of Brain and Cognition, Universitat Pompeu Fabra, Barcelona, Spain. gustavo.deco@upf.edu', 'Spain|Spain', 57, 'Action Potentials|Animals|Computer Simulation|Excitatory Postsynaptic Potentials|Feedback, Physiological|Humans|Models, Neurological|Nerve Net|Neurons|Reproducibility of Results|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002395', '22479168', 'It is well established that the variability of the neural activity across trials, as measured by the Fano factor, is elevated. This fact poses limits on information encoding by the neural activity. However, a series of recent neurophysiological experiments have changed this traditional view. Single cell recordings across a variety of species, brain areas, brain states and stimulus conditions demonstrate a remarkable reduction of the neural variability when an external stimulation is applied and when attention is allocated towards a stimulus within a neurons receptive field, suggesting an enhancement of information encoding. Using an heterogeneously connected neural network model whose dynamics exhibits multiple attractors, we demonstrate here how this variability reduction can arise from a network effect. In the spontaneous state, we show that the high degree of neural variability is mainly due to fluctuation-driven excursions from attractor to attractor. This occurs when, in the parameter space, the network working point is around the bifurcation allowing multistable attractors. The application of an external excitatory drive by stimulation or attention stabilizes one specific attractor, eliminating in this way the transitions between the different attractors and resulting in a net decrease in neural variability over trials. Importantly, non-responsive neurons also exhibit a reduction of variability. Finally, this reduced variability is found to arise from an increased regularity of the neural spike trains. In conclusion, these results suggest that the variability reduction under stimulation and attention is a property of neural circuits.'),
(85408, 2012, 'plos', 'Thermodynamic state ensemble models of cis-regulation', 'Sherman, Marc S|Cohen, Barak A', 'Computational and Molecular Biophysics, Washington University in St. Louis, St. Louis, Missouri, United States of America.|Computational and Molecular Biophysics, Washington University in St. Louis, St. Louis, Missouri, United States of America.', 'United States|United States', 0, 'Computer Simulation|DNA|Gene Expression Regulation|Models, Chemical|Models, Genetic|Regulatory Sequences, Nucleic Acid|Thermodynamics|Transcription Factors|Transcriptional Activation', 'Journal Article', '10.1371/journal.pcbi.1002407', '22479169', 'A major goal in computational biology is to develop models that accurately predict a genes expression from its surrounding regulatory DNA. Here we present one class of such models, thermodynamic state ensemble models. We describe the biochemical derivation of the thermodynamic framework in simple terms, and lay out the mathematical components that comprise each model. These components include (1) the possible states of a promoter, where a state is defined as a particular arrangement of transcription factors bound to a DNA promoter, (2) the binding constants that describe the affinity of the protein-protein and protein-DNA interactions that occur in each state, and (3) whether each state is capable of transcribing. Using these components, we demonstrate how to compute a cis-regulatory function that encodes the probability of a promoter being active. Our intention is to provide enough detail so that readers with little background in thermodynamics can compose their own cis-regulatory functions. To facilitate this goal, we also describe a matrix form of the model that can be easily coded in any programming language. This formalism has great flexibility, which we show by illustrating how phenomena such as competition between transcription factors and cooperativity are readily incorporated into these models. Using this framework, we also demonstrate that Michaelis-like functions, another class of cis-regulatory models, are a subset of the thermodynamic framework with specific assumptions. By recasting Michaelis-like functions as thermodynamic functions, we emphasize the relationship between these models and delineate the specific circumstances representable by each approach. Application of thermodynamic state ensemble models is likely to be an important tool in unraveling the physical basis of combinatorial cis-regulation and in generating formalisms that accurately predict gene expression from DNA sequence.'),
(85409, 2012, 'plos', 'Collective dynamics differentiates functional divergence in protein evolution', 'Glembo, Tyler J|Farrell, Daniel W|Gerek, Z Nevin|Thorpe, M F|Ozkan, S Banu', 'Center for Biological Physics, Department of Physics, Arizona State University, Tempe, Arizona, United States of America.|Center for Biological Physics, Department of Physics, Arizona State University, Tempe, Arizona, United States of America.|Center for Biological Physics, Department of Physics, Arizona State University, Tempe, Arizona, United States of America.|Center for Biological Physics, Department of Physics, Arizona State University, Tempe, Arizona, United States of America.|Center for Biological Physics, Department of Physics, Arizona State University, Tempe, Arizona, United States of America.', 'United States|United States|United States|United States|United States', 20, 'Amino Acid Sequence|Evolution, Molecular|Molecular Sequence Data|Mutation|Protein Conformation|Receptors, Steroid|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1002428', '22479170', 'Protein evolution is most commonly studied by analyzing related protein sequences and generating ancestral sequences through Bayesian and Maximum Likelihood methods, and/or by resurrecting ancestral proteins in the lab and performing ligand binding studies to determine function. Structural and dynamic evolution have largely been left out of molecular evolution studies. Here we incorporate both structure and dynamics to elucidate the molecular principles behind the divergence in the evolutionary path of the steroid receptor proteins. We determine the likely structure of three evolutionarily diverged ancestral steroid receptor proteins using the Zipping and Assembly Method with FRODA (ZAMF). Our predictions are within ~2.7 Å all-atom RMSD of the respective crystal structures of the ancestral steroid receptors. Beyond static structure prediction, a particular feature of ZAMF is that it generates protein dynamics information. We investigate the differences in conformational dynamics of diverged proteins by obtaining the most collective motion through essential dynamics. Strikingly, our analysis shows that evolutionarily diverged proteins of the same family do not share the same dynamic subspace, while those sharing the same function are simultaneously clustered together and distant from those, that have functionally diverged. Dynamic analysis also enables those mutations that most affect dynamics to be identified. It correctly predicts all mutations (functional and permissive) necessary to evolve new function and ~60% of permissive mutations necessary to recover ancestral function.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85410, 2012, 'plos', 'Ten simple rules for starting a company', 'Fletcher, Anthony C|Bourne, Philip E', 'Center for Biological Physics, Department of Physics, Arizona State University, Tempe, Arizona, United States of America.|Center for Biological Physics, Department of Physics, Arizona State University, Tempe, Arizona, United States of America.', 'United States|United States', 2, 'Algorithms|Entrepreneurship|Industry|Models, Organizational', 'Editorial', '10.1371/journal.pcbi.1002439', '22479171', '-'),
(85411, 2012, 'plos', 'Decoding unattended fearful faces with whole-brain correlations: an approach to identify condition-dependent large-scale functional connectivity', 'Pantazatos, Spiro P|Talati, Ardesheer|Pavlidis, Paul|Hirsch, Joy', 'fMRI Research Center, Columbia University, New York, New York, United States of America. spiropan@gmail.com|fMRI Research Center, Columbia University, New York, New York, United States of America. spiropan@gmail.com|fMRI Research Center, Columbia University, New York, New York, United States of America. spiropan@gmail.com|fMRI Research Center, Columbia University, New York, New York, United States of America. spiropan@gmail.com', 'United States|United States|United States|United States', 28, 'Adult|Brain|Brain Mapping|Computer Simulation|Facial Expression|Fear|Female|Humans|Male|Models, Neurological|Nerve Net|Statistics as Topic|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1002441', '22479172', 'Processing of unattended threat-related stimuli, such as fearful faces, has been previously examined using group functional magnetic resonance (fMRI) approaches. However, the identification of features of brain activity containing sufficient information to decode, or brain-read, unattended (implicit) fear perception remains an active research goal. Here we test the hypothesis that patterns of large-scale functional connectivity (FC) decode the emotional expression of implicitly perceived faces within single individuals using training data from separate subjects. fMRI and a blocked design were used to acquire BOLD signals during implicit (task-unrelated) presentation of fearful and neutral faces. A pattern classifier (linear kernel Support Vector Machine, or SVM) with linear filter feature selection used pair-wise FC as features to predict the emotional expression of implicitly presented faces. We plotted classification accuracy vs. number of top N selected features and observed that significantly higher than chance accuracies (between 90-100%) were achieved with 15-40 features. During fearful face presentation, the most informative and positively modulated FC was between angular gyrus and hippocampus, while the greatest overall contributing region was the thalamus, with positively modulated connections to bilateral middle temporal gyrus and insula. Other FCs that predicted fear included superior-occipital and parietal regions, cerebellum and prefrontal cortex. By comparison, patterns of spatial activity (as opposed to interactivity) were relatively uninformative in decoding implicit fear. These findings indicate that whole-brain patterns of interactivity are a sensitive and informative signature of unattended fearful emotion processing. At the same time, we demonstrate and propose a sensitive and exploratory approach for the identification of large-scale, condition-dependent FC. In contrast to model-based, group approaches, the current approach does not discount the multivariate, joint responses of multiple functional connections and is not hampered by signal loss and the need for multiple comparisons correction.'),
(85412, 2012, 'plos', 'Guilt by association is the exception rather than the rule in gene networks', 'Gillis, Jesse|Pavlidis, Paul', 'Centre for High-Throughput Biology and Department of Psychiatry, University of British Columbia, Vancouver, British Colombia, Canada.|Centre for High-Throughput Biology and Department of Psychiatry, University of British Columbia, Vancouver, British Colombia, Canada.', 'Canada|Canada', 112, 'Algorithms|Animals|Computer Simulation|Humans|Models, Biological|Protein Interaction Mapping|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002444', '22479173', 'Gene networks are commonly interpreted as encoding functional information in their connections. An extensively validated principle called guilt by association states that genes which are associated or interacting are more likely to share function. Guilt by association provides the central top-down principle for analyzing gene networks in functional terms or assessing their quality in encoding functional information. In this work, we show that functional information within gene networks is typically concentrated in only a very few interactions whose properties cannot be reliably related to the rest of the network. In effect, the apparent encoding of function within networks has been largely driven by outliers whose behaviour cannot even be generalized to individual genes, let alone to the network at large. While experimentalist-driven analysis of interactions may use prior expert knowledge to focus on the small fraction of critically important data, large-scale computational analyses have typically assumed that high-performance cross-validation in a network is due to a generalizable encoding of function. Because we find that gene function is not systemically encoded in networks, but dependent on specific and critical interactions, we conclude it is necessary to focus on the details of how networks encode function and what information computational analyses use to extract functional meaning. We explore a number of consequences of this and find that network structure itself provides clues as to which connections are critical and that systemic properties, such as scale-free-like behaviour, do not map onto the functional connectivity within networks.'),
(85413, 2012, 'plos', 'Topic pages: PLoS Computational Biology meets Wikipedia', 'Wodak, Shoshana J|Mietchen, Daniel|Collings, Andrew M|Russell, Robert B|Bourne, Philip E', 'Centre for High-Throughput Biology and Department of Psychiatry, University of British Columbia, Vancouver, British Colombia, Canada.|Centre for High-Throughput Biology and Department of Psychiatry, University of British Columbia, Vancouver, British Colombia, Canada.|Centre for High-Throughput Biology and Department of Psychiatry, University of British Columbia, Vancouver, British Colombia, Canada.|Centre for High-Throughput Biology and Department of Psychiatry, University of British Columbia, Vancouver, British Colombia, Canada.|Centre for High-Throughput Biology and Department of Psychiatry, University of British Columbia, Vancouver, British Colombia, Canada.', 'Canada|Canada|Canada|Canada|Canada', 13, 'Computational Biology|Information Dissemination|Internet|Peer Review, Research|Periodicals as Topic', 'Editorial', '10.1371/journal.pcbi.1002446', '22479174', '-'),
(85414, 2012, 'plos', 'The rate of beneficial mutations surfing on the wave of a range expansion', 'Lehe, Rémi|Hallatschek, Oskar|Peliti, Luca', 'Physico-Chimie Curie, UMR 168, Institut Curie, Paris, France.|Physico-Chimie Curie, UMR 168, Institut Curie, Paris, France.|Physico-Chimie Curie, UMR 168, Institut Curie, Paris, France.', 'France|France|France', 42, 'Biological Evolution|Computer Simulation|Ecosystem|Emigration and Immigration|Genetics, Population|Models, Genetic|Mutation|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002447', '22479175', 'Many theoretical and experimental studies suggest that range expansions can have severe consequences for the gene pool of the expanding population. Due to strongly enhanced genetic drift at the advancing frontier, neutral and weakly deleterious mutations can reach large frequencies in the newly colonized regions, as if they were surfing the front of the range expansion. These findings raise the question of how frequently beneficial mutations successfully surf at shifting range margins, thereby promoting adaptation towards a range-expansion phenotype. Here, we use individual-based simulations to study the surfing statistics of recurrent beneficial mutations on wave-like range expansions in linear habitats. We show that the rate of surfing depends on two strongly antagonistic factors, the probability of surfing given the spatial location of a novel mutation and the rate of occurrence of mutations at that location. The surfing probability strongly increases towards the tip of the wave. Novel mutations are unlikely to surf unless they enjoy a spatial head start compared to the bulk of the population. The needed head start is shown to be proportional to the inverse fitness of the mutant type, and only weakly dependent on the carrying capacity. The precise location dependence of surfing probabilities is derived from the non-extinction probability of a branching process within a moving field of growth rates. The second factor is the mutation occurrence which strongly decreases towards the tip of the wave. Thus, most successful mutations arise at an intermediate position in the front of the wave. We present an analytic theory for the tradeoff between these factors that allows to predict how frequently substitutions by beneficial mutations occur at invasion fronts. We find that small amounts of genetic drift increase the fixation rate of beneficial mutations at the advancing front, and thus could be important for adaptation during species invasions.'),
(85415, 2012, 'plos', 'Dynamical modeling of collective behavior from pigeon flight data: flock cohesion and dispersion', 'Dieck Kattas, Graciano|Xu, Xiao-Ke|Small, Michael', 'Department of Electronic and Information Engineering, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.|Department of Electronic and Information Engineering, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.|Department of Electronic and Information Engineering, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.', 'Hong Kong|Hong Kong|Hong Kong', 13, 'Animals|Behavior, Animal|Columbidae|Computer Simulation|Cooperative Behavior|Flight, Animal|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002449', '22479176', 'Several models of flocking have been promoted based on simulations with qualitatively naturalistic behavior. In this paper we provide the first direct application of computational modeling methods to infer flocking behavior from experimental field data. We show that this approach is able to infer general rules for interaction, or lack of interaction, among members of a flock or, more generally, any community. Using experimental field measurements of homing pigeons in flight we demonstrate the existence of a basic distance dependent attraction/repulsion relationship and show that this rule is sufficient to explain collective behavior observed in nature. Positional data of individuals over time are used as input data to a computational algorithm capable of building complex nonlinear functions that can represent the system behavior. Topological nearest neighbor interactions are considered to characterize the components within this model. The efficacy of this method is demonstrated with simulated noisy data generated from the classical (two dimensional) Vicsek model. When applied to experimental data from homing pigeon flights we show that the more complex three dimensional models are capable of simulating trajectories, as well as exhibiting realistic collective dynamics. The simulations of the reconstructed models are used to extract properties of the collective behavior in pigeons, and how it is affected by changing the initial conditions of the system. Our results demonstrate that this approach may be applied to construct models capable of simulating trajectories and collective dynamics using experimental field measurements of herd movement. From these models, the behavior of the individual agents (animals) may be inferred.'),
(85416, 2012, 'plos', 'Comprehensive modelling of the Neurospora circadian clock and its temperature compensation', 'Tseng, Yu-Yao|Hunt, Suzanne M|Heintzen, Christian|Crosthwaite, Susan K|Schwartz, Jean-Marc', 'University of Manchester, Manchester, United Kingdom.|University of Manchester, Manchester, United Kingdom.|University of Manchester, Manchester, United Kingdom.|University of Manchester, Manchester, United Kingdom.|University of Manchester, Manchester, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 19, 'Circadian Clocks|Circadian Rhythm Signaling Peptides and Proteins|Computer Simulation|Feedback, Physiological|Fungal Proteins|Models, Biological|Neurospora crassa|Thermosensing', 'Journal Article', '10.1371/journal.pcbi.1002437', '22496627', 'Circadian clocks provide an internal measure of external time allowing organisms to anticipate and exploit predictable daily changes in the environment. Rhythms driven by circadian clocks have a temperature compensated periodicity of approximately 24 hours that persists in constant conditions and can be reset by environmental time cues. Computational modelling has aided our understanding of the molecular mechanisms of circadian clocks, nevertheless it remains a major challenge to integrate the large number of clock components and their interactions into a single, comprehensive model that is able to account for the full breadth of clock phenotypes. Here we present a comprehensive dynamic model of the Neurospora crassa circadian clock that incorporates its key components and their transcriptional and post-transcriptional regulation. The model accounts for a wide range of clock characteristics including: a periodicity of 21.6 hours, persistent oscillation in constant conditions, arrhythmicity in constant light, resetting by brief light pulses, and entrainment to full photoperiods. Crucial components influencing the period and amplitude of oscillations were identified by control analysis. Furthermore, simulations enabled us to propose a mechanism for temperature compensation, which is achieved by simultaneously increasing the translation of frq RNA and decreasing the nuclear import of FRQ protein.'),
(85417, 2012, 'plos', 'Circular permutation in proteins', 'Bliven, Spencer|Prlixc4x87, Andreas', 'Bioinformatics Program, University of California, San Diego, La Jolla, California, United States of America. sbliven@ucsd.edu|Bioinformatics Program, University of California, San Diego, La Jolla, California, United States of America. sbliven@ucsd.edu', 'United States|United States', 0, 'Amino Acid Sequence|Computer Simulation|Models, Chemical|Models, Genetic|Molecular Sequence Data|Mutation|Proteins|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1002445', '22496628', '-'),
(85418, 2012, 'plos', 'Replication fork polarity gradients revealed by megabase-sized U-shaped replication timing domains in human cell lines', 'Baker, Antoine|Audit, Benjamin|Chen, Chun-Long|Moindrot, Benoit|Leleu, Antoine|Guilbaud, Guillaume|Rappailles, Aurélien|Vaillant, Cédric|Goldar, Arach|Mongelard, Fabien|dAubenton-Carafa, Yves|Hyrien, Olivier|Thermes, Claude|Arneodo, Alain', 'Université de Lyon, Lyon, France.|Université de Lyon, Lyon, France.|Université de Lyon, Lyon, France.|Université de Lyon, Lyon, France.|Université de Lyon, Lyon, France.|Université de Lyon, Lyon, France.|Université de Lyon, Lyon, France.|Université de Lyon, Lyon, France.|Université de Lyon, Lyon, France.|Université de Lyon, Lyon, France.|Université de Lyon, Lyon, France.|Université de Lyon, Lyon, France.|Université de Lyon, Lyon, France.|Université de Lyon, Lyon, France.', 'France|France|France|France|France|France|France|France|France|France|France|France|France|France', 51, 'Base Sequence|Cell Line|Chromosome Mapping|Computer Simulation|DNA|DNA Replication|Genome|Genome, Human|Humans|Models, Genetic|Molecular Sequence Data|Replication Origin', 'Journal Article', '10.1371/journal.pcbi.1002443', '22496629', 'In higher eukaryotes, replication program specification in different cell types remains to be fully understood. We show for seven human cell lines that about half of the genome is divided in domains that display a characteristic U-shaped replication timing profile with early initiation zones at borders and late replication at centers. Significant overlap is observed between U-domains of different cell lines and also with germline replication domains exhibiting a N-shaped nucleotide compositional skew. From the demonstration that the average fork polarity is directly reflected by both the compositional skew and the derivative of the replication timing profile, we argue that the fact that this derivative displays a N-shape in U-domains sustains the existence of large-scale gradients of replication fork polarity in somatic and germline cells. Analysis of chromatin interaction (Hi-C) and chromatin marker data reveals that U-domains correspond to high-order chromatin structural units. We discuss possible models for replication origin activation within U/N-domains. The compartmentalization of the genome into replication U/N-domains provides new insights on the organization of the replication program in the human genome.'),
(85419, 2012, 'plos', 'Molecular machines in the synapse: overlapping protein sets control distinct steps in neurosecretion', 'Cornelisse, L Niels|Tsivtsivadze, Evgeni|Meijer, Marieke|Dijkstra, Tjeerd M H|Heskes, Tom|Verhage, Matthijs', 'Functional Genomics, Center for Neurogenomics and Cognitive Research-CNCR, Department of Clinical Genetics, VUmc, Neuroscience Campus Amsterdam-NCA, VU University-VUA and VU University Medical Center-VUmc, Amsterdam, The Netherlands. l.n.cornelisse@vu.nl|Functional Genomics, Center for Neurogenomics and Cognitive Research-CNCR, Department of Clinical Genetics, VUmc, Neuroscience Campus Amsterdam-NCA, VU University-VUA and VU University Medical Center-VUmc, Amsterdam, The Netherlands. l.n.cornelisse@vu.nl|Functional Genomics, Center for Neurogenomics and Cognitive Research-CNCR, Department of Clinical Genetics, VUmc, Neuroscience Campus Amsterdam-NCA, VU University-VUA and VU University Medical Center-VUmc, Amsterdam, The Netherlands. l.n.cornelisse@vu.nl|Functional Genomics, Center for Neurogenomics and Cognitive Research-CNCR, Department of Clinical Genetics, VUmc, Neuroscience Campus Amsterdam-NCA, VU University-VUA and VU University Medical Center-VUmc, Amsterdam, The Netherlands. l.n.cornelisse@vu.nl|Functional Genomics, Center for Neurogenomics and Cognitive Research-CNCR, Department of Clinical Genetics, VUmc, Neuroscience Campus Amsterdam-NCA, VU University-VUA and VU University Medical Center-VUmc, Amsterdam, The Netherlands. l.n.cornelisse@vu.nl|Functional Genomics, Center for Neurogenomics and Cognitive Research-CNCR, Department of Clinical Genetics, VUmc, Neuroscience Campus Amsterdam-NCA, VU University-VUA and VU University Medical Center-VUmc, Amsterdam, The Netherlands. l.n.cornelisse@vu.nl', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 4, 'Animals|Computer Simulation|Humans|Models, Neurological|Nerve Tissue Proteins|Neurons|Neurotransmitter Agents|Synapses|Synaptic Vesicles', 'Journal Article', '10.1371/journal.pcbi.1002450', '22496630', 'Activity regulated neurotransmission shapes the computational properties of a neuron and involves the concerted action of many proteins. Classical, intuitive working models often assign specific proteins to specific steps in such complex cellular processes, whereas modern systems theories emphasize more integrated functions of proteins. To test how often synaptic proteins participate in multiple steps in neurotransmission we present a novel probabilistic method to analyze complex functional data from genetic perturbation studies on neuronal secretion. Our method uses a mixture of probabilistic principal component analyzers to cluster genetic perturbations on two distinct steps in synaptic secretion, vesicle priming and fusion, and accounts for the poor standardization between different studies. Clustering data from 121 perturbations revealed that different perturbations of a given protein are often assigned to different steps in the release process. Furthermore, vesicle priming and fusion are inversely correlated for most of those perturbations where a specific protein domain was mutated to create a gain-of-function variant. Finally, two different modes of vesicle release, spontaneous and action potential evoked release, were affected similarly by most perturbations. This data suggests that the presynaptic protein network has evolved as a highly integrated supramolecular machine, which is responsible for both spontaneous and activity induced release, with a group of core proteins using different domains to act on multiple steps in the release process.'),
(85420, 2012, 'plos', 'Evolutionary game theory and social learning can determine how vaccine scares unfold', 'Bauch, Chris T|Bhattacharyya, Samit', 'Department of Mathematics and Statistics, University of Guelph, Guelph, Canada. cbauch@uoguelph.ca|Department of Mathematics and Statistics, University of Guelph, Guelph, Canada. cbauch@uoguelph.ca', 'Canada|Canada', 0, 'Cultural Evolution|Disease Outbreaks|Game Theory|Health Behavior|Humans|Imitative Behavior|Learning|Mass Vaccination|Social Behavior|Virus Diseases', 'Journal Article', '10.1371/journal.pcbi.1002452', '22496631', 'Immunization programs have often been impeded by vaccine scares, as evidenced by the measles-mumps-rubella (MMR) autism vaccine scare in Britain. A free rider effect may be partly responsible: vaccine-generated herd immunity can reduce disease incidence to such low levels that real or imagined vaccine risks appear large in comparison, causing individuals to cease vaccinating. This implies a feedback loop between disease prevalence and strategic individual vaccinating behavior. Here, we analyze a model based on evolutionary game theory that captures this feedback in the context of vaccine scares, and that also includes social learning. Vaccine risk perception evolves over time according to an exogenously imposed curve. We test the model against vaccine coverage data and disease incidence data from two vaccine scares in England & Wales: the whole cell pertussis vaccine scare and the MMR vaccine scare. The model fits vaccine coverage data from both vaccine scares relatively well. Moreover, the model can explain the vaccine coverage data more parsimoniously than most competing models without social learning and/or feedback (hence, adding social learning and feedback to a vaccine scare model improves model fit with little or no parsimony penalty). Under some circumstances, the model can predict future vaccine coverage and disease incidence--up to 10 years in advance in the case of pertussis--including specific qualitative features of the dynamics, such as future incidence peaks and undulations in vaccine coverage due to the populations response to changing disease incidence. Vaccine scares could become more common as eradication goals are approached for more vaccine-preventable diseases. Such models could help us predict how vaccine scares might unfold and assist mitigation efforts.'),
(85421, 2012, 'plos', 'Automatic filtering and substantiation of drug safety signals', 'Bauer-Mehren, Anna|van Mullingen, Erik M|Avillach, Paul|Carrascosa, María Del Carmen|Garcia-Serna, Ricard|Piñero, Janet|Singh, Bharat|Lopes, Pedro|Oliveira, José L|Diallo, Gayo|Ahlberg Helgee, Ernst|Boyer, Scott|Mestres, Jordi|Sanz, Ferran|Kors, Jan A|Furlong, Laura I', 'Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.|Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.|Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.|Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.|Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.|Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.|Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.|Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.|Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.|Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.|Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.|Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.|Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.|Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.|Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.|Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.', 'Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain', 0, 'Computer Simulation|Database Management Systems|Databases, Factual|Documentation|Drug-Related Side Effects and Adverse Reactions|Humans|Information Storage and Retrieval|Models, Biological|Registries', 'Journal Article', '10.1371/journal.pcbi.1002457', '22496632', 'Drug safety issues pose serious health threats to the population and constitute a major cause of mortality worldwide. Due to the prominent implications to both public health and the pharmaceutical industry, it is of great importance to unravel the molecular mechanisms by which an adverse drug reaction can be potentially elicited. These mechanisms can be investigated by placing the pharmaco-epidemiologically detected adverse drug reaction in an information-rich context and by exploiting all currently available biomedical knowledge to substantiate it. We present a computational framework for the biological annotation of potential adverse drug reactions. First, the proposed framework investigates previous evidences on the drug-event association in the context of biomedical literature (signal filtering). Then, it seeks to provide a biological explanation (signal substantiation) by exploring mechanistic connections that might explain why a drug produces a specific adverse reaction. The mechanistic connections include the activity of the drug, related compounds and drug metabolites on protein targets, the association of protein targets to clinical events, and the annotation of proteins (both protein targets and proteins associated with clinical events) to biological pathways. Hence, the workflows for signal filtering and substantiation integrate modules for literature and database mining, in silico drug-target profiling, and analyses based on gene-disease networks and biological pathways. Application examples of these workflows carried out on selected cases of drug safety signals are discussed. The methodology and workflows presented offer a novel approach to explore the molecular mechanisms underlying adverse drug reactions.'),
(85422, 2012, 'plos', 'What can causal networks tell us about metabolic pathways?', 'Blair, Rachael Hageman|Kliebenstein, Daniel J|Churchill, Gary A', 'State University of New York at Buffalo, Buffalo, New York, United States of America.|State University of New York at Buffalo, Buffalo, New York, United States of America.|State University of New York at Buffalo, Buffalo, New York, United States of America.', 'United States|United States|United States', 0, 'Algorithms|Animals|Computer Graphics|Computer Simulation|Humans|Metabolome|Models, Biological|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002458', '22496633', 'Graphical models describe the linear correlation structure of data and have been used to establish causal relationships among phenotypes in genetic mapping populations. Data are typically collected at a single point in time. Biological processes on the other hand are often non-linear and display time varying dynamics. The extent to which graphical models can recapitulate the architecture of an underlying biological processes is not well understood. We consider metabolic networks with known stoichiometry to address the fundamental question: What can causal networks tell us about metabolic pathways?. Using data from an Arabidopsis Bay[Formula: see text]Sha population and simulated data from dynamic models of pathway motifs, we assess our ability to reconstruct metabolic pathways using graphical models. Our results highlight the necessity of non-genetic residual biological variation for reliable inference. Recovery of the ordering within a pathway is possible, but should not be expected. Causal inference is sensitive to subtle patterns in the correlation structure that may be driven by a variety of factors, which may not emphasize the substrate-product relationship. We illustrate the effects of metabolic pathway architecture, epistasis and stochastic variation on correlation structure and graphical model-derived networks. We conclude that graphical models should be interpreted cautiously, especially if the implied causal relationships are to be used in the design of intervention strategies.'),
(85423, 2012, 'plos', 'Parameters in dynamic models of complex traits are containers of missing heritability', 'Wang, Yunpeng|Gjuvsland, Arne B|Vik, Jon Olav|Smith, Nicolas P|Hunter, Peter J|Omholt, Stig W', 'Centre for Integrative Genetics, Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Ås, Norway.|Centre for Integrative Genetics, Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Ås, Norway.|Centre for Integrative Genetics, Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Ås, Norway.|Centre for Integrative Genetics, Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Ås, Norway.|Centre for Integrative Genetics, Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Ås, Norway.|Centre for Integrative Genetics, Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Ås, Norway.', 'Norway|Norway|Norway|Norway|Norway|Norway', 0, 'Action Potentials|Animals|Calcium Signaling|Cells, Cultured|Computer Simulation|Mice|Models, Genetic|Myocytes, Cardiac|Polymorphism, Single Nucleotide|Quantitative Trait, Heritable', 'Journal Article', '10.1371/journal.pcbi.1002459', '22496634', 'Polymorphisms identified in genome-wide association studies of human traits rarely explain more than a small proportion of the heritable variation, and improving this situation within the current paradigm appears daunting. Given a well-validated dynamic model of a complex physiological trait, a substantial part of the underlying genetic variation must manifest as variation in model parameters. These parameters are themselves phenotypic traits. By linking whole-cell phenotypic variation to genetic variation in a computational model of a single heart cell, incorporating genotype-to-parameter maps, we show that genome-wide association studies on parameters reveal much more genetic variation than when using higher-level cellular phenotypes. The results suggest that letting such studies be guided by computational physiology may facilitate a causal understanding of the genotype-to-phenotype map of complex traits, with strong implications for the development of phenomics technology.'),
(85424, 2012, 'plos', 'Energetic selection of topology in ferredoxins', 'Kim, J Dongun|Rodriguez-Granillo, Agustina|Case, David A|Nanda, Vikas|Falkowski, Paul G', 'Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, United States of America.|Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, United States of America.|Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, United States of America.|Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, United States of America.|Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, United States of America.', 'Jersey|Jersey|Jersey|Jersey|Jersey', 0, 'Binding Sites|Computer Simulation|Energy Transfer|Evolution, Molecular|Ferredoxins|Models, Chemical|Models, Genetic|Models, Molecular|Protein Binding|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1002463', '22496635', 'Models of early protein evolution posit the existence of short peptides that bound metals and ions and served as transporters, membranes or catalysts. The Cys-X-X-Cys-X-X-Cys heptapeptide located within bacterial ferredoxins, enclosing an Fexe2x82x84Sxe2x82x84 metal center, is an attractive candidate for such an early peptide. Ferredoxins are ancient proteins and the simple xcexb1+xcexb2 fold is found alone or as a domain in larger proteins throughout all three kingdoms of life. Previous analyses of the heptapeptide conformation in experimentally determined ferredoxin structures revealed a pervasive right-handed topology, despite the fact that the Fexe2x82x84Sxe2x82x84 cluster is achiral. Conformational enumeration of a model CGGCGGC heptapeptide bound to a cubane iron-sulfur cluster indicates both left-handed and right-handed folds could exist and have comparable stabilities. However, only the natural ferredoxin topology provides a significant network of backbone-to-cluster hydrogen bonds that would stabilize the metal-peptide complex. The optimal peptide configuration (alternating xcexb1(L),xcexb1(R)) is that of an xcexb1-sheet, providing an additional mechanism where oligomerization could stabilize the peptide and facilitate iron-sulfur cluster binding.'),
(85425, 2012, 'plos', 'RNA-Seq mapping and detection of gene fusions with a suffix array algorithm', 'Sakarya, Onur|Breu, Heinz|Radovich, Milan|Chen, Yongzhi|Wang, Yulei N|Barbacioru, Catalin|Utiramerur, Sowmi|Whitley, Penn P|Brockman, Joel P|Vatta, Paolo|Zhang, Zheng|Popescu, Liviu|Muller, Matthew W|Kudlingar, Vidya|Garg, Nriti|Li, Chieh-Yuan|Kong, Benjamin S|Bodeau, John P|Nutter, Robert C|Gu, Jian|Bramlett, Kelli S|Ichikawa, Jeffrey K|Hyland, Fiona C|Siddiqui, Asim S', 'Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com|Life Technologies, Foster City, California, United States of America. osakarya@yahoo.com', 'United States|United States|United States|United States|United States|United States|United States|Un', 32, 'Algorithms|Base Sequence|Gene Fusion|Molecular Sequence Data|Oligonucleotide Array Sequence Analysis|Sequence Analysis, RNA|Software', 'Journal Article', '10.1371/journal.pcbi.1002464', '22496636', 'High-throughput RNA sequencing enables quantification of transcripts (both known and novel), exon/exon junctions and fusions of exons from different genes. Discovery of gene fusions-particularly those expressed with low abundance- is a challenge with short- and medium-length sequencing reads. To address this challenge, we implemented an RNA-Seq mapping pipeline within the LifeScope software. We introduced new features including filter and junction mapping, annotation-aided pairing rescue and accurate mapping quality values. We combined this pipeline with a Suffix Array Spliced Read (SASR) aligner to detect chimeric transcripts. Performing paired-end RNA-Seq of the breast cancer cell line MCF-7 using the SOLiD system, we called 40 gene fusions among over 120,000 splicing junctions. We validated 36 of these 40 fusions with TaqMan assays, of which 25 were expressed in MCF-7 but not the Human Brain Reference. An intra-chromosomal gene fusion involving the estrogen receptor alpha gene ESR1, and another involving the RPS6KB1 (Ribosomal protein S6 kinase beta-1) were recurrently expressed in a number of breast tumor cell lines and a clinical tumor sample.'),
(85426, 2012, 'plos', 'On conduction in a bacterial sodium channel', 'Furini, Simone|Domene, Carmen', 'Physical and Theoretical Chemistry Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.|Physical and Theoretical Chemistry Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.', 'United Kingdom|United Kingdom', 0, 'Bacterial Proteins|Computer Simulation|Electric Conductivity|Ion Channel Gating|Models, Chemical|Models, Molecular|Protein Conformation|Sodium|Sodium Channels', 'Journal Article', '10.1371/journal.pcbi.1002476', '22496637', 'Voltage-gated Naxe2x81xba-channels are transmembrane proteins that are responsible for the fast depolarizing phase of the action potential in nerve and muscular cells. Selective permeability of Naxe2x81xba over Caxc2xb2xe2x81xba or Kxe2x81xba ions is essential for the biological function of Naxe2x81xba-channels. After the emergence of the first high-resolution structure of a Naxe2x81xba-channel, an anionic coordination site was proposed to confer Naxe2x81xba selectivity through partial dehydration of Naxe2x81xba via its direct interaction with conserved glutamate side chains. By combining molecular dynamics simulations and free-energy calculations, a low-energy permeation pathway for Naxe2x81xba ion translocation through the selectivity filter of the recently determined crystal structure of a prokaryotic sodium channel from Arcobacter butzleri is characterised. The picture that emerges is that of a pore preferentially occupied by two ions, which can switch between different configurations by crossing low free-energy barriers. In contrast to Kxe2x81xba-channels, the movements of the ions appear to be weakly coupled in Naxe2x81xba-channels. When the free-energy maps for Naxe2x81xba and Kxe2x81xba ions are compared, a selective site is characterised in the narrowest region of the filter, where a hydrated Naxe2x81xba ion, and not a hydrated Kxe2x81xba ion, is energetically stable.'),
(85427, 2012, 'plos', 'Evolution of the multi-domain structures of virulence genes in the human malaria parasite, Plasmodium falciparum', 'Buckee, Caroline O|Recker, Mario', 'Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.|Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.', 'United States|United States', 0, 'Amino Acid Sequence|Base Sequence|Evolution, Molecular|Genetic Variation|Molecular Sequence Data|Plasmodium falciparum|Protein Structure, Tertiary|Protozoan Proteins|Virulence Factors', 'Journal Article', '10.1371/journal.pcbi.1002451', '22511852', 'The var gene family of Plasmodium falciparum encodes the immunodominant variant surface antigens PfEMP1. These highly polymorphic proteins are important virulence factors that mediate cytoadhesion to a variety of host tissues, causing sequestration of parasitized red blood cells in vital organs, including the brain or placenta. Acquisition of variant-specific antibodies correlates with protection against severe malarial infections, however, understanding the relationship between gene expression and infection outcome is complicated by the modular genetic architectures of var genes that encode varying numbers of antigenic domains with differential binding specificities. By analyzing the domain architectures of fully sequenced var gene repertoires we reveal a significant, non-random association between the number of domains comprising a var gene and their sequence conservation. As such, var genes can be grouped into those that are short and diverse and genes that are long and conserved, suggesting gene length as an important characteristic in the classification of var genes. We then use an evolutionary framework to demonstrate how the same evolutionary forces acting on the level of an individual gene may have also shaped the parasites gene repertoire. The observed associations between sequence conservation, gene architecture and repertoire structure can thus be explained by a trade-off between optimizing within-host fitness and minimizing between-host immune selection pressure. Our results demonstrate how simple evolutionary mechanisms can explain var gene structuring on multiple levels and have important implications for understanding the multifaceted epidemiology of P. falciparum malaria.'),
(85428, 2012, 'plos', 'A new perceptual bias reveals suboptimal population decoding of sensory responses', 'Putzeys, Tom|Bethge, Matthias|Wichmann, Felix|Wagemans, Johan|Goris, Robbe', 'Laboratory of Experimental Psychology, University of Leuven, Leuven, Belgium. tom.putzeys@psy.kuleuven.be|Laboratory of Experimental Psychology, University of Leuven, Leuven, Belgium. tom.putzeys@psy.kuleuven.be|Laboratory of Experimental Psychology, University of Leuven, Leuven, Belgium. tom.putzeys@psy.kuleuven.be|Laboratory of Experimental Psychology, University of Leuven, Leuven, Belgium. tom.putzeys@psy.kuleuven.be|Laboratory of Experimental Psychology, University of Leuven, Leuven, Belgium. tom.putzeys@psy.kuleuven.be', 'Belgium|Belgium|Belgium|Belgium|Belgium', 5, 'Computer Simulation|Cues|Decision Making|Humans|Models, Neurological|Perceptual Masking|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1002453', '22511853', 'Several studies have reported optimal population decoding of sensory responses in two-alternative visual discrimination tasks. Such decoding involves integrating noisy neural responses into a more reliable representation of the likelihood that the stimuli under consideration evoked the observed responses. Importantly, an ideal observer must be able to evaluate likelihood with high precision and only consider the likelihood of the two relevant stimuli involved in the discrimination task. We report a new perceptual bias suggesting that observers read out the likelihood representation with remarkably low precision when discriminating grating spatial frequencies. Using spectrally filtered noise, we induced an asymmetry in the likelihood function of spatial frequency. This manipulation mainly affects the likelihood of spatial frequencies that are irrelevant to the task at hand. Nevertheless, we find a significant shift in perceived grating frequency, indicating that observers evaluate likelihoods of a broad range of irrelevant frequencies and discard prior knowledge of stimulus alternatives when performing two-alternative discrimination.'),
(85429, 2012, 'plos', 'Quantifying type-specific reproduction numbers for nosocomial pathogens: evidence for heightened transmission of an Asian sequence type 239 MRSA clone', 'Cooper, Ben S|Kypraios, Theodore|Batra, Rahul|Wyncoll, Duncan|Tosas, Olga|Edgeworth, Jonathan D', 'Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom. ben@tropmedres.ac|Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom. ben@tropmedres.ac|Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom. ben@tropmedres.ac|Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom. ben@tropmedres.ac|Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom. ben@tropmedres.ac|Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom. ben@tropmedres.ac', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 21, 'Asia|Clone Cells|Computer Simulation|Cross Infection|Humans|Methicillin-Resistant Staphylococcus aureus|Models, Statistical|Proportional Hazards Models|Staphylococcal Infections', 'Journal Article', '10.1371/journal.pcbi.1002454', '22511854', 'An important determinant of a pathogens success is the rate at which it is transmitted from infected to susceptible hosts. Although there are anecdotal reports that methicillin-resistant Staphylococcus aureus (MRSA) clones vary in their transmissibility in hospital settings, attempts to quantify such variation are lacking for common subtypes, as are methods for addressing this question using routinely-collected MRSA screening data in endemic settings. Here we present a method to quantify the time-varying transmissibility of different subtypes of common bacterial nosocomial pathogens using routine surveillance data. The method adapts approaches for estimating reproduction numbers based on the probabilistic reconstruction of epidemic trees, but uses relative hazards rather than serial intervals to assign probabilities to different sources for observed transmission events. The method is applied to data collected as part of a retrospective observational study of a concurrent MRSA outbreak in the United Kingdom with dominant endemic MRSA clones (ST22 and ST36) and an Asian ST239 MRSA strain (ST239-TW) in two linked adult intensive care units, and compared with an approach based on a fully parametric transmission model. The results provide support for the hypothesis that the clones responded differently to an infection control measure based on the use of topical antiseptics, which was more effective at reducing transmission of endemic clones. They also suggest that in one of the two ICUs patients colonized or infected with the ST239-TW MRSA clone had consistently higher risks of transmitting MRSA to patients free of MRSA. These findings represent some of the first quantitative evidence of enhanced transmissibility of a pandemic MRSA lineage, and highlight the potential value of tailoring hospital infection control measures to specific pathogen subtypes.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85430, 2012, 'plos', 'Warm body temperature facilitates energy efficient cortical action potentials', 'Yu, Yuguo|Hill, Adam P|McCormick, David A', 'Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut, United States of America.|Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut, United States of America.|Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut, United States of America.', 'United States|United States|United States', 45, 'Action Potentials|Animals|Body Temperature|Brain|Computer Simulation|Energy Transfer|Humans|Models, Neurological|Neurons', 'Journal Article', '10.1371/journal.pcbi.1002456', '22511855', 'The energy efficiency of neural signal transmission is important not only as a limiting factor in brain architecture, but it also influences the interpretation of functional brain imaging signals. Action potential generation in mammalian, versus invertebrate, axons is remarkably energy efficient. Here we demonstrate that this increase in energy efficiency is due largely to a warmer body temperature. Increases in temperature result in an exponential increase in energy efficiency for single action potentials by increasing the rate of Na(+) channel inactivation, resulting in a marked reduction in overlap of the inward Na(+), and outward K(+), currents and a shortening of action potential duration. This increase in single spike efficiency is, however, counterbalanced by a temperature-dependent decrease in the amplitude and duration of the spike afterhyperpolarization, resulting in a nonlinear increase in the spike firing rate, particularly at temperatures above approximately 35°C. Interestingly, the total energy cost, as measured by the multiplication of total Na(+) entry per spike and average firing rate in response to a constant input, reaches a global minimum between 37-42°C. Our results indicate that increases in temperature result in an unexpected increase in energy efficiency, especially near normal body temperature, thus allowing the brain to utilize an energy efficient neural code.'),
(85431, 2012, 'plos', 'Power-law inter-spike interval distributions infer a conditional maximization of entropy in cortical neurons', 'Tsubo, Yasuhiro|Isomura, Yoshikazu|Fukai, Tomoki', 'Laboratory for Neural Circuit Theory, RIKEN Brain Science Institute, Wako, Saitama, Japan. yasuhirotsubo@riken.jp|Laboratory for Neural Circuit Theory, RIKEN Brain Science Institute, Wako, Saitama, Japan. yasuhirotsubo@riken.jp|Laboratory for Neural Circuit Theory, RIKEN Brain Science Institute, Wako, Saitama, Japan. yasuhirotsubo@riken.jp', 'Japan|Japan|Japan', 23, 'Action Potentials|Animals|Brain|Cerebral Cortex|Computer Simulation|Energy Transfer|Entropy|Models, Neurological|Models, Statistical|Neurons|Rats', 'Journal Article', '10.1371/journal.pcbi.1002461', '22511856', 'The brain is considered to use a relatively small amount of energy for its efficient information processing. Under a severe restriction on the energy consumption, the maximization of mutual information (MMI), which is adequate for designing artificial processing machines, may not suit for the brain. The MMI attempts to send information as accurate as possible and this usually requires a sufficient energy supply for establishing clearly discretized communication bands. Here, we derive an alternative hypothesis for neural code from the neuronal activities recorded juxtacellularly in the sensorimotor cortex of behaving rats. Our hypothesis states that in vivo cortical neurons maximize the entropy of neuronal firing under two constraints, one limiting the energy consumption (as assumed previously) and one restricting the uncertainty in output spike sequences at given firing rate. Thus, the conditional maximization of firing-rate entropy (CMFE) solves a tradeoff between the energy cost and noise in neuronal response. In short, the CMFE sends a rich variety of information through broader communication bands (i.e., widely distributed firing rates) at the cost of accuracy. We demonstrate that the CMFE is reflected in the long-tailed, typically power law, distributions of inter-spike intervals obtained for the majority of recorded neurons. In other words, the power-law tails are more consistent with the CMFE rather than the MMI. Thus, we propose the mathematical principle by which cortical neurons may represent information about synaptic input into their output spike trains.'),
(85432, 2012, 'plos', 'Optimization of muscle activity for task-level goals predicts complex changes in limb forces across biomechanical contexts', 'McKay, J Lucas|Ting, Lena H', 'The Wallace H. Coulter Department of Biomedical Engineering, Emory University and the Georgia Institute of Technology, Atlanta, Georgia, United States of America.|The Wallace H. Coulter Department of Biomedical Engineering, Emory University and the Georgia Institute of Technology, Atlanta, Georgia, United States of America.', 'Georgia|Georgia', 36, 'Animals|Cats|Computer Simulation|Models, Neurological|Movement|Muscle Contraction|Muscle, Skeletal|Postural Balance|Posture|Task Performance and Analysis', 'Journal Article', '10.1371/journal.pcbi.1002465', '22511857', 'Optimality principles have been proposed as a general framework for understanding motor control in animals and humans largely based on their ability to predict general features movement in idealized motor tasks. However, generalizing these concepts past proof-of-principle to understand the neuromechanical transformation from task-level control to detailed execution-level muscle activity and forces during behaviorally-relevant motor tasks has proved difficult. In an unrestrained balance task in cats, we demonstrate that achieving task-level constraints center of mass forces and moments while minimizing control effort predicts detailed patterns of muscle activity and ground reaction forces in an anatomically-realistic musculoskeletal model. Whereas optimization is typically used to resolve redundancy at a single level of the motor hierarchy, we simultaneously resolved redundancy across both muscles and limbs and directly compared predictions to experimental measures across multiple perturbation directions that elicit different intra- and interlimb coordination patterns. Further, although some candidate task-level variables and cost functions generated indistinguishable predictions in a single biomechanical context, we identified a common optimization framework that could predict up to 48 experimental conditions per animal (n = 3) across both perturbation directions and different biomechanical contexts created by altering animals postural configuration. Predictions were further improved by imposing experimentally-derived muscle synergy constraints, suggesting additional task variables or costs that may be relevant to the neural control of balance. These results suggested that reduced-dimension neural control mechanisms such as muscle synergies can achieve similar kinetics to the optimal solution, but with increased control effort (xe2x89x882xc3x97) compared to individual muscle control. Our results are consistent with the idea that hierarchical, task-level neural control mechanisms previously associated with voluntary tasks may also be used in automatic brainstem-mediated pathways for balance.'),
(85433, 2012, 'plos', 'Differences in cell division rates drive the evolution of terminal differentiation in microbes', 'Rodrigues, João F Matias|Rankin, Daniel J|Rossetti, Valentina|Wagner, Andreas|Bagheri, Homayoun C', 'Institute of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland. joao.rodrigues@imls.uzh.ch|Institute of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland. joao.rodrigues@imls.uzh.ch|Institute of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland. joao.rodrigues@imls.uzh.ch|Institute of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland. joao.rodrigues@imls.uzh.ch|Institute of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland. joao.rodrigues@imls.uzh.ch', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 6, 'Cell Communication|Cell Differentiation|Cell Division|Clonal Evolution|Computer Simulation|Cyanobacteria|Models, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002468', '22511858', 'Multicellular differentiated organisms are composed of cells that begin by developing from a single pluripotent germ cell. In many organisms, a proportion of cells differentiate into specialized somatic cells. Whether these cells lose their pluripotency or are able to reverse their differentiated state has important consequences. Reversibly differentiated cells can potentially regenerate parts of an organism and allow reproduction through fragmentation. In many organisms, however, somatic differentiation is terminal, thereby restricting the developmental paths to reproduction. The reason why terminal differentiation is a common developmental strategy remains unexplored. To understand the conditions that affect the evolution of terminal versus reversible differentiation, we developed a computational model inspired by differentiating cyanobacteria. We simulated the evolution of a population of two cell types -nitrogen fixing or photosynthetic- that exchange resources. The traits that control differentiation rates between cell types are allowed to evolve in the model. Although the topology of cell interactions and differentiation costs play a role in the evolution of terminal and reversible differentiation, the most important factor is the difference in division rates between cell types. Faster dividing cells always evolve to become the germ line. Our results explain why most multicellular differentiated cyanobacteria have terminally differentiated cells, while some have reversibly differentiated cells. We further observed that symbioses involving two cooperating lineages can evolve under conditions where aggregate size, connectivity, and differentiation costs are high. This may explain why plants engage in symbiotic interactions with diazotrophic bacteria.'),
(85434, 2012, 'plos', 'The impact of imitation on vaccination behavior in social contact networks', 'Ndeffo Mbah, Martial L|Liu, Jingzhou|Bauch, Chris T|Tekel, Yonas I|Medlock, Jan|Meyers, Lauren Ancel|Galvani, Alison P', 'Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, United States of America. martial.ndeffo-mbah@yale.edu|Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, United States of America. martial.ndeffo-mbah@yale.edu|Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, United States of America. martial.ndeffo-mbah@yale.edu|Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, United States of America. martial.ndeffo-mbah@yale.edu|Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, United States of America. martial.ndeffo-mbah@yale.edu|Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, United States of America. martial.ndeffo-mbah@yale.edu|Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, United States of America. martial.ndeffo-mbah@yale.edu', 'United States|United States|United States|United States|United States|United States|United States', 75, 'Choice Behavior|Communicable Disease Control|Communicable Diseases|Computer Simulation|Humans|Imitative Behavior|Mass Vaccination|Models, Statistical|Population Dynamics|Social Behavior|Social Support', 'Journal Article', '10.1371/journal.pcbi.1002469', '22511859', 'Previous game-theoretic studies of vaccination behavior typically have often assumed that populations are homogeneously mixed and that individuals are fully rational. In reality, there is heterogeneity in the number of contacts per individual, and individuals tend to imitate others who appear to have adopted successful strategies. Here, we use network-based mathematical models to study the effects of both imitation behavior and contact heterogeneity on vaccination coverage and disease dynamics. We integrate contact network epidemiological models with a framework for decision-making, within which individuals make their decisions either based purely on payoff maximization or by imitating the vaccination behavior of a social contact. Simulations suggest that when the cost of vaccination is high imitation behavior may decrease vaccination coverage. However, when the cost of vaccination is small relative to that of infection, imitation behavior increases vaccination coverage, but, surprisingly, also increases the magnitude of epidemics through the clustering of non-vaccinators within the network. Thus, imitation behavior may impede the eradication of infectious diseases. Calculations that ignore behavioral clustering caused by imitation may significantly underestimate the levels of vaccination coverage required to attain herd immunity.'),
(85435, 2012, 'plos', 'Optimizing provider recruitment for influenza surveillance networks', 'Scarpino, Samuel V|Dimitrov, Nedialko B|Meyers, Lauren Ancel', 'The University of Texas at Austin, Section of Integrative Biology, Austin, Texas, United States of America. scarpino@utexas.edu|The University of Texas at Austin, Section of Integrative Biology, Austin, Texas, United States of America. scarpino@utexas.edu|The University of Texas at Austin, Section of Integrative Biology, Austin, Texas, United States of America. scarpino@utexas.edu', 'United States|United States|United States', 29, 'Community Networks|Computer Simulation|Data Mining|Disease Outbreaks|Humans|Influenza, Human|Internet|Models, Statistical|Population Surveillance', 'Journal Article', '10.1371/journal.pcbi.1002472', '22511860', 'The increasingly complex and rapid transmission dynamics of many infectious diseases necessitates the use of new, more advanced methods for surveillance, early detection, and decision-making. Here, we demonstrate that a new method for optimizing surveillance networks can improve the quality of epidemiological information produced by typical provider-based networks. Using past surveillance and Internet search data, it determines the precise locations where providers should be enrolled. When applied to redesigning the provider-based, influenza-like-illness surveillance network (ILINet) for the state of Texas, the method identifies networks that are expected to significantly outperform the existing network with far fewer providers. This optimized network avoids informational redundancies and is thereby more effective than networks designed by conventional methods and a recently published algorithm based on maximizing population coverage. We show further that Google Flu Trends data, when incorporated into a network as a virtual provider, can enhance but not replace traditional surveillance methods.'),
(85436, 2012, 'plos', 'Impact of adaptation currents on synchronization of coupled exponential integrate-and-fire neurons', 'Ladenbauer, Josef|Augustin, Moritz|Shiau, LieJune|Obermayer, Klaus', 'Department of Software Engineering and Theoretical Computer Science, Technische Universität Berlin, Berlin, Germany. jl@ni.tu-berlin.de|Department of Software Engineering and Theoretical Computer Science, Technische Universität Berlin, Berlin, Germany. jl@ni.tu-berlin.de|Department of Software Engineering and Theoretical Computer Science, Technische Universität Berlin, Berlin, Germany. jl@ni.tu-berlin.de|Department of Software Engineering and Theoretical Computer Science, Technische Universität Berlin, Berlin, Germany. jl@ni.tu-berlin.de', 'Germany|Germany|Germany|Germany', 30, 'Action Potentials|Adaptation, Physiological|Animals|Computer Simulation|Humans|Membrane Potentials|Models, Neurological|Nerve Net|Neuronal Plasticity|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002478', '22511861', 'The ability of spiking neurons to synchronize their activity in a network depends on the response behavior of these neurons as quantified by the phase response curve (PRC) and on coupling properties. The PRC characterizes the effects of transient inputs on spike timing and can be measured experimentally. Here we use the adaptive exponential integrate-and-fire (aEIF) neuron model to determine how subthreshold and spike-triggered slow adaptation currents shape the PRC. Based on that, we predict how synchrony and phase locked states of coupled neurons change in presence of synaptic delays and unequal coupling strengths. We find that increased subthreshold adaptation currents cause a transition of the PRC from only phase advances to phase advances and delays in response to excitatory perturbations. Increased spike-triggered adaptation currents on the other hand predominantly skew the PRC to the right. Both adaptation induced changes of the PRC are modulated by spike frequency, being more prominent at lower frequencies. Applying phase reduction theory, we show that subthreshold adaptation stabilizes synchrony for pairs of coupled excitatory neurons, while spike-triggered adaptation causes locking with a small phase difference, as long as synaptic heterogeneities are negligible. For inhibitory pairs synchrony is stable and robust against conduction delays, and adaptation can mediate bistability of in-phase and anti-phase locking. We further demonstrate that stable synchrony and bistable in/anti-phase locking of pairs carry over to synchronization and clustering of larger networks. The effects of adaptation in aEIF neurons on PRCs and network dynamics qualitatively reflect those of biophysical adaptation currents in detailed Hodgkin-Huxley-based neurons, which underscores the utility of the aEIF model for investigating the dynamical behavior of networks. Our results suggest neuronal spike frequency adaptation as a mechanism synchronizing low frequency oscillations in local excitatory networks, but indicate that inhibition rather than excitation generates coherent rhythms at higher frequencies.'),
(85437, 2012, 'plos', 'Establishment and validation of computational model for MT1-MMP dependent ECM degradation and intervention strategies', 'Hoshino, Daisuke|Koshikawa, Naohiko|Suzuki, Takashi|Quaranta, Vito|Weaver, Alissa M|Seiki, Motoharu|Ichikawa, Kazuhisa', 'Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.|Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.|Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.|Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.|Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.|Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.|Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.', 'Japan|Japan|Japan|Japan|Japan|Japan|Japan', 43, 'Animals|Carcinoma, Squamous Cell|Cell Line, Tumor|Cell Membrane|Computer Simulation|Extracellular Matrix|Matrix Metalloproteinase 14|Models, Biological|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002479', '22511862', 'MT1-MMP is a potent invasion-promoting membrane protease employed by aggressive cancer cells. MT1-MMP localizes preferentially at membrane protrusions called invadopodia where it plays a central role in degradation of the surrounding extracellular matrix (ECM). Previous reports suggested a role for a continuous supply of MT1-MMP in ECM degradation. However, the turnover rate of MT1-MMP and the extent to which the turnover contributes to the ECM degradation at invadopodia have not been clarified. To approach this problem, we first performed FRAP (Fluorescence Recovery after Photobleaching) experiments with fluorescence-tagged MT1-MMP focusing on a single invadopodium and found very rapid recovery in FRAP signals, approximated by double-exponential plots with time constants of 26 s and 259 s. The recovery depended primarily on vesicle transport, but negligibly on lateral diffusion. Next we constructed a computational model employing the observed kinetics of the FRAP experiments. The simulations successfully reproduced our FRAP experiments. Next we inhibited the vesicle transport both experimentally, and in simulation. Addition of drugs inhibiting vesicle transport blocked ECM degradation experimentally, and the simulation showed no appreciable ECM degradation under conditions inhibiting vesicle transport. In addition, the degree of the reduction in ECM degradation depended on the degree of the reduction in the MT1-MMP turnover. Thus, our experiments and simulations have established the role of the rapid turnover of MT1-MMP in ECM degradation at invadopodia. Furthermore, our simulations suggested synergetic contributions of proteolytic activity and the MT1-MMP turnover to ECM degradation because there was a nonlinear and marked reduction in ECM degradation if both factors were reduced simultaneously. Thus our computational model provides a new in silico tool to design and evaluate intervention strategies in cancer cell invasion.'),
(85438, 2012, 'plos', 'Mapping the environmental fitness landscape of a synthetic gene circuit', 'Nevozhay, Dmitry|Adams, Rhys M|Van Itallie, Elizabeth|Bennett, Matthew R|Balázsi, Gábor', 'Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Chromosome Mapping|Computer Simulation|Drug Resistance, Microbial|Gene-Environment Interaction|Genes, Synthetic|Models, Genetic|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins', 'Journal Article', '10.1371/journal.pcbi.1002480', '22511863', 'Gene expression actualizes the organismal phenotypes encoded within the genome in an environment-dependent manner. Among all encoded phenotypes, cell population growth rate (fitness) is perhaps the most important, since it determines how well-adapted a genotype is in various environments. Traditional biological measurement techniques have revealed the connection between the environment and fitness based on the gene expression mean. Yet, recently it became clear that cells with identical genomes exposed to the same environment can differ dramatically from the population average in their gene expression and division rate (individual fitness). For cell populations with bimodal gene expression, this difference is particularly pronounced, and may involve stochastic transitions between two cellular states that form distinct sub-populations. Currently it remains unclear how a cell populations growth rate and its subpopulation fractions emerge from the molecular-level kinetics of gene networks and the division rates of single cells. To address this question we developed and quantitatively characterized an inducible, bistable synthetic gene circuit controlling the expression of a bifunctional antibiotic resistance gene in Saccharomyces cerevisiae. Following fitness and fluorescence measurements in two distinct environments (inducer alone and antibiotic alone), we applied a computational approach to predict cell population fitness and subpopulation fractions in the combination of these environments based on stochastic cellular movement in gene expression space and fitness space. We found that knowing the fitness and nongenetic (cellular) memory associated with specific gene expression states were necessary for predicting the overall fitness of cell populations in combined environments. We validated these predictions experimentally and identified environmental conditions that defined a sweet spot of drug resistance. These findings may provide a roadmap for connecting the molecular-level kinetics of gene networks to cell population fitness in well-defined environments, and may have important implications for phenotypic variability of drug resistance in natural settings.'),
(85439, 2012, 'plos', 'Genome-scale modeling of light-driven reductant partitioning and carbon fluxes in diazotrophic unicellular cyanobacterium Cyanothece sp ATCC 51142', 'Vu, Trang T|Stolyar, Sergey M|Pinchuk, Grigoriy E|Hill, Eric A|Kucek, Leo A|Brown, Roslyn N|Lipton, Mary S|Osterman, Andrei|Fredrickson, Jim K|Konopka, Allan E|Beliaev, Alexander S|Reed, Jennifer L', 'Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Bacterial Proteins|Carbon Cycle|Computer Simulation|Cyanothece|Genome|Light|Models, Biological|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002460', '22529767', 'Genome-scale metabolic models have proven useful for answering fundamental questions about metabolic capabilities of a variety of microorganisms, as well as informing their metabolic engineering. However, only a few models are available for oxygenic photosynthetic microorganisms, particularly in cyanobacteria in which photosynthetic and respiratory electron transport chains (ETC) share components. We addressed the complexity of cyanobacterial ETC by developing a genome-scale model for the diazotrophic cyanobacterium, Cyanothece sp. ATCC 51142. The resulting metabolic reconstruction, iCce806, consists of 806 genes associated with 667 metabolic reactions and includes a detailed representation of the ETC and a biomass equation based on experimental measurements. Both computational and experimental approaches were used to investigate light-driven metabolism in Cyanothece sp. ATCC 51142, with a particular focus on reductant production and partitioning within the ETC. The simulation results suggest that growth and metabolic flux distributions are substantially impacted by the relative amounts of light going into the individual photosystems. When growth is limited by the flux through photosystem I, terminal respiratory oxidases are predicted to be an important mechanism for removing excess reductant. Similarly, under photosystem II flux limitation, excess electron carriers must be removed via cyclic electron transport. Furthermore, in silico calculations were in good quantitative agreement with the measured growth rates whereas predictions of reaction usage were qualitatively consistent with protein and mRNA expression data, which we used to further improve the resolution of intracellular flux values.'),
(85440, 2012, 'plos', 'Non-additive coupling enables propagation of synchronous spiking activity in purely random networks', 'Memmesheimer, Raoul-Martin|Timme, Marc', 'Department for Neuroinformatics, Radboud University Nijmegen, Nijmegen, Netherlands. r.memmesheimer@science.ru.nl|Department for Neuroinformatics, Radboud University Nijmegen, Nijmegen, Netherlands. r.memmesheimer@science.ru.nl', 'Netherlands|Netherlands', 11, 'Action Potentials|Animals|Computer Simulation|Humans|Models, Neurological|Models, Statistical|Nerve Net|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002384', '22532791', 'Despite the current debate about the computational role of experimentally observed precise spike patterns it is still theoretically unclear under which conditions and how they may emerge in neural circuits. Here, we study spiking neural networks with non-additive dendritic interactions that were recently uncovered in single-neuron experiments. We show that supra-additive dendritic interactions enable the persistent propagation of synchronous activity already in purely random networks without superimposed structures and explain the mechanism underlying it. This study adds a novel perspective on the dynamics of networks with nonlinear interactions in general and presents a new viable mechanism for the occurrence of patterns of precisely timed spikes in recurrent networks.'),
(85441, 2012, 'plos', 'Exploration of multi-state conformational dynamics and underlying global functional landscape of maltose binding protein', 'Wang, Yong|Tang, Chun|Wang, Erkang|Wang, Jin', 'State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, China.|State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, China.|State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, China.|State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, China.', 'China|China|China|China', 38, 'Computer Simulation|Maltose-Binding Proteins|Models, Chemical|Models, Molecular|Protein Conformation|Protein Structure, Tertiary', 'Journal Article', '10.1371/journal.pcbi.1002471', '22532792', 'An increasing number of biological machines have been revealed to have more than two macroscopic states. Quantifying the underlying multiple-basin functional landscape is essential for understanding their functions. However, the present models seem to be insufficient to describe such multiple-state systems. To meet this challenge, we have developed a coarse grained triple-basin structure-based model with implicit ligand. Based on our model, the constructed functional landscape is sufficiently sampled by the brute-force molecular dynamics simulation. We explored maltose-binding protein (MBP) which undergoes large-scale domain motion between open, apo-closed (partially closed) and holo-closed (fully closed) states responding to ligand binding. We revealed an underlying mechanism whereby major induced fit and minor population shift pathways co-exist by quantitative flux analysis. We found that the hinge regions play an important role in the functional dynamics as well as that increases in its flexibility promote population shifts. This finding provides a theoretical explanation of the mechanistic discrepancies in PBP protein family. We also found a functional backtracking behavior that favors conformational change. We further explored the underlying folding landscape in response to ligand binding. Consistent with earlier experimental findings, the presence of ligand increases the cooperativity and stability of MBP. This work provides the first study to explore the folding dynamics and functional dynamics under the same theoretical framework using our triple-basin functional model.'),
(85442, 2012, 'plos', 'Ligand-dependent conformations and dynamics of the serotonin 5-HT(2A) receptor determine its activation and membrane-driven oligomerization properties', 'Shan, Jufang|Khelashvili, George|Mondal, Sayan|Mehler, Ernest L|Weinstein, Harel', 'Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, United States of America.|Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, United States of America.|Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, United States of America.|Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, United States of America.|Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Binding Sites|Cell Membrane|Computer Simulation|Ketanserin|Ligands|Lysergic Acid Diethylamide|Models, Chemical|Models, Molecular|Protein Binding|Protein Conformation|Receptor, Serotonin, 5-HT2A|Serotonin|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1002473', '22532793', 'From computational simulations of a serotonin 2A receptor (5-HT(2A)R) model complexed with pharmacologically and structurally diverse ligands we identify different conformational states and dynamics adopted by the receptor bound to the full agonist 5-HT, the partial agonist LSD, and the inverse agonist Ketanserin. The results from the unbiased all-atom molecular dynamics (MD) simulations show that the three ligands affect differently the known GPCR activation elements including the toggle switch at W6.48, the changes in the ionic lock between E6.30 and R3.50 of the DRY motif in TM3, and the dynamics of the NPxxY motif in TM7. The computational results uncover a sequence of steps connecting these experimentally-identified elements of GPCR activation. The differences among the properties of the receptor molecule interacting with the ligands correlate with their distinct pharmacological properties. Combining these results with quantitative analysis of membrane deformation obtained with our new method (Mondal et al, Biophysical Journal 2011), we show that distinct conformational rearrangements produced by the three ligands also elicit different responses in the surrounding membrane. The differential reorganization of the receptor environment is reflected in (i)-the involvement of cholesterol in the activation of the 5-HT(2A)R, and (ii)-different extents and patterns of membrane deformations. These findings are discussed in the context of their likely functional consequences and a predicted mechanism of ligand-specific GPCR oligomerization.'),
(85443, 2012, 'plos', 'Persisting viral sequences shape microbial CRISPR-based immunity', 'Weinberger, Ariel D|Sun, Christine L|Plucixc5x84ski, Mateusz M|Denef, Vincent J|Thomas, Brian C|Horvath, Philippe|Barrangou, Rodolphe|Gilmore, Michael S|Getz, Wayne M|Banfield, Jillian F', 'Biophysics Graduate Group, University of California, Berkeley, California, United States of America. ariel_weinberger@meei.harvard.edu|Biophysics Graduate Group, University of California, Berkeley, California, United States of America. ariel_weinberger@meei.harvard.edu|Biophysics Graduate Group, University of California, Berkeley, California, United States of America. ariel_weinberger@meei.harvard.edu|Biophysics Graduate Group, University of California, Berkeley, California, United States of America. ariel_weinberger@meei.harvard.edu|Biophysics Graduate Group, University of California, Berkeley, California, United States of America. ariel_weinberger@meei.harvard.edu|Biophysics Graduate Group, University of California, Berkeley, California, United States of America. ariel_weinberger@meei.harvard.edu|Biophysics Graduate Group, University of California, Berkeley, California, United States of America. ariel_weinberger@meei.harvard.edu|Biophysics Graduate Group, University of California, Berkeley, California, United States of America. ariel_weinberger@meei.harvard.edu|Biophysics Graduate Group, University of California, Berkeley, California, United States of America. ariel_weinberger@meei.harvard.edu|Biophysics Graduate Group, University of California, Berkeley, California, United States of America. ariel_weinberger@meei.harvard.edu', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Computer Simulation|Genetics, Population|Immunogenetic Phenomena|Inverted Repeat Sequences|Models, Genetic|Models, Immunological|Virus Physiological Phenomena', 'Journal Article', '10.1371/journal.pcbi.1002475', '22532794', 'Well-studied innate immune systems exist throughout bacteria and archaea, but a more recently discovered genomic locus may offer prokaryotes surprising immunological adaptability. Mediated by a cassette-like genomic locus termed Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), the microbial adaptive immune system differs from its eukaryotic immune analogues by incorporating new immunities unidirectionally. CRISPR thus stores genomically recoverable timelines of virus-host coevolution in natural organisms refractory to laboratory cultivation. Here we combined a population genetic mathematical model of CRISPR-virus coevolution with six years of metagenomic sequencing to link the recoverable genomic dynamics of CRISPR loci to the unknown population dynamics of virus and host in natural communities. Metagenomic reconstructions in an acid-mine drainage system document CRISPR loci conserving ancestral immune elements to the base-pair across thousands of microbial generations. This trailer-end conservation occurs despite rapid viral mutation and despite rapid prokaryotic genomic deletion. The trailer-ends of many reconstructed CRISPR loci are also largely identical across a population. Trailer-end clonality occurs despite predictions of host immunological diversity due to negative frequency dependent selection (kill the winner dynamics). Statistical clustering and model simulations explain this lack of diversity by capturing rapid selective sweeps by highly immune CRISPR lineages. Potentially explaining trailer-end conservation, we record the first example of a viral bloom overwhelming a CRISPR system. The polyclonal viruses bloom even though they share sequences previously targeted by host CRISPR loci. Simulations show how increasing random genomic deletions in CRISPR loci purges immunological controls on long-lived viral sequences, allowing polyclonal viruses to bloom and depressing host fitness. Our results thus link documented patterns of genomic conservation in CRISPR loci to an evolutionary advantage against persistent viruses. By maintaining old immunities, selection may be tuning CRISPR-mediated immunity against viruses reemerging from lysogeny or migration.'),
(85444, 2012, 'plos', 'Computational design of a PDZ domain peptide inhibitor that rescues CFTR activity', 'Roberts, Kyle E|Cushing, Patrick R|Boisguerin, Prisca|Madden, Dean R|Donald, Bruce R', 'Department of Computer Science, Duke University, Durham, North Carolina, United States of America.|Department of Computer Science, Duke University, Durham, North Carolina, United States of America.|Department of Computer Science, Duke University, Durham, North Carolina, United States of America.|Department of Computer Science, Duke University, Durham, North Carolina, United States of America.|Department of Computer Science, Duke University, Durham, North Carolina, United States of America.', 'United States|United States|United States|United States|United States', 82, 'Binding Sites|Carrier Proteins|Computer Simulation|Cystic Fibrosis Transmembrane Conductance Regulator|Drug Design|Membrane Proteins|Models, Chemical|Models, Molecular|PDZ Domains|Peptides|Protein Binding', 'Journal Article', '10.1371/journal.pcbi.1002477', '22532795', 'The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial chloride channel mutated in patients with cystic fibrosis (CF). The most prevalent CFTR mutation, xcex94F508, blocks folding in the endoplasmic reticulum. Recent work has shown that some xcex94F508-CFTR channel activity can be recovered by pharmaceutical modulators (potentiators and correctors), but xcex94F508-CFTR can still be rapidly degraded via a lysosomal pathway involving the CFTR-associated ligand (CAL), which binds CFTR via a PDZ interaction domain. We present a study that goes from theory, to new structure-based computational design algorithms, to computational predictions, to biochemical testing and ultimately to epithelial-cell validation of novel, effective CAL PDZ inhibitors (called stabilizers) that rescue xcex94F508-CFTR activity. To design the stabilizers, we extended our structural ensemble-based computational protein redesign algorithm K* to encompass protein-protein and protein-peptide interactions. The computational predictions achieved high accuracy: all of the top-predicted peptide inhibitors bound well to CAL. Furthermore, when compared to state-of-the-art CAL inhibitors, our design methodology achieved higher affinity and increased binding efficiency. The designed inhibitor with the highest affinity for CAL (kCAL01) binds six-fold more tightly than the previous best hexamer (iCAL35), and 170-fold more tightly than the CFTR C-terminus. We show that kCAL01 has physiological activity and can rescue chloride efflux in CF patient-derived airway epithelial cells. Since stabilizers address a different cellular CF defect from potentiators and correctors, our inhibitors provide an additional therapeutic pathway that can be used in conjunction with current methods.'),
(85445, 2012, 'plos', 'Inference of genotype-phenotype relationships in the antigenic evolution of human influenza A (H3N2) viruses', 'Steinbrück, Lars|McHardy, Alice Carolyn', 'Department for Algorithmic Bioinformatics, Heinrich Heine University, Düsseldorf, Germany.|Department for Algorithmic Bioinformatics, Heinrich Heine University, Düsseldorf, Germany.', 'Germany|Germany', 0, 'Antigens, Viral|Chromosome Mapping|Computer Simulation|Evolution, Molecular|Genotype|Hemagglutinins|Influenza A Virus, H3N2 Subtype|Models, Genetic|Phenotype', 'Journal Article', '10.1371/journal.pcbi.1002492', '22532796', 'Distinguishing mutations that determine an organisms phenotype from (near-) neutral hitchhikers is a fundamental challenge in genome research, and is relevant for numerous medical and biotechnological applications. For human influenza viruses, recognizing changes in the antigenic phenotype and a strains capability to evade pre-existing host immunity is important for the production of efficient vaccines. We have developed a method for inferring antigenic trees for the major viral surface protein hemagglutinin. In the antigenic tree, antigenic weights are assigned to all tree branches, which allows us to resolve the antigenic impact of the associated amino acid changes. Our technique predicted antigenic distances with comparable accuracy to antigenic cartography. Additionally, it identified both known and novel sites, and amino acid changes with antigenic impact in the evolution of influenza A (H3N2) viruses from 1968 to 2003. The technique can also be applied for inference of phenotype trees and genotype-phenotype relationships from other types of pairwise phenotype distances.'),
(85446, 2012, 'plos', 'The emergence and early evolution of biological carbon-fixation', 'Braakman, Rogier|Smith, Eric', 'Santa Fe Institute, Santa Fe, New Mexico, United States of America.|Santa Fe Institute, Santa Fe, New Mexico, United States of America.', 'Mexico|Mexico', 81, 'Animals|Carbon Cycle|Computer Simulation|Evolution, Molecular|Humans|Models, Genetic|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002455', '22536150', 'The fixation of COxe2x82x82 into living matter sustains all life on Earth, and embeds the biosphere within geochemistry. The six known chemical pathways used by extant organisms for this function are recognized to have overlaps, but their evolution is incompletely understood. Here we reconstruct the complete early evolutionary history of biological carbon-fixation, relating all modern pathways to a single ancestral form. We find that innovations in carbon-fixation were the foundation for most major early divergences in the tree of life. These findings are based on a novel method that fully integrates metabolic and phylogenetic constraints. Comparing gene-profiles across the metabolic cores of deep-branching organisms and requiring that they are capable of synthesizing all their biomass components leads to the surprising conclusion that the most common form for deep-branching autotrophic carbon-fixation combines two disconnected sub-networks, each supplying carbon to distinct biomass components. One of these is a linear folate-based pathway of COxe2x82x82 reduction previously only recognized as a fixation route in the complete Wood-Ljungdahl pathway, but which more generally may exclude the final step of synthesizing acetyl-CoA. Using metabolic constraints we then reconstruct a phylometabolic tree with a high degree of parsimony that traces the evolution of complete carbon-fixation pathways, and has a clear structure down to the root. This tree requires few instances of lateral gene transfer or convergence, and instead suggests a simple evolutionary dynamic in which all divergences have primary environmental causes. Energy optimization and oxygen toxicity are the two strongest forces of selection. The root of this tree combines the reductive citric acid cycle and the Wood-Ljungdahl pathway into a single connected network. This linked network lacks the selective optimization of modern fixation pathways but its redundancy leads to a more robust topology, making it more plausible than any modern pathway as a primitive universal ancestral form.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85447, 2012, 'plos', 'The effects of NMDA subunit composition on calcium influx and spike timing-dependent plasticity in striatal medium spiny neurons', 'Evans, Rebekah C|Morera-Herreras, Teresa|Cui, Yihui|Du, Kai|Sheehan, Tom|Kotaleski, Jeanette Hellgren|Venance, Laurent|Blackwell, Kim T', 'George Mason University, The Krasnow Institute for Advanced Study, MS 2A1, Fairfax, Virginia, United States of America.|George Mason University, The Krasnow Institute for Advanced Study, MS 2A1, Fairfax, Virginia, United States of America.|George Mason University, The Krasnow Institute for Advanced Study, MS 2A1, Fairfax, Virginia, United States of America.|George Mason University, The Krasnow Institute for Advanced Study, MS 2A1, Fairfax, Virginia, United States of America.|George Mason University, The Krasnow Institute for Advanced Study, MS 2A1, Fairfax, Virginia, United States of America.|George Mason University, The Krasnow Institute for Advanced Study, MS 2A1, Fairfax, Virginia, United States of America.|George Mason University, The Krasnow Institute for Advanced Study, MS 2A1, Fairfax, Virginia, United States of America.|George Mason University, The Krasnow Institute for Advanced Study, MS 2A1, Fairfax, Virginia, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Action Potentials|Animals|Calcium|Computer Simulation|Corpus Striatum|Humans|Models, Chemical|Models, Neurological|N-Methylaspartate|Neuronal Plasticity|Neurons|Protein Subunits|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1002493', '22536151', 'Calcium through NMDA receptors (NMDARs) is necessary for the long-term potentiation (LTP) of synaptic strength, however, NMDARs differ in several properties that can influence the amount of calcium influx into the spine. These properties, such as sensitivity to magnesium block and conductance decay kinetics, change the receptors response to spike timing dependent plasticity (STDP) protocols, and thereby shape synaptic integration and information processing. This study investigates the role of GluN2 subunit differences on spine calcium concentration during several STDP protocols in a model of a striatal medium spiny projection neuron (MSPN). The multi-compartment, multi-channel model exhibits firing frequency, spike width, and latency to first spike similar to current clamp data from mouse dorsal striatum MSPN. We find that NMDAR-mediated calcium is dependent on GluN2 subunit type, action potential timing, duration of somatic depolarization, and number of action potentials. Furthermore, the model demonstrates that in MSPNs, GluN2A and GluN2B control which STDP intervals allow for substantial calcium elevation in spines. The model predicts that blocking GluN2B subunits would modulate the range of intervals that cause long term potentiation. We confirmed this prediction experimentally, demonstrating that blocking GluN2B in the striatum, narrows the range of STDP intervals that cause long term potentiation. This ability of the GluN2 subunit to modulate the shape of the STDP curve could underlie the role that GluN2 subunits play in learning and development.'),
(85448, 2012, 'plos', 'Geometric theory predicts bifurcations in minimal wiring cost trees in biology are flat', 'Kim, Yihwa|Sinclair, Robert|Chindapol, Nol|Kaandorp, Jaap A|De Schutter, Erik', 'Computational Neuroscience Unit, Okinawa Institute of Science and Technology, Okinawa, Japan.|Computational Neuroscience Unit, Okinawa Institute of Science and Technology, Okinawa, Japan.|Computational Neuroscience Unit, Okinawa Institute of Science and Technology, Okinawa, Japan.|Computational Neuroscience Unit, Okinawa Institute of Science and Technology, Okinawa, Japan.|Computational Neuroscience Unit, Okinawa Institute of Science and Technology, Okinawa, Japan.', 'Japan|Japan|Japan|Japan|Japan', 12, 'Animals|Anthozoa|Computer Simulation|Models, Anatomic|Models, Biological|Morphogenesis', 'Journal Article', '10.1371/journal.pcbi.1002474', '22557937', 'The complex three-dimensional shapes of tree-like structures in biology are constrained by optimization principles, but the actual costs being minimized can be difficult to discern. We show that despite quite variable morphologies and functions, bifurcations in the scleractinian coral Madracis and in many different mammalian neuron types tend to be planar. We prove that in fact bifurcations embedded in a spatial tree that minimizes wiring cost should lie on planes. This biologically motivated generalization of the classical mathematical theory of Euclidean Steiner trees is compatible with many different assumptions about the type of cost function. Since the geometric proof does not require any correlation between consecutive planes, we predict that, in an environment without directional biases, consecutive planes would be oriented independently of each other. We confirm this is true for many branching corals and neuron types. We conclude that planar bifurcations are characteristic of wiring cost optimization in any type of biological spatial tree structure.'),
(85449, 2012, 'plos', 'Storage of correlated patterns in standard and bistable Purkinje cell models', 'Clopath, Claudia|Nadal, Jean-Pierre|Brunel, Nicolas', 'Laboratory of Neurophysics and Physiology, CNRS and Université Paris Descartes, Paris, France. claudia.clopath@parisdescartes.fr|Laboratory of Neurophysics and Physiology, CNRS and Université Paris Descartes, Paris, France. claudia.clopath@parisdescartes.fr|Laboratory of Neurophysics and Physiology, CNRS and Université Paris Descartes, Paris, France. claudia.clopath@parisdescartes.fr', 'France|France|France', 0, 'Action Potentials|Animals|Computer Simulation|Humans|Information Storage and Retrieval|Memory|Models, Neurological|Pattern Recognition, Physiological|Purkinje Cells|Statistics as Topic', 'Journal Article', '10.1371/journal.pcbi.1002448', '22570592', 'The cerebellum has long been considered to undergo supervised learning, with climbing fibers acting as a teaching or error signal. Purkinje cells (PCs), the sole output of the cerebellar cortex, have been considered as analogs of perceptrons storing input/output associations. In support of this hypothesis, a recent study found that the distribution of synaptic weights of a perceptron at maximal capacity is in striking agreement with experimental data in adult rats. However, the calculation was performed using random uncorrelated inputs and outputs. This is a clearly unrealistic assumption since sensory inputs and motor outputs carry a substantial degree of temporal correlations. In this paper, we consider a binary output neuron with a large number of inputs, which is required to store associations between temporally correlated sequences of binary inputs and outputs, modelled as Markov chains. Storage capacity is found to increase with both input and output correlations, and diverges in the limit where both go to unity. We also investigate the capacity of a bistable output unit, since PCs have been shown to be bistable in some experimental conditions. Bistability is shown to enhance storage capacity whenever the output correlation is stronger than the input correlation. Distribution of synaptic weights at maximal capacity is shown to be independent on correlations, and is also unaffected by the presence of bistability.'),
(85450, 2012, 'plos', 'Deconvolution of the cellular force-generating subsystems that govern cytokinesis furrow ingression', 'Poirier, Christopher C|Ng, Win Pin|Robinson, Douglas N|Iglesias, Pablo A', 'Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.', 'United States|United States|United States|United States', 39, 'Cell Size|Computer Simulation|Cytokinesis|Cytoskeleton|Dictyostelium|Models, Biological|Molecular Motor Proteins|Myosin Type II|Stress, Mechanical', 'Journal Article', '10.1371/journal.pcbi.1002467', '22570593', 'Cytokinesis occurs through the coordinated action of several biochemically-mediated stresses acting on the cytoskeleton. Here, we develop a computational model of cellular mechanics, and using a large number of experimentally measured biophysical parameters, we simulate cell division under a number of different scenarios. We demonstrate that traction-mediated protrusive forces or contractile forces due to myosin II are sufficient to initiate furrow ingression. Furthermore, we show that passive forces due to the cells cortical tension and surface curvature allow the furrow to complete ingression. We compare quantitatively the furrow thinning trajectories obtained from simulation with those observed experimentally in both wild-type and myosin II null Dictyostelium cells. Our simulations highlight the relative contributions of different biomechanical subsystems to cell shape progression during cell division.'),
(85451, 2012, 'plos', 'Determinants of sexual network structure and their impact on cumulative network measures', 'Schmid, Boris V|Kretzschmar, Mirjam', 'Unit Epidemiology & Surveillance, Centre for Infectious Disease Control, National Institute of Public Health and the Environment-RIVM, Bilthoven, The Netherlands. Boris.Schmid@gmail.com|Unit Epidemiology & Surveillance, Centre for Infectious Disease Control, National Institute of Public Health and the Environment-RIVM, Bilthoven, The Netherlands. Boris.Schmid@gmail.com', 'Netherlands|Netherlands', 0, 'Carrier State|Chlamydia Infections|Computer Simulation|Contact Tracing|Humans|Models, Statistical|Prevalence|Sexual Behavior|Social Support|United Kingdom', 'Journal Article', '10.1371/journal.pcbi.1002470', '22570594', 'There are four major quantities that are measured in sexual behavior surveys that are thought to be especially relevant for the performance of sexual network models in terms of disease transmission. These are (i) the cumulative distribution of lifetime number of partners, (ii) the distribution of partnership durations, (iii) the distribution of gap lengths between partnerships, and (iv) the number of recent partners. Fitting a network model to these quantities as measured in sexual behavior surveys is expected to result in a good description of Chlamydia trachomatis transmission in terms of the heterogeneity of the distribution of infection in the population. Here we present a simulation model of a sexual contact network, in which we explored the role of behavioral heterogeneity of simulated individuals on the ability of the model to reproduce population-level sexual survey data from the Netherlands and UK. We find that a high level of heterogeneity in the ability of individuals to acquire and maintain (additional) partners strongly facilitates the ability of the model to accurately simulate the powerlaw-like distribution of the lifetime number of partners, and the age at which these partnerships were accumulated, as surveyed in actual sexual contact networks. Other sexual network features, such as the gap length between partnerships and the partnership duration, could-at the current level of detail of sexual survey data against which they were compared-be accurately modeled by a constant value (for transitional concurrency) and by exponential distributions (for partnership duration). Furthermore, we observe that epidemiological measures on disease prevalence in survey data can be used as a powerful tool for building accurate sexual contact networks, as these measures provide information on the level of mixing between individuals of different levels of sexual activity in the population, a parameter that is hard to acquire through surveying individuals.'),
(85452, 2012, 'plos', 'Modeling planarian regeneration: a primer for reverse-engineering the worm', 'Lobo, Daniel|Beane, Wendy S|Levin, Michael', 'Center for Regenerative and Developmental Biology, and Department of Biology, Tufts University, Medford, Massachusetts, United States of America.|Center for Regenerative and Developmental Biology, and Department of Biology, Tufts University, Medford, Massachusetts, United States of America.|Center for Regenerative and Developmental Biology, and Department of Biology, Tufts University, Medford, Massachusetts, United States of America.', 'United States|United States|United States', 56, 'Animals|Annelida|Models, Biological|Regeneration', 'Journal Article', '10.1371/journal.pcbi.1002481', '22570595', 'A mechanistic understanding of robust self-assembly and repair capabilities of complex systems would have enormous implications for basic evolutionary developmental biology as well as for transformative applications in regenerative biomedicine and the engineering of highly fault-tolerant cybernetic systems. Molecular biologists are working to identify the pathways underlying the remarkable regenerative abilities of model species that perfectly regenerate limbs, brains, and other complex body parts. However, a profound disconnect remains between the deluge of high-resolution genetic and protein data on pathways required for regeneration, and the desired spatial, algorithmic models that show how self-monitoring and growth control arise from the synthesis of cellular activities. This barrier to progress in the understanding of morphogenetic controls may be breached by powerful techniques from the computational sciences-using non-traditional modeling approaches to reverse-engineer systems such as planaria: flatworms with a complex bodyplan and nervous system that are able to regenerate any body part after traumatic injury. Currently, the involvement of experts from outside of molecular genetics is hampered by the specialist literature of molecular developmental biology: impactful collaborations across such different fields require that review literature be available that presents the key functional capabilities of important biological model systems while abstracting away from the often irrelevant and confusing details of specific genes and proteins. To facilitate modeling efforts by computer scientists, physicists, engineers, and mathematicians, we present a different kind of review of planarian regeneration. Focusing on the main patterning properties of this system, we review what is known about the signal exchanges that occur during regenerative repair in planaria and the cellular mechanisms that are thought to underlie them. By establishing an engineering-like style for reviews of the molecular developmental biology of biomedically important model systems, significant fresh insights and quantitative computational models will be developed by new collaborations between biology and the information sciences.'),
(85453, 2012, 'plos', 'Exploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis', 'Gaudet, Suzanne|Spencer, Sabrina L|Chen, William W|Sorger, Peter K', 'Department of Cancer Biology and Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. suzanne_gaudet@dfci.harvard.edu|Department of Cancer Biology and Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. suzanne_gaudet@dfci.harvard.edu|Department of Cancer Biology and Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. suzanne_gaudet@dfci.harvard.edu|Department of Cancer Biology and Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. suzanne_gaudet@dfci.harvard.edu', 'United States|United States|United States|United States', 0, 'Adaptation, Physiological|Animals|Apoptosis|Apoptosis Regulatory Proteins|Computer Simulation|Humans|Models, Biological|TNF-Related Apoptosis-Inducing Ligand|Tumor Necrosis Factor-alpha', 'Journal Article', '10.1371/journal.pcbi.1002482', '22570596', 'Stochastic fluctuations in gene expression give rise to cell-to-cell variability in protein levels which can potentially cause variability in cellular phenotype. For TRAIL (TNF-related apoptosis-inducing ligand) variability manifests itself as dramatic differences in the time between ligand exposure and the sudden activation of the effector caspases that kill cells. However, the contribution of individual proteins to phenotypic variability has not been explored in detail. In this paper we use feature-based sensitivity analysis as a means to estimate the impact of variation in key apoptosis regulators on variability in the dynamics of cell death. We use Monte Carlo sampling from measured protein concentration distributions in combination with a previously validated ordinary differential equation model of apoptosis to simulate the dynamics of receptor-mediated apoptosis. We find that variation in the concentrations of some proteins matters much more than variation in others and that precisely which proteins matter depends both on the concentrations of other proteins and on whether correlations in protein levels are taken into account. A prediction from simulation that we confirm experimentally is that variability in fate is sensitive to even small increases in the levels of Bcl-2. We also show that sensitivity to Bcl-2 levels is itself sensitive to the levels of interacting proteins. The contextual dependency is implicit in the mathematical formulation of sensitivity, but our data show that it is also important for biologically relevant parameter values. Our work provides a conceptual and practical means to study and understand the impact of cell-to-cell variability in protein expression levels on cell fate using deterministic models and sampling from parameter distributions.'),
(85454, 2012, 'plos', 'Testing biochemistry revisited: how in vivo metabolism can be understood from in vitro enzyme kinetics', 'van Eunen, Karen|Kiewiet, José A L|Westerhoff, Hans V|Bakker, Barbara M', 'Department of Molecular Cell Physiology, VU University Amsterdam, Amsterdam, The Netherlands.|Department of Molecular Cell Physiology, VU University Amsterdam, Amsterdam, The Netherlands.|Department of Molecular Cell Physiology, VU University Amsterdam, Amsterdam, The Netherlands.|Department of Molecular Cell Physiology, VU University Amsterdam, Amsterdam, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands', 57, 'Cell Proliferation|Cell Survival|Computer Simulation|Enzymes|Fungal Proteins|Glycolysis|Models, Biological|Signal Transduction|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1002483', '22570597', 'A decade ago, a team of biochemists including two of us, modeled yeast glycolysis and showed that one of the most studied biochemical pathways could not be quite understood in terms of the kinetic properties of the constituent enzymes as measured in cell extract. Moreover, when the same model was later applied to different experimental steady-state conditions, it often exhibited unrestrained metabolite accumulation.Here we resolve this issue by showing that the results of such ab initio modeling are improved substantially by (i) including appropriate allosteric regulation and (ii) measuring the enzyme kinetic parameters under conditions that resemble the intracellular environment. The following modifications proved crucial: (i) implementation of allosteric regulation of hexokinase and pyruvate kinase, (ii) implementation of V(max) values measured under conditions that resembled the yeast cytosol, and (iii) redetermination of the kinetic parameters of glyceraldehyde-3-phosphate dehydrogenase under physiological conditions.Model predictions and experiments were compared under five different conditions of yeast growth and starvation. When either the original model was used (which lacked important allosteric regulation), or the enzyme parameters were measured under conditions that were, as usual, optimal for high enzyme activity, fructose 1,6-bisphosphate and some other glycolytic intermediates tended to accumulate to unrealistically high concentrations. Combining all adjustments yielded an accurate correspondence between model and experiments for all five steady-state and dynamic conditions. This enhances our understanding of in vivo metabolism in terms of in vitro biochemistry.'),
(85455, 2012, 'plos', 'Theoretical analysis of competing conformational transitions in superhelical DNA', 'Zhabinskaya, Dina|Benham, Craig J', 'UC Davis Genome Center, University of California, Davis, California, United States of America. dzhabinskaya@ucdavis.edu|UC Davis Genome Center, University of California, Davis, California, United States of America. dzhabinskaya@ucdavis.edu', 'United States|United States', 0, 'Base Sequence|Computer Simulation|DNA, Superhelical|Models, Chemical|Models, Molecular|Molecular Sequence Data|Nucleic Acid Conformation', 'Journal Article', '10.1371/journal.pcbi.1002484', '22570598', 'We develop a statistical mechanical model to analyze the competitive behavior of transitions to multiple alternate conformations in a negatively supercoiled DNA molecule of kilobase length and specified base sequence. Since DNA superhelicity topologically couples together the transition behaviors of all base pairs, a unified model is required to analyze all the transitions to which the DNA sequence is susceptible. Here we present a first model of this type. Our numerical approach generalizes the strategy of previously developed algorithms, which studied superhelical transitions to a single alternate conformation. We apply our multi-state model to study the competition between strand separation and B-Z transitions in superhelical DNA. We show this competition to be highly sensitive to temperature and to the imposed level of supercoiling. Comparison of our results with experimental data shows that, when the energetics appropriate to the experimental conditions are used, the competition between these two transitions is accurately captured by our algorithm. We analyze the superhelical competition between B-Z transitions and denaturation around the c-myc oncogene, where both transitions are known to occur when this gene is transcribing. We apply our model to explore the correlation between stress-induced transitions and transcriptional activity in various organisms. In higher eukaryotes we find a strong enhancement of Z-forming regions immediately 5 to their transcription start sites (TSS), and a depletion of strand separating sites in a broad region around the TSS. The opposite patterns occur around transcript end locations. We also show that susceptibility to each type of transition is different in eukaryotes and prokaryotes. By analyzing a set of untranscribed pseudogenes we show that the Z-susceptibility just downstream of the TSS is not preserved, suggesting it may be under selection pressure.'),
(85456, 2012, 'plos', 'Microarray analysis of LTR retrotransposon silencing identifies Hdac1 as a regulator of retrotransposon expression in mouse embryonic stem cells', 'Reichmann, Judith|Crichton, James H|Madej, Monika J|Taggart, Mary|Gautier, Philippe|Garcia-Perez, Jose Luis|Meehan, Richard R|Adams, Ian R', 'MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.|MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.|MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.|MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.|MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.|MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.|MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.|MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Animals|Cells, Cultured|Embryonic Stem Cells|Gene Expression Profiling|Gene Expression Regulation, Developmental|Gene Silencing|Histone Deacetylase 1|Interspersed Repetitive Sequences|Mice|Oligonucleotide Array Sequence Analysis|Regulatory Sequences, Nucleic Acid|Retroelements', 'Journal Article', '10.1371/journal.pcbi.1002486', '22570599', 'Retrotransposons are highly prevalent in mammalian genomes due to their ability to amplify in pluripotent cells or developing germ cells. Host mechanisms that silence retrotransposons in germ cells and pluripotent cells are important for limiting the accumulation of the repetitive elements in the genome during evolution. However, although silencing of selected individual retrotransposons can be relatively well-studied, many mammalian retrotransposons are seldom analysed and their silencing in germ cells, pluripotent cells or somatic cells remains poorly understood. Here we show, and experimentally verify, that cryptic repetitive element probes present in Illumina and Affymetrix gene expression microarray platforms can accurately and sensitively monitor repetitive element expression data. This computational approach to genome-wide retrotransposon expression has allowed us to identify the histone deacetylase Hdac1 as a component of the retrotransposon silencing machinery in mouse embryonic stem cells, and to determine the retrotransposon targets of Hdac1 in these cells. We also identify retrotransposons that are targets of other retrotransposon silencing mechanisms such as DNA methylation, Eset-mediated histone modification, and Ring1B/Eed-containing polycomb repressive complexes in mouse embryonic stem cells. Furthermore, our computational analysis of retrotransposon silencing suggests that multiple silencing mechanisms are independently targeted to retrotransposons in embryonic stem cells, that different genomic copies of the same retrotransposon can be differentially sensitive to these silencing mechanisms, and helps define retrotransposon sequence elements that are targeted by silencing machineries. Thus repeat annotation of gene expression microarray data suggests that a complex interplay between silencing mechanisms represses retrotransposon loci in germ cells and embryonic stem cells.'),
(85457, 2012, 'plos', 'Rise and demise of bioinformatics? Promise and progress', 'Ouzounis, Christos A', 'Institute of Agrobiotechnology, Centre for Research & Technology Hellas-CERTH, Thessaloniki, Greece. ouzounis@certh.gr', 'Greece', 33, 'Computational Biology|Forecasting', 'Journal Article', '10.1371/journal.pcbi.1002487', '22570600', 'The field of bioinformatics and computational biology has gone through a number of transformations during the past 15 years, establishing itself as a key component of new biology. This spectacular growth has been challenged by a number of disruptive changes in science and technology. Despite the apparent fatigue of the linguistic use of the term itself, bioinformatics has grown perhaps to a point beyond recognition. We explore both historical aspects and future trends and argue that as the field expands, key questions remain unanswered and acquire new meaning while at the same time the range of applications is widening to cover an ever increasing number of biological disciplines. These trends appear to be pointing to a redefinition of certain objectives, milestones, and possibly the field itself.'),
(85458, 2012, 'plos', 'Predictive features of persistent activity emergence in regular spiking and intrinsic bursting model neurons', 'Sidiropoulou, Kyriaki|Poirazi, Panayiota', 'Institute of Molecular Biology and Biotechnology-IMBB, Foundation for Research and Technology-Hellas-FORTH, Heraklion, Crete, Greece.|Institute of Molecular Biology and Biotechnology-IMBB, Foundation for Research and Technology-Hellas-FORTH, Heraklion, Crete, Greece.', 'Greece|Greece', 0, 'Action Potentials|Biological Clocks|Computer Simulation|Humans|Memory|Models, Neurological|Neurons|Pyramidal Cells|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002489', '22570601', 'Proper functioning of working memory involves the expression of stimulus-selective persistent activity in pyramidal neurons of the prefrontal cortex (PFC), which refers to neural activity that persists for seconds beyond the end of the stimulus. The mechanisms which PFC pyramidal neurons use to discriminate between preferred vs. neutral inputs at the cellular level are largely unknown. Moreover, the presence of pyramidal cell subtypes with different firing patterns, such as regular spiking and intrinsic bursting, raises the question as to what their distinct role might be in persistent firing in the PFC. Here, we use a compartmental modeling approach to search for discriminatory features in the properties of incoming stimuli to a PFC pyramidal neuron and/or its response that signal which of these stimuli will result in persistent activity emergence. Furthermore, we use our modeling approach to study cell-type specific differences in persistent activity properties, via implementing a regular spiking (RS) and an intrinsic bursting (IB) model neuron. We identify synaptic location within the basal dendrites as a feature of stimulus selectivity. Specifically, persistent activity-inducing stimuli consist of activated synapses that are located more distally from the soma compared to non-inducing stimuli, in both model cells. In addition, the action potential (AP) latency and the first few inter-spike-intervals of the neuronal response can be used to reliably detect inducing vs. non-inducing inputs, suggesting a potential mechanism by which downstream neurons can rapidly decode the upcoming emergence of persistent activity. While the two model neurons did not differ in the coding features of persistent activity emergence, the properties of persistent activity, such as the firing pattern and the duration of temporally-restricted persistent activity were distinct. Collectively, our results pinpoint to specific features of the neuronal response to a given stimulus that code for its ability to induce persistent activity and predict differential roles of RS and IB neurons in persistent activity expression.'),
(85459, 2012, 'plos', 'Challenges and new approaches to proving the existence of muscle synergies of neural origin', 'Kutch, Jason J|Valero-Cuevas, Francisco J', 'Division of Biokinesiology & Physical Therapy, University of Southern California, Los Angeles, California, United States of America.|Division of Biokinesiology & Physical Therapy, University of Southern California, Los Angeles, California, United States of America.', 'United States|United States', 0, 'Animals|Computer Simulation|Feedback, Physiological|Humans|Models, Neurological|Movement|Muscle Contraction|Muscle, Skeletal|Postural Balance|Spinal Cord', 'Journal Article', '10.1371/journal.pcbi.1002434', '22570602', 'Muscle coordination studies repeatedly show low-dimensionality of muscle activations for a wide variety of motor tasks. The basis vectors of this low-dimensional subspace, termed muscle synergies, are hypothesized to reflect neurally-established functional muscle groupings that simplify body control. However, the muscle synergy hypothesis has been notoriously difficult to prove or falsify. We use cadaveric experiments and computational models to perform a crucial thought experiment and develop an alternative explanation of how muscle synergies could be observed without the nervous system having controlled muscles in groups. We first show that the biomechanics of the limb constrains musculotendon length changes to a low-dimensional subspace across all possible movement directions. We then show that a modest assumption--that each muscle is independently instructed to resist length change--leads to the result that electromyographic (EMG) synergies will arise without the need to conclude that they are a product of neural coupling among muscles. Finally, we show that there are dimensionality-reducing constraints in the isometric production of force in a variety of directions, but that these constraints are more easily controlled for, suggesting new experimental directions. These counter-examples to current thinking clearly show how experimenters could adequately control for the constraints described here when designing experiments to test for muscle synergies--but, to the best of our knowledge, this has not yet been done.'),
(85460, 2012, 'plos', 'Adhesion failures determine the pattern of choroidal neovascularization in the eye: a computer simulation study', 'Shirinifard, Abbas|Glazier, James Alexander|Swat, Maciej|Gens, J Scott|Family, Fereydoon|Jiang, Yi|Grossniklaus, Hans E', 'The Biocomplexity Institute and Department of Physics, Indiana University Bloomington, Bloomington, Indiana, United States of America. ashirini@indiana.edu|The Biocomplexity Institute and Department of Physics, Indiana University Bloomington, Bloomington, Indiana, United States of America. ashirini@indiana.edu|The Biocomplexity Institute and Department of Physics, Indiana University Bloomington, Bloomington, Indiana, United States of America. ashirini@indiana.edu|The Biocomplexity Institute and Department of Physics, Indiana University Bloomington, Bloomington, Indiana, United States of America. ashirini@indiana.edu|The Biocomplexity Institute and Department of Physics, Indiana University Bloomington, Bloomington, Indiana, United States of America. ashirini@indiana.edu|The Biocomplexity Institute and Department of Physics, Indiana University Bloomington, Bloomington, Indiana, United States of America. ashirini@indiana.edu|The Biocomplexity Institute and Department of Physics, Indiana University Bloomington, Bloomington, Indiana, United States of America. ashirini@indiana.edu', 'India|India|India|India|India|India|India', 23, 'Animals|Cell Adhesion|Choroid|Choroidal Neovascularization|Computer Simulation|Endothelial Cells|Focal Adhesions|Humans|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002440', '22570603', 'Choroidal neovascularization (CNV) of the macular area of the retina is the major cause of severe vision loss in adults. In CNV, after choriocapillaries initially penetrate Bruchs membrane (BrM), invading vessels may regress or expand (CNV initiation). Next, during Early and Late CNV, the expanding vasculature usually spreads in one of three distinct patterns: in a layer between BrM and the retinal pigment epithelium (sub-RPE or Type 1 CNV), in a layer between the RPE and the photoreceptors (sub-retinal or Type 2 CNV) or in both loci simultaneously (combined pattern or Type 3 CNV). While most studies hypothesize that CNV primarily results from growth-factor effects or holes in BrM, our three-dimensional simulations of multi-cell model of the normal and pathological maculae recapitulate the three growth patterns, under the hypothesis that CNV results from combinations of impairment of: 1) RPE-RPE epithelial junctional adhesion, 2) Adhesion of the RPE basement membrane complex to BrM (RPE-BrM adhesion), and 3) Adhesion of the RPE to the photoreceptor outer segments (RPE-POS adhesion). Our key findings are that when an endothelial tip cell penetrates BrM: 1) RPE with normal epithelial junctions, basal attachment to BrM and apical attachment to POS resists CNV. 2) Small holes in BrM do not, by themselves, initiate CNV. 3) RPE with normal epithelial junctions and normal apical RPE-POS adhesion, but weak adhesion to BrM (e.g. due to lipid accumulation in BrM) results in Early sub-RPE CNV. 4) Normal adhesion of RBaM to BrM, but reduced apical RPE-POS or epithelial RPE-RPE adhesion (e.g. due to inflammation) results in Early sub-retinal CNV. 5) Simultaneous reduction in RPE-RPE epithelial binding and RPE-BrM adhesion results in either sub-RPE or sub-retinal CNV which often progresses to combined pattern CNV. These findings suggest that defects in adhesion dominate CNV initiation and progression.'),
(85461, 2012, 'plos', 'Homeostatic scaling of excitability in recurrent neural networks', 'Remme, Michiel W H|Wadman, Wytse J', 'Center for Neurosciences, University of Amsterdam, Amsterdam, The Netherlands. michiel.remme@hu-berlin.de|Center for Neurosciences, University of Amsterdam, Amsterdam, The Netherlands. michiel.remme@hu-berlin.de', 'Netherlands|Netherlands', 18, 'Action Potentials|Animals|Biological Clocks|Computer Simulation|Excitatory Postsynaptic Potentials|Feedback, Physiological|Homeostasis|Humans|Models, Neurological|Nerve Net|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002494', '22570604', 'Neurons adjust their intrinsic excitability when experiencing a persistent change in synaptic drive. This process can prevent neural activity from moving into either a quiescent state or a saturated state in the face of ongoing plasticity, and is thought to promote stability of the network in which neurons reside. However, most neurons are embedded in recurrent networks, which require a delicate balance between excitation and inhibition to maintain network stability. This balance could be disrupted when neurons independently adjust their intrinsic excitability. Here, we study the functioning of activity-dependent homeostatic scaling of intrinsic excitability (HSE) in a recurrent neural network. Using both simulations of a recurrent network consisting of excitatory and inhibitory neurons that implement HSE, and a mean-field description of adapting excitatory and inhibitory populations, we show that the stability of such adapting networks critically depends on the relationship between the adaptation time scales of both neuron populations. In a stable adapting network, HSE can keep all neurons functioning within their dynamic range, while the network is undergoing several (patho)physiologically relevant types of plasticity, such as persistent changes in external drive, changes in connection strengths, or the loss of inhibitory cells from the network. However, HSE cannot prevent the unstable network dynamics that result when, due to such plasticity, recurrent excitation in the network becomes too strong compared to feedback inhibition. This suggests that keeping a neural network in a stable and functional state requires the coordination of distinct homeostatic mechanisms that operate not only by adjusting neural excitability, but also by controlling network connectivity.'),
(85462, 2012, 'plos', 'Modeling meiotic chromosomes indicates a size dependent contribution of telomere clustering and chromosome rigidity to homologue juxtaposition', 'Penfold, Christopher A|Brown, Paul E|Lawrence, Neil D|Goldman, Alastair S H', 'Department of Molecular Biology and Biotechnology, Krebs Institute, The University of Sheffield, Sheffield, United Kingdom.|Department of Molecular Biology and Biotechnology, Krebs Institute, The University of Sheffield, Sheffield, United Kingdom.|Department of Molecular Biology and Biotechnology, Krebs Institute, The University of Sheffield, Sheffield, United Kingdom.|Department of Molecular Biology and Biotechnology, Krebs Institute, The University of Sheffield, Sheffield, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Animals|Chromosome Pairing|Chromosomes, Fungal|Humans|Meiosis|Models, Chemical|Models, Genetic|Models, Molecular|Saccharomyces cerevisiae|Sequence Homology, Nucleic Acid|Structure-Activity Relationship|Telomere', 'Journal Article', '10.1371/journal.pcbi.1002496', '22570605', 'Meiosis is the cell division that halves the genetic component of diploid cells to form gametes or spores. To achieve this, meiotic cells undergo a radical spatial reorganisation of chromosomes. This reorganisation is a prerequisite for the pairing of parental homologous chromosomes and the reductional division, which halves the number of chromosomes in daughter cells. Of particular note is the change from a centromere clustered layout (Rabl configuration) to a telomere clustered conformation (bouquet stage). The contribution of the bouquet structure to homologous chromosome pairing is uncertain. We have developed a new in silico model to represent the chromosomes of Saccharomyces cerevisiae in space, based on a worm-like chain model constrained by attachment to the nuclear envelope and clustering forces. We have asked how these constraints could influence chromosome layout, with particular regard to the juxtaposition of homologous chromosomes and potential nonallelic, ectopic, interactions. The data support the view that the bouquet may be sufficient to bring short chromosomes together, but the contribution to long chromosomes is less. We also find that persistence length is critical to how much influence the bouquet structure could have, both on pairing of homologues and avoiding contacts with heterologues. This work represents an important development in computer modeling of chromosomes, and suggests new explanations for why elucidating the functional significance of the bouquet by genetics has been so difficult.'),
(85463, 2012, 'plos', 'Tension and robustness in multitasking cellular networks', 'Wong, Jeffrey V|Li, Bochong|You, Lingchong', 'Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.|Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.|Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.', 'United States|United States|United States', 7, 'Cell Communication|Cell Cycle|Computer Simulation|E2F Transcription Factors|Models, Biological|Retinoblastoma Protein', 'Journal Article', '10.1371/journal.pcbi.1002491', '22577355', 'Cellular networks multitask by exhibiting distinct, context-dependent dynamics. However, network states (parameters) that generate a particular dynamic are often sub-optimal for others, defining a source of tension between them. Though multitasking is pervasive, it is not clear where tension arises, what consequences it has, and how it is resolved. We developed a generic computational framework to examine the source and consequences of tension between pairs of dynamics exhibited by the well-studied RB-E2F switch regulating cell cycle entry. We found that tension arose from task-dependent shifts in parameters associated with network modules. Although parameter sets common to distinct dynamics did exist, tension reduced both their accessibility and resilience to perturbation, indicating a trade-off between one-size-fits-all solutions and robustness. With high tension, robustness can be preserved by dynamic shifting of modules, enabling the network to toggle between tasks, and by increasing network complexity, in this case by gene duplication. We propose that tension is a general constraint on the architecture and operation of multitasking biological networks. To this end, our work provides a framework to quantify the extent of tension between any network dynamics and how it affects network robustness. Such analysis would suggest new ways to interfere with network elements to elucidate the design principles of cellular networks.'),
(85464, 2012, 'plos', 'Social interaction, noise and antibiotic-mediated switches in the intestinal microbiota', 'Bucci, Vanni|Bradde, Serena|Biroli, Giulio|Xavier, Joao B', 'Program in Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. bucciv@mskcc.org|Program in Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. bucciv@mskcc.org|Program in Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. bucciv@mskcc.org|Program in Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. bucciv@mskcc.org', 'United States|United States|United States|United States', 0, 'Anti-Bacterial Agents|Cell Communication|Computer Simulation|Intestines|Models, Biological|Models, Statistical|Social Behavior', 'Journal Article', '10.1371/journal.pcbi.1002497', '22577356', 'The intestinal microbiota plays important roles in digestion and resistance against entero-pathogens. As with other ecosystems, its species composition is resilient against small disturbances but strong perturbations such as antibiotics can affect the consortium dramatically. Antibiotic cessation does not necessarily restore pre-treatment conditions and disturbed microbiota are often susceptible to pathogen invasion. Here we propose a mathematical model to explain how antibiotic-mediated switches in the microbiota composition can result from simple social interactions between antibiotic-tolerant and antibiotic-sensitive bacterial groups. We build a two-species (e.g. two functional-groups) model and identify regions of domination by antibiotic-sensitive or antibiotic-tolerant bacteria, as well as a region of multistability where domination by either group is possible. Using a new framework that we derived from statistical physics, we calculate the duration of each microbiota composition state. This is shown to depend on the balance between random fluctuations in the bacterial densities and the strength of microbial interactions. The singular value decomposition of recent metagenomic data confirms our assumption of grouping microbes as antibiotic-tolerant or antibiotic-sensitive in response to a single antibiotic. Our methodology can be extended to multiple bacterial groups and thus it provides an ecological formalism to help interpret the present surge in microbiome data.'),
(85465, 2012, 'plos', 'Are long-range structural correlations behind the aggregration phenomena of polyglutamine diseases?', 'Moradi, Mahmoud|Babin, Volodymyr|Roland, Christopher|Sagui, Celeste', 'Center for High Performance Simulations (CHiPS) and Department of Physics, North Carolina State University, Raleigh, North Carolina, USA.|Center for High Performance Simulations (CHiPS) and Department of Physics, North Carolina State University, Raleigh, North Carolina, USA.|Center for High Performance Simulations (CHiPS) and Department of Physics, North Carolina State University, Raleigh, North Carolina, USA.|Center for High Performance Simulations (CHiPS) and Department of Physics, North Carolina State University, Raleigh, North Carolina, USA.', 'United States|United States|United States|United States', 13, 'Amino Acid Sequence|Animals|Computer Simulation|Humans|Models, Chemical|Models, Molecular|Molecular Sequence Data|Neurodegenerative Diseases|Peptides|Protein Conformation|Statistics as Topic', 'Journal Article', '10.1371/journal.pcbi.1002501', '22577357', 'We have characterized the conformational ensembles of polyglutamine Qn peptides of various lengths n (ranging from 6 to 40), both with and without the presence of a C-terminal polyproline hexapeptide. For this, we used state-of-the-art molecular dynamics simulations combined with a novel statistical analysis to characterize the various properties of the backbone dihedral angles and secondary structural motifs of the glutamine residues. For Q40 (i.e., just above the pathological length xe2x89x8336 for Huntingtons disease), the equilibrium conformations of the monomer consist primarily of disordered, compact structures with non-negligible xcexb1-helical and turn content. We also observed a relatively small population of extended structures suitable for forming aggregates including xcexb2- and xcexb1-strands, and xcexb2- and xcexb1-hairpins. Most importantly, for Q40 we find that there exists a long-range correlation (ranging for at least 20 residues) among the backbone dihedral angles of the Q residues. For polyglutamine peptides below the pathological length, the population of the extended strands and hairpins is considerably smaller, and the correlations are short-range (at most 5 residues apart). Adding a C-terminal hexaproline to Q40 suppresses both the population of these rare motifs and the long-range correlation of the dihedral angles. We argue that the long-range correlation of the polyglutamine homopeptide, along with the presence of these rare motifs, could be responsible for its aggregation phenomena.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85466, 2012, 'plos', 'NIBBS-search for fast and accurate prediction of phenotype-biased metabolic systems', 'Schmidt, Matthew C|Rocha, Andrea M|Padmanabhan, Kanchana|Shpanskaya, Yekaterina|Banfield, Jill|Scott, Kathleen|Mihelcic, James R|Samatova, Nagiza F', 'Department of Computer Science, North Carolina State University, Raleigh, North Carolina, United States of America.|Department of Computer Science, North Carolina State University, Raleigh, North Carolina, United States of America.|Department of Computer Science, North Carolina State University, Raleigh, North Carolina, United States of America.|Department of Computer Science, North Carolina State University, Raleigh, North Carolina, United States of America.|Department of Computer Science, North Carolina State University, Raleigh, North Carolina, United States of America.|Department of Computer Science, North Carolina State University, Raleigh, North Carolina, United States of America.|Department of Computer Science, North Carolina State University, Raleigh, North Carolina, United States of America.|Department of Computer Science, North Carolina State University, Raleigh, North Carolina, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 3, 'Algorithms|Animals|Computer Simulation|Data Mining|Databases, Protein|Humans|Metabolome|Models, Biological|Periodicals as Topic|Phenotype|Protein Interaction Mapping|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002490', '22589706', 'Understanding of genotype-phenotype associations is important not only for furthering our knowledge on internal cellular processes, but also essential for providing the foundation necessary for genetic engineering of microorganisms for industrial use (e.g., production of bioenergy or biofuels). However, genotype-phenotype associations alone do not provide enough information to alter an organisms genome to either suppress or exhibit a phenotype. It is important to look at the phenotype-related genes in the context of the genome-scale network to understand how the genes interact with other genes in the organism. Identification of metabolic subsystems involved in the expression of the phenotype is one way of placing the phenotype-related genes in the context of the entire network. A metabolic system refers to a metabolic network subgraph, nodes are compounds and edges labels are the enzymes that catalyze the reaction. The metabolic subsystem could be part of a single metabolic pathway or span parts of multiple pathways. Arguably, comparative genome-scale metabolic network analysis is a promising strategy to identify these phenotype-related metabolic subsystems. Network Instance-Based Biased Subgraph Search (NIBBS) is a graph-theoretic method for genome-scale metabolic network comparative analysis that can identify metabolic systems that are statistically biased toward phenotype-expressing organismal networks. We set up experiments with target phenotypes like hydrogen production, TCA expression, and acid-tolerance. We show via extensive literature search that some of the resulting metabolic subsystems are indeed phenotype-related and formulate hypotheses for other systems in terms of their role in phenotype expression. NIBBS is also orders of magnitude faster than MULE, one of the most efficient maximal frequent subgraph mining algorithms that could be adjusted for this problem. Also, the set of phenotype-biased metabolic systems output by NIBBS comes very close to the set of phenotype-biased subgraphs output by an exact maximally-biased subgraph enumeration algorithm ( MBS-Enum ). The code (NIBBS and the module to visualize the identified subsystems) is available at http://freescience.org/cs/NIBBS.'),
(85467, 2012, 'plos', 'Intermittent motion in desert locusts: behavioural complexity in simple environments', 'Bazazi, Sepideh|Bartumeus, Frederic|Hale, Joseph J|Couzin, Iain D', 'Department of Zoology, University of Oxford, Oxford, United Kingdom. sbazazi@gmail.com|Department of Zoology, University of Oxford, Oxford, United Kingdom. sbazazi@gmail.com|Department of Zoology, University of Oxford, Oxford, United Kingdom. sbazazi@gmail.com|Department of Zoology, University of Oxford, Oxford, United Kingdom. sbazazi@gmail.com', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 51, 'Animals|Behavior, Animal|Computer Simulation|Crowding|Ecosystem|Gait|Grasshoppers|Locomotion|Models, Biological|Models, Statistical', 'Journal Article', '10.1371/journal.pcbi.1002498', '22589707', 'Animals can exhibit complex movement patterns that may be the result of interactions with their environment or may be directly the mechanism by which their behaviour is governed. In order to understand the drivers of these patterns we examine the movement behaviour of individual desert locusts in a homogenous experimental arena with minimal external cues. Locust motion is intermittent and we reveal that as pauses become longer, the probability that a locust changes direction from its previous direction of travel increases. Long pauses (of greater than 100 s) can be considered reorientation bouts, while shorter pauses (of less than 6 s) appear to act as periods of resting between displacements. We observe power-law behaviour in the distribution of move and pause lengths of over 1.5 orders of magnitude. While Lévy features do exist, locusts movement patterns are more fully described by considering moves, pauses and turns in combination. Further analysis reveals that these combinations give rise to two behavioural modes that are organized in time: local search behaviour (long exploratory pauses with short moves) and relocation behaviour (long displacement moves with shorter resting pauses). These findings offer a new perspective on how complex animal movement patterns emerge in nature.'),
(85468, 2012, 'plos', 'Virus capsid dissolution studied by microsecond molecular dynamics simulations', 'Larsson, Daniel S D|Liljas, Lars|van der Spoel, David', 'Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.|Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.|Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.', 'Sweden|Sweden|Sweden', 0, 'Binding Sites|Calcium|Capsid|Computer Simulation|Models, Biological|Models, Chemical|Models, Molecular|Molecular Conformation|Tobacco necrosis satellite virus', 'Journal Article', '10.1371/journal.pcbi.1002502', '22589708', 'Dissolution of many plant viruses is thought to start with swelling of the capsid caused by calcium removal following infection, but no high-resolution structures of swollen capsids exist. Here we have used microsecond all-atom molecular simulations to describe the dynamics of the capsid of satellite tobacco necrosis virus with and without the 92 structural calcium ions. The capsid expanded 2.5% upon removal of the calcium, in good agreement with experimental estimates. The water permeability of the native capsid was similar to that of a phospholipid membrane, but the permeability increased 10-fold after removing the calcium, predominantly between the 2-fold and 3-fold related subunits. The two calcium binding sites close to the icosahedral 3-fold symmetry axis were pivotal in the expansion and capsid-opening process, while the binding site on the 5-fold axis changed little structurally. These findings suggest that the dissociation of the capsid is initiated at the 3-fold axis.'),
(85469, 2012, 'plos', 'Prediction of drug-target interactions and drug repositioning via network-based inference', 'Cheng, Feixiong|Liu, Chuang|Jiang, Jing|Lu, Weiqiang|Li, Weihua|Liu, Guixia|Zhou, Weixing|Huang, Jin|Tang, Yun', 'Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.|Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.|Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.|Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.|Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.|Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.|Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.|Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.|Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.', 'China|China|China|China|China|China|China|China|China', 451, 'Binding Sites|Databases, Protein|Drug Delivery Systems|Drug Design|Pharmaceutical Preparations|Protein Binding|Proteins', 'Journal Article', '10.1371/journal.pcbi.1002503', '22589709', 'Drug-target interaction (DTI) is the basis of drug discovery and design. It is time consuming and costly to determine DTI experimentally. Hence, it is necessary to develop computational methods for the prediction of potential DTI. Based on complex network theory, three supervised inference methods were developed here to predict DTI and used for drug repositioning, namely drug-based similarity inference (DBSI), target-based similarity inference (TBSI) and network-based inference (NBI). Among them, NBI performed best on four benchmark data sets. Then a drug-target network was created with NBI based on 12,483 FDA-approved and experimental drug-target binary links, and some new DTIs were further predicted. In vitro assays confirmed that five old drugs, namely montelukast, diclofenac, simvastatin, ketoconazole, and itraconazole, showed polypharmacological features on estrogen receptors or dipeptidyl peptidase-IV with half maximal inhibitory or effective concentration ranged from 0.2 to 10 µM. Moreover, simvastatin and ketoconazole showed potent antiproliferative activities on human MDA-MB-231 breast cancer cell line in MTT assays. The results indicated that these methods could be powerful tools in prediction of DTIs and drug repositioning.'),
(85470, 2012, 'plos', 'Filament compliance influences cooperative activation of thin filaments and the dynamics of force production in skeletal muscle', 'Tanner, Bertrand C W|Daniel, Thomas L|Regnier, Michael', 'Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont, United States of America. btanner@uvm.edu|Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont, United States of America. btanner@uvm.edu|Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont, United States of America. btanner@uvm.edu', 'United States|United States|United States', 33, 'Actin Cytoskeleton|Animals|Calcium|Calcium Signaling|Computer Simulation|Humans|Models, Biological|Molecular Motor Proteins|Muscle Contraction|Muscle, Skeletal|Sarcomeres|Stress, Mechanical', 'Journal Article', '10.1371/journal.pcbi.1002506', '22589710', 'Striated muscle contraction is a highly cooperative process initiated by Caxc2xb2xe2x81xba binding to the troponin complex, which leads to tropomyosin movement and myosin cross-bridge (XB) formation along thin filaments. Experimental and computational studies suggest skeletal muscle fiber activation is greatly augmented by cooperative interactions between neighboring thin filament regulatory units (RU-RU cooperativity, 1 RUxe2x80x8a=xe2x80x8a7 actin monomers+1 troponin complex+1 tropomyosin molecule). XB binding can also amplify thin filament activation through interactions with RUs (XB-RU cooperativity). Because these interactions occur with a temporal order, they can be considered kinetic forms of cooperativity. Our previous spatially-explicit models illustrated that mechanical forms of cooperativity also exist, arising from XB-induced XB binding (XB-XB cooperativity). These mechanical and kinetic forms of cooperativity are likely coordinated during muscle contraction, but the relative contribution from each of these mechanisms is difficult to separate experimentally. To investigate these contributions we built a multi-filament model of the half sarcomere, allowing RU activation kinetics to vary with the state of neighboring RUs or XBs. Simulations suggest Caxc2xb2xe2x81xba binding to troponin activates a thin filament distance spanning 9 to 11 actins and coupled RU-RU interactions dominate the cooperative force response in skeletal muscle, consistent with measurements from rabbit psoas fibers. XB binding was critical for stabilizing thin filament activation, particularly at submaximal Caxc2xb2xe2x81xba levels, even though XB-RU cooperativity amplified force less than RU-RU cooperativity. Similar to previous studies, XB-XB cooperativity scaled inversely with lattice stiffness, leading to slower rates of force development as stiffness decreased. Including RU-RU and XB-RU cooperativity in this model resulted in the novel prediction that the force-[Caxc2xb2xe2x81xba] relationship can vary due to filament and XB compliance. Simulations also suggest kinetic forms of cooperativity occur rapidly and dominate early to get activation, while mechanical forms of cooperativity act more slowly, augmenting XB binding as force continues to develop.'),
(85471, 2012, 'plos', 'Modeling HIV-1 drug resistance as episodic directional selection', 'Murrell, Ben|de Oliveira, Tulio|Seebregts, Chris|Kosakovsky Pond, Sergei L|Scheffler, Konrad|Southern African Treatment and Resistance Network-SATuRN Consortium', 'Biomedical Informatics Research Division, eHealth Research and Innovation Platform, Medical Research Council, Tygerberg, South Africa.|Biomedical Informatics Research Division, eHealth Research and Innovation Platform, Medical Research Council, Tygerberg, South Africa.|Biomedical Informatics Research Division, eHealth Research and Innovation Platform, Medical Research Council, Tygerberg, South Africa.|Biomedical Informatics Research Division, eHealth Research and Innovation Platform, Medical Research Council, Tygerberg, South Africa.|Biomedical Informatics Research Division, eHealth Research and Innovation Platform, Medical Research Council, Tygerberg, South Africa.|Biomedical Informatics Research Division, eHealth Research and Innovation Platform, Medical Research Council, Tygerberg, South Africa.', 'South Africa|South Africa|South Africa|South Africa|South Africa|South Africa', 20, 'Anti-HIV Agents|Biological Evolution|Computer Simulation|Drug Resistance, Viral|Evolution, Molecular|Genetic Variation|HIV-1|Models, Genetic|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002507', '22589711', 'The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS) which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.'),
(85472, 2012, 'plos', 'Dynamic prestress in a globular protein', 'Edwards, Scott A|Wagner, Johannes|Gräter, Frauke', 'CAS-MPG Partner Institute and Key Laboratory for Computational Biology, Shanghai, China.|CAS-MPG Partner Institute and Key Laboratory for Computational Biology, Shanghai, China.|CAS-MPG Partner Institute and Key Laboratory for Computational Biology, Shanghai, China.', 'China|China|China', 0, 'Computer Simulation|Energy Transfer|Models, Chemical|Models, Molecular|Protein Conformation|Stress, Mechanical|Ubiquitin', 'Journal Article', '10.1371/journal.pcbi.1002509', '22589712', 'A protein at equilibrium is commonly thought of as a fully relaxed structure, with the intra-molecular interactions showing fluctuations around their energy minimum. In contrast, here we find direct evidence for a protein as a molecular tensegrity structure, comprising a balance of tensed and compressed interactions, a concept that has been put forward for macroscopic structures. We quantified the distribution of inter-residue prestress in ubiquitin and immunoglobulin from all-atom molecular dynamics simulations. The network of highly fluctuating yet significant inter-residue forces in proteins is a consequence of the intrinsic frustration of a protein when sampling its rugged energy landscape. In beta sheets, this balance of forces is found to compress the intra-strand hydrogen bonds. We estimate that the observed magnitude of this pre-compression is enough to induce significant changes in the hydrogen bond lifetimes, thus, prestress, which can be as high as a few 100 pN, can be considered a key factor in determining the unfolding kinetics and pathway of proteins under force. Strong pre-tension in certain salt bridges on the other hand is connected to the thermodynamic stability of ubiquitin. Effective force profiles between some side-chains reveal the signature of multiple, distinct conformational states, and such static disorder could be one factor explaining the growing body of experiments revealing non-exponential unfolding kinetics of proteins. The design of prestress distributions in engineering proteins promises to be a new tool for tailoring the mechanical properties of made-to-order nanomaterials.'),
(85473, 2012, 'plos', 'A spatial model of mosquito host-seeking behavior', 'Cummins, Bree|Cortez, Ricardo|Foppa, Ivo M|Walbeck, Justin|Hyman, James M', 'Mathematics Department, Tulane University, New Orleans, Louisiana, USA. bcummins@tulane.edu|Mathematics Department, Tulane University, New Orleans, Louisiana, USA. bcummins@tulane.edu|Mathematics Department, Tulane University, New Orleans, Louisiana, USA. bcummins@tulane.edu|Mathematics Department, Tulane University, New Orleans, Louisiana, USA. bcummins@tulane.edu|Mathematics Department, Tulane University, New Orleans, Louisiana, USA. bcummins@tulane.edu', 'United States|United States|United States|United States|United States', 35, 'Animals|Appetitive Behavior|Computer Simulation|Culicidae|Disease Vectors|Flight, Animal|Host-Parasite Interactions|Models, Biological|Smell|Wind', 'Journal Article', '10.1371/journal.pcbi.1002500', '22615546', 'Mosquito host-seeking behavior and heterogeneity in host distribution are important factors in predicting the transmission dynamics of mosquito-borne infections such as dengue fever, malaria, chikungunya, and West Nile virus. We develop and analyze a new mathematical model to describe the effect of spatial heterogeneity on the contact rate between mosquito vectors and hosts. The model includes odor plumes generated by spatially distributed hosts, wind velocity, and mosquito behavior based on both the prevailing wind and the odor plume. On a spatial scale of meters and a time scale of minutes, we compare the effectiveness of different plume-finding and plume-tracking strategies that mosquitoes could use to locate a host. The results show that two different models of chemotaxis are capable of producing comparable results given appropriate parameter choices and that host finding is optimized by a strategy of flying across the wind until the odor plume is intercepted. We also assess the impact of changing the level of host aggregation on mosquito host-finding success near the end of the host-seeking flight. When clusters of hosts are more tightly associated on smaller patches, the odor plume is narrower and the biting rate per host is decreased. For two host groups of unequal number but equal spatial density, the biting rate per host is lower in the group with more individuals, indicative of an attack abatement effect of host aggregation. We discuss how this approach could assist parameter choices in compartmental models that do not explicitly model the spatial arrangement of individuals and how the model could address larger spatial scales and other probability models for mosquito behavior, such as Lévy distributions.'),
(85474, 2012, 'plos', 'Insights into the fold organization of TIM barrel from interaction energy based structure networks', 'Vijayabaskar, M S|Vishveshwara, Saraswathi', 'Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.|Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.', 'India|India', 0, 'Amino Acid Sequence|Computer Simulation|Energy Transfer|Models, Chemical|Models, Molecular|Molecular Sequence Data|Protein Conformation|Protein Folding|Sequence Alignment|Sequence Analysis, Protein|Triose-Phosphate Isomerase', 'Journal Article', '10.1371/journal.pcbi.1002505', '22615547', 'There are many well-known examples of proteins with low sequence similarity, adopting the same structural fold. This aspect of sequence-structure relationship has been extensively studied both experimentally and theoretically, however with limited success. Most of the studies consider remote homology or sequence conservation as the basis for their understanding. Recently interaction energy based network formalism (Protein Energy Networks (PENs)) was developed to understand the determinants of protein structures. In this paper we have used these PENs to investigate the common non-covalent interactions and their collective features which stabilize the TIM barrel fold. We have also developed a method of aligning PENs in order to understand the spatial conservation of interactions in the fold. We have identified key common interactions responsible for the conservation of the TIM fold, despite high sequence dissimilarity. For instance, the central beta barrel of the TIM fold is stabilized by long-range high energy electrostatic interactions and low-energy contiguous vdW interactions in certain families. The other interfaces like the helix-sheet or the helix-helix seem to be devoid of any high energy conserved interactions. Conserved interactions in the loop regions around the catalytic site of the TIM fold have also been identified, pointing out their significance in both structural and functional evolution. Based on these investigations, we have developed a novel network based phylogenetic analysis for remote homologues, which can perform better than sequence based phylogeny. Such an analysis is more meaningful from both structural and functional evolutionary perspective. We believe that the information obtained through the interaction conservation viewpoint and the subsequently developed method of structure network alignment, can shed new light in the fields of fold organization and de novo computational protein design.'),
(85475, 2012, 'plos', 'Optimal control of saccades by spatial-temporal activity patterns in the monkey superior colliculus', 'Goossens, H H L M|van Opstal, A J', 'Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition, and Behaviour, Department of Cognitive Neuroscience, Section Biophysics, Nijmegen, The Netherlands. J.Goossens@donders.ru.nl|Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition, and Behaviour, Department of Cognitive Neuroscience, Section Biophysics, Nijmegen, The Netherlands. J.Goossens@donders.ru.nl', 'Netherlands|Netherlands', 0, 'Action Potentials|Animals|Computer Simulation|Feedback, Physiological|Macaca mulatta|Models, Neurological|Nerve Net|Neurons|Oculomotor Muscles|Recruitment, Neurophysiological|Saccades|Superior Colliculi', 'Journal Article', '10.1371/journal.pcbi.1002508', '22615548', 'A major challenge in computational neurobiology is to understand how populations of noisy, broadly-tuned neurons produce accurate goal-directed actions such as saccades. Saccades are high-velocity eye movements that have stereotyped, nonlinear kinematics, their duration increases with amplitude, while peak eye-velocity saturates for large saccades. Recent theories suggest that these characteristics reflect a deliberate strategy that optimizes a speed-accuracy tradeoff in the presence of signal-dependent noise in the neural control signals. Here we argue that the midbrain superior colliculus (SC), a key sensorimotor interface that contains a topographically-organized map of saccade vectors, is in an ideal position to implement such an optimization principle. Most models attribute the nonlinear saccade kinematics to saturation in the brainstem pulse generator downstream from the SC. However, there is little data to support this assumption. We now present new neurophysiological evidence for an alternative scheme, which proposes that these properties reside in the spatial-temporal dynamics of SC activity. As predicted by this scheme, we found a remarkably systematic organization in the burst properties of saccade-related neurons along the rostral-to-caudal (i.e., amplitude-coding) dimension of the SC motor map: peak firing-rates systematically decrease for cells encoding larger saccades, while burst durations and skewness increase, suggesting that this spatial gradient underlies the increase in duration and skewness of the eye velocity profiles with amplitude. We also show that all neurons in the recruited population synchronize their burst profiles, indicating that the burst-timing of each cell is determined by the planned saccade vector in which it participates, rather than by its anatomical location. Together with the observation that saccade-related SC cells indeed show signal-dependent noise, this precisely tuned organization of SC burst activity strongly supports the notion of an optimal motor-control principle embedded in the SC motor map as it fully accounts for the straight trajectories and kinematic nonlinearity of saccades.'),
(85476, 2012, 'plos', 'Google goes cancer: improving outcome prediction for cancer patients by network-based ranking of marker genes', 'Winter, Christof|Kristiansen, Glen|Kersting, Stephan|Roy, Janine|Aust, Daniela|Knösel, Thomas|Rümmele, Petra|Jahnke, Beatrix|Hentrich, Vera|Rückert, Felix|Niedergethmann, Marco|Weichert, Wilko|Bahra, Marcus|Schlitt, Hans J|Settmacher, Utz|Friess, Helmut|Büchler, Markus|Saeger, Hans-Detlev|Schroeder, Michael|Pilarsky, Christian|Grützmann, Robert', 'Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de|Department of Bioinformatics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany. winter@biotec.tu-dresden.de', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germ', 112, 'Biomarkers, Tumor|Genetic Markers|Genetic Predisposition to Disease|Humans|Male|Neural Networks (Computer)|Outcome Assessment (Health Care)|Pancreatic Neoplasms|Sensitivity and Specificity', 'Journal Article', '10.1371/journal.pcbi.1002511', '22615549', 'Predicting the clinical outcome of cancer patients based on the expression of marker genes in their tumors has received increasing interest in the past decade. Accurate predictors of outcome and response to therapy could be used to personalize and thereby improve therapy. However, state of the art methods used so far often found marker genes with limited prediction accuracy, limited reproducibility, and unclear biological relevance. To address this problem, we developed a novel computational approach to identify genes prognostic for outcome that couples gene expression measurements from primary tumor samples with a network of known relationships between the genes. Our approach ranks genes according to their prognostic relevance using both expression and network information in a manner similar to Googles PageRank. We applied this method to gene expression profiles which we obtained from 30 patients with pancreatic cancer, and identified seven candidate marker genes prognostic for outcome. Compared to genes found with state of the art methods, such as Pearson correlation of gene expression with survival time, we improve the prediction accuracy by up to 7%. Accuracies were assessed using support vector machine classifiers and Monte Carlo cross-validation. We then validated the prognostic value of our seven candidate markers using immunohistochemistry on an independent set of 412 pancreatic cancer samples. Notably, signatures derived from our candidate markers were independently predictive of outcome and superior to established clinical prognostic factors such as grade, tumor size, and nodal status. As the amount of genomic data of individual tumors grows rapidly, our algorithm meets the need for powerful computational approaches that are key to exploit these data for personalized cancer therapies in clinical practice.'),
(85477, 2012, 'plos', 'Mechanical stress inference for two dimensional cell arrays', 'Chiou, Kevin K|Hufnagel, Lars|Shraiman, Boris I', 'Department of Physics, University of California, Santa Barbara, California, USA.|Department of Physics, University of California, Santa Barbara, California, USA.|Department of Physics, University of California, Santa Barbara, California, USA.', 'United States|United States|United States', 0, 'Animals|Cell Adhesion|Cell Membrane|Computer Simulation|Epithelial Cells|Mechanotransduction, Cellular|Models, Biological|Morphogenesis|Pressure|Stress, Mechanical', 'Journal Article', '10.1371/journal.pcbi.1002512', '22615550', 'Many morphogenetic processes involve mechanical rearrangements of epithelial tissues that are driven by precisely regulated cytoskeletal forces and cell adhesion. The mechanical state of the cell and intercellular adhesion are not only the targets of regulation, but are themselves the likely signals that coordinate developmental process. Yet, because it is difficult to directly measure mechanical stress in vivo on sub-cellular scale, little is understood about the role of mechanics in development. Here we present an alternative approach which takes advantage of the recent progress in live imaging of morphogenetic processes and uses computational analysis of high resolution images of epithelial tissues to infer relative magnitude of forces acting within and between cells. We model intracellular stress in terms of bulk pressure and interfacial tension, allowing these parameters to vary from cell to cell and from interface to interface. Assuming that epithelial cell layers are close to mechanical equilibrium, we use the observed geometry of the two dimensional cell array to infer interfacial tensions and intracellular pressures. Here we present the mathematical formulation of the proposed Mechanical Inverse method and apply it to the analysis of epithelial cell layers observed at the onset of ventral furrow formation in the Drosophila embryo and in the process of hair-cell determination in the avian cochlea. The analysis reveals mechanical anisotropy in the former process and mechanical heterogeneity, correlated with cell differentiation, in the latter process. The proposed method opens a way for quantitative and detailed experimental tests of models of cell and tissue mechanics.'),
(85478, 2012, 'plos', 'Resolving the ortholog conjecture: orthologs tend to be weakly, but significantly, more similar in function than paralogs', 'Altenhoff, Adrian M|Studer, Romain A|Robinson-Rechavi, Marc|Dessimoz, Christophe', 'ETH Zurich, Department of Computer Science, Zürich, Switzerland.|ETH Zurich, Department of Computer Science, Zürich, Switzerland.|ETH Zurich, Department of Computer Science, Zürich, Switzerland.|ETH Zurich, Department of Computer Science, Zürich, Switzerland.', 'Switzerland|Switzerland|Switzerland|Switzerland', 99, 'Amino Acid Sequence|Computer Simulation|Evolution, Molecular|Models, Chemical|Models, Genetic|Molecular Sequence Data|Proteins|Sequence Analysis, Protein|Sequence Homology, Amino Acid|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1002514', '22615551', 'The function of most proteins is not determined experimentally, but is extrapolated from homologs. According to the ortholog conjecture, or standard model of phylogenomics, protein function changes rapidly after duplication, leading to paralogs with different functions, while orthologs retain the ancestral function. We report here that a comparison of experimentally supported functional annotations among homologs from 13 genomes mostly supports this model. We show that to analyze GO annotation effectively, several confounding factors need to be controlled: authorship bias, variation of GO term frequency among species, variation of background similarity among species pairs, and propagated annotation bias. After controlling for these biases, we observe that orthologs have generally more similar functional annotations than paralogs. This is especially strong for sub-cellular localization. We observe only a weak decrease in functional similarity with increasing sequence divergence. These findings hold over a large diversity of species, notably orthologs from model organisms such as E. coli, yeast or mouse have conserved function with human proteins.'),
(85479, 2012, 'plos', 'Proteome sampling by the HLA class I antigen processing pathway', 'Hoof, Ilka|van Baarle, Debbie|Hildebrand, William H|Kexc5x9fmir, Can', 'Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, The Netherlands. ilka.hoof@gmail.com|Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, The Netherlands. ilka.hoof@gmail.com|Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, The Netherlands. ilka.hoof@gmail.com|Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, The Netherlands. ilka.hoof@gmail.com', 'Netherlands|Netherlands|Netherlands|Netherlands', 20, 'Animals|Autoantigens|Computer Simulation|Genes, MHC Class I|HLA Antigens|Humans|Models, Immunological|Protein Binding|Proteome|Sample Size|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002517', '22615552', 'The peptide repertoire that is presented by the set of HLA class I molecules of an individual is formed by the different players of the antigen processing pathway and the stringent binding environment of the HLA class I molecules. Peptide elution studies have shown that only a subset of the human proteome is sampled by the antigen processing machinery and represented on the cell surface. In our study, we quantified the role of each factor relevant in shaping the HLA class I peptide repertoire by combining peptide elution data, in silico predictions of antigen processing and presentation, and data on gene expression and protein abundance. Our results indicate that gene expression level, protein abundance, and rate of potential binding peptides per protein have a clear impact on sampling probability. Furthermore, once a protein is available for the antigen processing machinery in sufficient amounts, C-terminal processing efficiency and binding affinity to the HLA class I molecule determine the identity of the presented peptides. Having studied the impact of each of these factors separately, we subsequently combined all factors in a logistic regression model in order to quantify their relative impact. This model demonstrated the superiority of protein abundance over gene expression level in predicting sampling probability. Being able to discriminate between sampled and non-sampled proteins to a significant degree, our approach can potentially be used to predict the sampling probability of self proteins and of pathogen-derived proteins, which is of importance for the identification of autoimmune antigens and vaccination targets.'),
(85480, 2012, 'plos', 'Reconstruction of genome-scale active metabolic networks for 69 human cell types and 16 cancer types using INIT', 'Agren, Rasmus|Bordel, Sergio|Mardinoglu, Adil|Pornputtapong, Natapol|Nookaew, Intawat|Nielsen, Jens', 'Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.|Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.|Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.|Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.|Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.|Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.', 'Sweden|Sweden|Sweden|Sweden|Sweden|Sweden', 0, 'Algorithms|Animals|Chromosome Mapping|Computer Simulation|Databases, Protein|Humans|Metabolome|Models, Biological|Neoplasms|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002518', '22615553', 'Development of high throughput analytical methods has given physicians the potential access to extensive and patient-specific data sets, such as gene sequences, gene expression profiles or metabolite footprints. This opens for a new approach in health care, which is both personalized and based on system-level analysis. Genome-scale metabolic networks provide a mechanistic description of the relationships between different genes, which is valuable for the analysis and interpretation of large experimental data-sets. Here we describe the generation of genome-scale active metabolic networks for 69 different cell types and 16 cancer types using the INIT (Integrative Network Inference for Tissues) algorithm. The INIT algorithm uses cell type specific information about protein abundances contained in the Human Proteome Atlas as the main source of evidence. The generated models constitute the first step towards establishing a Human Metabolic Atlas, which will be a comprehensive description (accessible online) of the metabolism of different human cell types, and will allow for tissue-level and organism-level simulations in order to achieve a better understanding of complex diseases. A comparative analysis between the active metabolic networks of cancer types and healthy cell types allowed for identification of cancer-specific metabolic features that constitute generic potential drug targets for cancer treatment.'),
(85481, 2012, 'plos', 'The layer-oriented approach to declarative languages for biological modeling', 'Raikov, Ivan|De Schutter, Erik', 'Okinawa Institute of Science and Technology, Onna-son, Okinawa, Japan. raikov@oist.jp|Okinawa Institute of Science and Technology, Onna-son, Okinawa, Japan. raikov@oist.jp', 'Japan|Japan', 7, 'Animals|Computational Biology|Computer Simulation|Humans|Models, Biological|Natural Language Processing|Programming Languages|Terminology as Topic', 'Journal Article', '10.1371/journal.pcbi.1002521', '22615554', 'We present a new approach to modeling languages for computational biology, which we call the layer-oriented approach. The approach stems from the observation that many diverse biological phenomena are described using a small set of mathematical formalisms (e.g. differential equations), while at the same time different domains and subdomains of computational biology require that models are structured according to the accepted terminology and classification of that domain. Our approach uses distinct semantic layers to represent the domain-specific biological concepts and the underlying mathematical formalisms. Additional functionality can be transparently added to the language by adding more layers. This approach is specifically concerned with declarative languages, and throughout the paper we note some of the limitations inherent to declarative approaches. The layer-oriented approach is a way to specify explicitly how high-level biological modeling concepts are mapped to a computational representation, while abstracting away details of particular programming languages and simulation environments. To illustrate this process, we define an example language for describing models of ionic currents, and use a general mathematical notation for semantic transformations to show how to generate model simulation code for various simulation environments. We use the example language to describe a Purkinje neuron model and demonstrate how the layer-oriented approach can be used for solving several practical issues of computational neuroscience model development. We discuss the advantages and limitations of the approach in comparison with other modeling language efforts in the domain of computational biology and outline some principles for extensible, flexible modeling language design. We conclude by describing in detail the semantic transformations defined for our language.'),
(85482, 2012, 'plos', 'Emergence of a small-world functional network in cultured neurons', 'Downes, Julia H|Hammond, Mark W|Xydas, Dimitris|Spencer, Matthew C|Becerra, Victor M|Warwick, Kevin|Whalley, Ben J|Nasuto, Slawomir J', 'School of Systems Engineering, University of Reading, Whiteknights, Reading, Berkshire, UK. j.downes@reading.ac.uk|School of Systems Engineering, University of Reading, Whiteknights, Reading, Berkshire, UK. j.downes@reading.ac.uk|School of Systems Engineering, University of Reading, Whiteknights, Reading, Berkshire, UK. j.downes@reading.ac.uk|School of Systems Engineering, University of Reading, Whiteknights, Reading, Berkshire, UK. j.downes@reading.ac.uk|School of Systems Engineering, University of Reading, Whiteknights, Reading, Berkshire, UK. j.downes@reading.ac.uk|School of Systems Engineering, University of Reading, Whiteknights, Reading, Berkshire, UK. j.downes@reading.ac.uk|School of Systems Engineering, University of Reading, Whiteknights, Reading, Berkshire, UK. j.downes@reading.ac.uk|School of Systems Engineering, University of Reading, Whiteknights, Reading, Berkshire, UK. j.downes@reading.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 79, 'Action Potentials|Animals|Cell Proliferation|Cells, Cultured|Computer Simulation|Humans|Models, Neurological|Models, Statistical|Nerve Net|Neurogenesis|Neurons', 'Journal Article', '10.1371/journal.pcbi.1002522', '22615555', 'The functional networks of cultured neurons exhibit complex network properties similar to those found in vivo. Starting from random seeding, cultures undergo significant reorganization during the initial period in vitro, yet despite providing an ideal platform for observing developmental changes in neuronal connectivity, little is known about how a complex functional network evolves from isolated neurons. In the present study, evolution of functional connectivity was estimated from correlations of spontaneous activity. Network properties were quantified using complex measures from graph theory and used to compare cultures at different stages of development during the first 5 weeks in vitro. Networks obtained from young cultures (14 days in vitro) exhibited a random topology, which evolved to a small-world topology during maturation. The topology change was accompanied by an increased presence of highly connected areas (hubs) and network efficiency increased with age. The small-world topology balances integration of network areas with segregation of specialized processing units. The emergence of such network structure in cultured neurons, despite a lack of external input, points to complex intrinsic biological mechanisms. Moreover, the functional network of cultures at mature ages is efficient and highly suited to complex processing tasks.'),
(85483, 2012, 'plos', 'Network topologies and dynamics leading to endotoxin tolerance and priming in innate immune cells', 'Fu, Yan|Glaros, Trevor|Zhu, Meng|Wang, Ping|Wu, Zhanghan|Tyson, John J|Li, Liwu|Xing, Jianhua', 'Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.|Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.|Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.|Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.|Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.|Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.|Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.|Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States', 0, 'Animals|Computer Simulation|Drug Tolerance|Endotoxins|Humans|Immunity, Innate|Lipopolysaccharides|Macrophages|Models, Immunological|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002526', '22615556', 'The innate immune system, acting as the first line of host defense, senses and adapts to foreign challenges through complex intracellular and intercellular signaling networks. Endotoxin tolerance and priming elicited by macrophages are classic examples of the complex adaptation of innate immune cells. Upon repetitive exposures to different doses of bacterial endotoxin (lipopolysaccharide) or other stimulants, macrophages show either suppressed or augmented inflammatory responses compared to a single exposure to the stimulant. Endotoxin tolerance and priming are critically involved in both immune homeostasis and the pathogenesis of diverse inflammatory diseases. However, the underlying molecular mechanisms are not well understood. By means of a computational search through the parameter space of a coarse-grained three-node network with a two-stage Metropolis sampling approach, we enumerated all the network topologies that can generate priming or tolerance. We discovered three major mechanisms for priming (pathway synergy, suppressor deactivation, activator induction) and one for tolerance (inhibitor persistence). These results not only explain existing experimental observations, but also reveal intriguing test scenarios for future experimental studies to clarify mechanisms of endotoxin priming and tolerance.');
