INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85135, 2011, 'plos', 'Signalling and the evolution of cooperative foraging in dynamic environments', 'Torney, Colin J|Berdahl, Andrew|Couzin, Iain D', 'Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America. ctorney@princeton.edu|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America. ctorney@princeton.edu|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America. ctorney@princeton.edu', 'Jersey|Jersey|Jersey', 35, 'Animal Communication|Animals|Appetitive Behavior|Biological Evolution|Computer Simulation|Cooperative Behavior|Feeding Behavior|Models, Biological|Swallows', 'Journal Article', '10.1371/journal.pcbi.1002194', '21966265', 'Understanding cooperation in animal social groups remains a significant challenge for evolutionary theory. Observed behaviours that benefit others but incur some cost appear incompatible with classical notions of natural selection, however, these behaviours may be explained by concepts such as inclusive fitness, reciprocity, intra-specific mutualism or manipulation. In this work, we examine a seemingly altruistic behaviour, the active recruitment of conspecifics to a food resource through signalling. Here collective, cooperative behaviour may provide highly nonlinear benefits to individuals, since group functionality has the potential to be far greater than the sum of the component parts, for example by enabling the effective tracking of a dynamic resource. We show that due to this effect, signalling to others is an evolutionarily stable strategy under certain environmental conditions, even when there is a cost associated to this behaviour. While exploitation is possible, in the limiting case of a sparse, ephemeral but locally abundant nutrient source, a given environmental profile will support a fixed number of signalling individuals. Through a quantitative analysis, this effective carrying capacity for cooperation is related to the characteristic length and time scales of the resource field.'),
(85136, 2011, 'plos', 'Dynamics and mechanical stability of the developing dorsoventral organizer of the wing imaginal disc', 'Canela-Xandri, Oriol|Sagués, Francesc|Casademunt, Jaume|Buceta, Javier', 'Computer Simulation and Modeling (Co.S.Mo.) Lab, Parc Científic de Barcelona, Barcelona, Spain.|Computer Simulation and Modeling (Co.S.Mo.) Lab, Parc Científic de Barcelona, Barcelona, Spain.|Computer Simulation and Modeling (Co.S.Mo.) Lab, Parc Científic de Barcelona, Barcelona, Spain.|Computer Simulation and Modeling (Co.S.Mo.) Lab, Parc Científic de Barcelona, Barcelona, Spain.', 'Spain|Spain|Spain|Spain', 0, 'Animals|Biomechanical Phenomena|Body Patterning|Cell Communication|Cell Cycle|Cell Proliferation|Computational Biology|Computer Simulation|Cytoskeleton|Drosophila|Imaginal Discs|Models, Biological|Mutation|Wings, Animal', 'Journal Article', '10.1371/journal.pcbi.1002153', '21980267', 'Shaping the primordia during development relies on forces and mechanisms able to control cell segregation. In the imaginal discs of Drosophila the cellular populations that will give rise to the dorsal and ventral parts on the wing blade are segregated and do not intermingle. A cellular population that becomes specified by the boundary of the dorsal and ventral cellular domains, the so-called organizer, controls this process. In this paper we study the dynamics and stability of the dorsal-ventral organizer of the wing imaginal disc of Drosophila as cell proliferation advances. Our approach is based on a vertex model to perform in silico experiments that are fully dynamical and take into account the available experimental data such as: cell packing properties, orientation of the cellular divisions, response upon membrane ablation, and robustness to mechanical perturbations induced by fast growing clones. Our results shed light on the complex interplay between the cytoskeleton mechanics, the cell cycle, the cell growth, and the cellular interactions in order to shape the dorsal-ventral organizer as a robust source of positional information and a lineage controller. Specifically, we elucidate the necessary and sufficient ingredients that enforce its functionality: distinctive mechanical properties, including increased tension, longer cell cycle duration, and a cleavage criterion that satisfies the Hertwig rule. Our results provide novel insights into the developmental mechanisms that drive the dynamics of the DV organizer and set a definition of the so-called Notch fence model in quantitative terms.'),
(85137, 2011, 'plos', 'A mathematical model of muscle containing heterogeneous half-sarcomeres exhibits residual force enhancement', 'Campbell, Stuart G|Hatfield, P Chris|Campbell, Kenneth S', 'Department of Physiology and the Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, United States of America. k.s.campbell@uky.edu|Department of Physiology and the Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, United States of America. k.s.campbell@uky.edu|Department of Physiology and the Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, United States of America. k.s.campbell@uky.edu', 'United States|United States|United States', 31, 'Animals|Biomechanical Phenomena|Computational Biology|Computer Simulation|Isometric Contraction|Models, Biological|Muscle Contraction|Muscle Fibers, Skeletal|Muscle, Skeletal|Sarcomeres|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002156', '21980268', 'A skeletal muscle fiber that is stimulated to contract and then stretched from Lxe2x82x81 to Lxe2x82x82 produces more force after the initial transient decays than if it is stimulated at Lxe2x82x82. This behavior has been well studied experimentally, and is known as residual force enhancement. The underlying mechanism remains controversial. We hypothesized that residual force enhancement could reflect mechanical interactions between heterogeneous half-sarcomeres. To test this hypothesis, we subjected a computational model of interacting heterogeneous half-sarcomeres to the same activation and stretch protocols that produce residual force enhancement in real preparations. Following a transient period of elevated force associated with active stretching, the model predicted a slowly decaying force enhancement lasting >30 seconds after stretch. Enhancement was on the order of 13% above isometric tension at the post-stretch muscle length, which agrees well with experimental measurements. Force enhancement in the model was proportional to stretch magnitude but did not depend strongly on the velocity of stretch, also in agreement with experiments. Even small variability in the strength of half-sarcomeres (2.1% standard deviation, normally distributed) was sufficient to produce a 5% force enhancement over isometric tension. Analysis of the model suggests that heterogeneity in half-sarcomeres leads to residual force enhancement by storing strain energy introduced during active stretch in distributions of bound cross-bridges. Complex interactions between the heterogeneous half-sarcomeres then dissipate this stored energy at a rate much slower than isolated cross-bridges would cycle. Given the variations in half-sarcomere length that have been observed in real muscle preparations and the stochastic variability inherent in all biological systems, half-sarcomere heterogeneity cannot be excluded as a contributing source of residual force enhancement.'),
(85138, 2011, 'plos', 'A model for the origin and properties of flicker-induced geometric phosphenes', 'Rule, Michael|Stoffregen, Matthew|Ermentrout, Bard', 'Department of Neuroscience, Brown University, Providence, Rhode Island, United States of America.|Department of Neuroscience, Brown University, Providence, Rhode Island, United States of America.|Department of Neuroscience, Brown University, Providence, Rhode Island, United States of America.', 'United States|United States|United States', 0, 'Computational Biology|Computer Simulation|Flicker Fusion|Hallucinations|Humans|Models, Neurological|Nerve Net|Phosphenes|Photic Stimulation|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1002158', '21980269', 'We present a model for flicker phosphenes, the spontaneous appearance of geometric patterns in the visual field when a subject is exposed to diffuse flickering light. We suggest that the phenomenon results from interaction of cortical lateral inhibition with resonant periodic stimuli. We find that the best temporal frequency for eliciting phosphenes is a multiple of intrinsic (damped) oscillatory rhythms in the cortex. We show how both the quantitative and qualitative aspects of the patterns change with frequency of stimulation and provide an explanation for these differences. We use Floquet theory combined with the theory of pattern formation to derive the parameter regimes where the phosphenes occur. We use symmetric bifurcation theory to show why low frequency flicker should produce hexagonal patterns while high frequency produces pinwheels, targets, and spirals.'),
(85139, 2011, 'plos', 'A multi-compartment model for interneurons in the dorsal lateral geniculate nucleus', 'Halnes, Geir|Augustinaite, Sigita|Heggelund, Paul|Einevoll, Gaute T|Migliore, Michele', 'IMT, Norwegian University of Life Sciences, Ås, Norway. geir.halnes@umb.no|IMT, Norwegian University of Life Sciences, Ås, Norway. geir.halnes@umb.no|IMT, Norwegian University of Life Sciences, Ås, Norway. geir.halnes@umb.no|IMT, Norwegian University of Life Sciences, Ås, Norway. geir.halnes@umb.no|IMT, Norwegian University of Life Sciences, Ås, Norway. geir.halnes@umb.no', 'Norway|Norway|Norway|Norway|Norway', 20, 'Action Potentials|Animals|Calcium|Computational Biology|Computer Simulation|Dendrites|Electrophysiological Phenomena|Geniculate Bodies|In Vitro Techniques|Interneurons|Ion Channels|Kinetics|Mice|Mice, Transgenic|Models, Neurological|Nerve Net|Patch-Clamp Techniques|Synapses', 'Journal Article', '10.1371/journal.pcbi.1002160', '21980270', 'GABAergic interneurons (INs) in the dorsal lateral geniculate nucleus (dLGN) shape the information flow from retina to cortex, presumably by controlling the number of visually evoked spikes in geniculate thalamocortical (TC) neurons, and refining their receptive field. The INs exhibit a rich variety of firing patterns: Depolarizing current injections to the soma may induce tonic firing, periodic bursting or an initial burst followed by tonic spiking, sometimes with prominent spike-time adaptation. When released from hyperpolarization, some INs elicit rebound bursts, while others return more passively to the resting potential. A full mechanistic understanding that explains the function of the dLGN on the basis of neuronal morphology, physiology and circuitry is currently lacking. One way to approach such an understanding is by developing a detailed mathematical model of the involved cells and their interactions. Limitations of the previous models for the INs of the dLGN region prevent an accurate representation of the conceptual framework needed to understand the computational properties of this region. We here present a detailed compartmental model of INs using, for the first time, a morphological reconstruction and a set of active dendritic conductances constrained by experimental somatic recordings from INs under several different current-clamp conditions. The model makes a number of experimentally testable predictions about the role of specific mechanisms for the firing properties observed in these neurons. In addition to accounting for the significant features of all experimental traces, it quantitatively reproduces the experimental recordings of the action-potential- firing frequency as a function of injected current. We show how and why relative differences in conductance values, rather than differences in ion channel composition, could account for the distinct differences between the responses observed in two different neurons, suggesting that INs may be individually tuned to optimize network operation under different input conditions.'),
(85140, 2011, 'plos', 'Long-range intra-protein communication can be transmitted by correlated side-chain fluctuations alone', 'Dubay, Kateri H|Bothma, Jacques P|Geissler, Phillip L', 'Department of Chemistry, University of California at Berkeley, Berkeley, California, United States of America.|Department of Chemistry, University of California at Berkeley, Berkeley, California, United States of America.|Department of Chemistry, University of California at Berkeley, Berkeley, California, United States of America.', 'United States|United States|United States', 0, 'Allosteric Regulation|Bacterial Proteins|Binding Sites|Calmodulin|Computational Biology|Computer Simulation|Hydrogen Bonding|Models, Molecular|Monte Carlo Method|Nuclear Magnetic Resonance, Biomolecular|Protein Folding|Protein Interaction Domains and Motifs|Proteins|Solvents', 'Journal Article', '10.1371/journal.pcbi.1002168', '21980271', 'Allosteric regulation is a key component of cellular communication, but the way in which information is passed from one site to another within a folded protein is not often clear. While backbone motions have long been considered essential for long-range information conveyance, side-chain motions have rarely been considered. In this work, we demonstrate their potential utility using Monte Carlo sampling of side-chain torsional angles on a fixed backbone to quantify correlations amongst side-chain inter-rotameric motions. Results indicate that long-range correlations of side-chain fluctuations can arise independently from several different types of interactions: steric repulsions, implicit solvent interactions, or hydrogen bonding and salt-bridge interactions. These robust correlations persist across the entire protein (up to 60 Å in the case of calmodulin) and can propagate long-range changes in side-chain variability in response to single residue perturbations.'),
(85141, 2011, 'plos', 'LsrR quorum sensing switch is revealed by a bottom-up approach', 'Hooshangi, Sara|Bentley, William E', 'College of Professional Studies, The George Washington University, Washington, DC, United States of America.|College of Professional Studies, The George Washington University, Washington, DC, United States of America.', 'United States|United States', 19, 'Bacterial Proteins|Carbon-Sulfur Lyases|Computational Biology|Computer Simulation|Escherichia coli|Escherichia coli Proteins|Feedback, Physiological|Gene Expression Regulation, Bacterial|Gene Knockout Techniques|Genes, Bacterial|Homoserine|Lactones|Models, Biological|Phosphotransferases (Alcohol Group Acceptor)|Quorum Sensing|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002172', '21980272', 'Quorum sensing (QS) enables bacterial multicellularity and selective advantage for communicating populations. While genetic switching phenomena are a common feature, their mechanistic underpinnings have remained elusive. The interplay between circuit components and their regulation are intertwined and embedded. Observable phenotypes are complex and context dependent. We employed a combination of experimental work and mathematical models to decipher network connectivity and signal transduction in the autoinducer-2 (AI-2) quorum sensing system of E. coli. Negative and positive feedback mechanisms were examined by separating the network architecture into sub-networks. A new unreported negative feedback interaction was hypothesized and tested via a simple mathematical model. Also, the importance of the LsrR regulator and its determinant role in the E. coli QS switch, normally masked by interfering regulatory loops, were revealed. Our simple model allowed mechanistic understanding of the interplay among regulatory sub-structures and their contributions to the overall native functioning network. This bottom up approach in understanding gene regulation will serve to unravel complex QS network architectures and lead to the directed coordination of emergent behaviors.'),
(85142, 2011, 'plos', 'The effect of heterogeneity on invasion in spatial epidemics: from theory to experimental evidence in a model system', 'Neri, Franco M|Bates, Anne|Füchtbauer, Winnie S|Pérez-Reche, Francisco J|Taraskin, Sergei N|Otten, Wilfred|Bailey, Douglas J|Gilligan, Christopher A', 'Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom. fmn22@cam.ac.uk|Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom. fmn22@cam.ac.uk|Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom. fmn22@cam.ac.uk|Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom. fmn22@cam.ac.uk|Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom. fmn22@cam.ac.uk|Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom. fmn22@cam.ac.uk|Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom. fmn22@cam.ac.uk|Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom. fmn22@cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Animals|Bayes Theorem|Communicable Disease Control|Computational Biology|Computer Simulation|Disease Transmission, Infectious|Epidemics|Host-Pathogen Interactions|Humans|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002174', '21980273', 'Heterogeneity in host populations is an important factor affecting the ability of a pathogen to invade, yet the quantitative investigation of its effects on epidemic spread is still an open problem. In this paper, we test recent theoretical results, which extend the established percolation paradigm to the spread of a pathogen in discrete heterogeneous host populations. In particular, we test the hypothesis that the probability of epidemic invasion decreases when host heterogeneity is increased. We use replicated experimental microcosms, in which the ubiquitous pathogenic fungus Rhizoctonia solani grows through a population of discrete nutrient sites on a lattice, with nutrient sites representing hosts. The degree of host heterogeneity within different populations is adjusted by changing the proportion and the nutrient concentration of nutrient sites. The experimental data are analysed via Bayesian inference methods, estimating pathogen transmission parameters for each individual population. We find a significant, negative correlation between heterogeneity and the probability of pathogen invasion, thereby validating the theory. The value of the correlation is also in remarkably good agreement with the theoretical predictions. We briefly discuss how our results can be exploited in the design and implementation of disease control strategies.'),
(85143, 2011, 'plos', 'Smart swarms of bacteria-inspired agents with performance adaptable interactions', 'Shklarsh, Adi|Ariel, Gil|Schneidman, Elad|Ben-Jacob, Eshel', 'School of Computer Science, Tel Aviv University, Tel Aviv, Israel.|School of Computer Science, Tel Aviv University, Tel Aviv, Israel.|School of Computer Science, Tel Aviv University, Tel Aviv, Israel.|School of Computer Science, Tel Aviv University, Tel Aviv, Israel.', 'Israel|Israel|Israel|Israel', 46, 'Adaptation, Physiological|Bacterial Physiological Phenomena|Computational Biology|Computer Simulation|Microbial Interactions|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002177', '21980274', 'Collective navigation and swarming have been studied in animal groups, such as fish schools, bird flocks, bacteria, and slime molds. Computer modeling has shown that collective behavior of simple agents can result from simple interactions between the agents, which include short range repulsion, intermediate range alignment, and long range attraction. Here we study collective navigation of bacteria-inspired smart agents in complex terrains, with adaptive interactions that depend on performance. More specifically, each agent adjusts its interactions with the other agents according to its local environment--by decreasing the peers influence while navigating in a beneficial direction, and increasing it otherwise. We show that inclusion of such performance dependent adaptable interactions significantly improves the collective swarming performance, leading to highly efficient navigation, especially in complex terrains. Notably, to afford such adaptable interactions, each modeled agent requires only simple computational capabilities with short-term memory, which can easily be implemented in simple swarming robots.'),
(85144, 2011, 'plos', 'Protein networks as logic functions in development and cancer', 'Dutkowski, Janusz|Ideker, Trey', 'Department of Medicine, University of California San Diego, La Jolla, California, United States of America. janusz@ucsd.edu|Department of Medicine, University of California San Diego, La Jolla, California, United States of America. janusz@ucsd.edu', 'United States|United States', 0, 'Breast Neoplasms|Computational Biology|Computer Simulation|Decision Trees|Disease Progression|Female|Gene Regulatory Networks|Glioma|Growth and Development|Humans|Logic|Neoplasms|Protein Interaction Maps|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002180', '21980275', 'Many biological and clinical outcomes are based not on single proteins, but on modules of proteins embedded in protein networks. A fundamental question is how the proteins within each module contribute to the overall module activity. Here, we study the modules underlying three representative biological programs related to tissue development, breast cancer metastasis, or progression of brain cancer, respectively. For each case we apply a new method, called Network-Guided Forests, to identify predictive modules together with logic functions which tie the activity of each module to the activity of its component genes. The resulting modules implement a diverse repertoire of decision logic which cannot be captured using the simple approximations suggested in previous work such as gene summation or subtraction. We show that in cancer, certain combinations of oncogenes and tumor suppressors exert competing forces on the system, suggesting that medical genetics should move beyond cataloguing individual cancer genes to cataloguing their combinatorial logic.'),
(85145, 2011, 'plos', 'War of ontology worlds: mathematics, computer code, or Esperanto?', 'Rzhetsky, Andrey|Evans, James A', 'Department of Medicine, University of Chicago, Chicago, Illinois, United States of America. arzhetsky@uchicago.edu|Department of Medicine, University of Chicago, Chicago, Illinois, United States of America. arzhetsky@uchicago.edu', 'United States|United States', 0, 'Computational Biology|Computer Simulation|Data Mining|Humans|Knowledge|Language|Mathematical Concepts|Programming Languages|Software|User-Computer Interface|Vocabulary, Controlled', 'Journal Article', '10.1371/journal.pcbi.1002191', '21980276', 'The use of structured knowledge representations-ontologies and terminologies-has become standard in biomedicine. Definitions of ontologies vary widely, as do the values and philosophies that underlie them. In seeking to make these views explicit, we conducted and summarized interviews with a dozen leading ontologists. Their views clustered into three broad perspectives that we summarize as mathematics, computer code, and Esperanto. Ontology as mathematics puts the ultimate premium on rigor and logic, symmetry and consistency of representation across scientific subfields, and the inclusion of only established, non-contradictory knowledge. Ontology as computer code focuses on utility and cultivates diversity, fitting ontologies to their purpose. Like computer languages C++, Prolog, and HTML, the code perspective holds that diverse applications warrant custom designed ontologies. Ontology as Esperanto focuses on facilitating cross-disciplinary communication, knowledge cross-referencing, and computation across datasets from diverse communities. We show how these views align with classical divides in science and suggest how a synthesis of their concerns could strengthen the next generation of biomedical ontologies.'),
(85146, 2011, 'plos', 'A single-rate context-dependent learning process underlies rapid adaptation to familiar object dynamics', 'Ingram, James N|Howard, Ian S|Flanagan, J Randall|Wolpert, Daniel M', 'Department of Engineering, University of Cambridge, Cambridge, United Kingdom. jni20@cam.ac.uk|Department of Engineering, University of Cambridge, Cambridge, United Kingdom. jni20@cam.ac.uk|Department of Engineering, University of Cambridge, Cambridge, United Kingdom. jni20@cam.ac.uk|Department of Engineering, University of Cambridge, Cambridge, United Kingdom. jni20@cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Adaptation, Physiological|Computational Biology|Computer Simulation|Humans|Learning|Models, Biological|Motor Skills|Robotics|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1002196', '21980277', 'Motor learning has been extensively studied using dynamic (force-field) perturbations. These induce movement errors that result in adaptive changes to the motor commands. Several state-space models have been developed to explain how trial-by-trial errors drive the progressive adaptation observed in such studies. These models have been applied to adaptation involving novel dynamics, which typically occurs over tens to hundreds of trials, and which appears to be mediated by a dual-rate adaptation process. In contrast, when manipulating objects with familiar dynamics, subjects adapt rapidly within a few trials. Here, we apply state-space models to familiar dynamics, asking whether adaptation is mediated by a single-rate or dual-rate process. Previously, we reported a task in which subjects rotate an object with known dynamics. By presenting the object at different visual orientations, adaptation was shown to be context-specific, with limited generalization to novel orientations. Here we show that a multiple-context state-space model, with a generalization function tuned to visual object orientation, can reproduce the time-course of adaptation and de-adaptation as well as the observed context-dependent behavior. In contrast to the dual-rate process associated with novel dynamics, we show that a single-rate process mediates adaptation to familiar object dynamics. The model predicts that during exposure to the object across multiple orientations, there will be a degree of independence for adaptation and de-adaptation within each context, and that the states associated with all contexts will slowly de-adapt during exposure in one particular context. We confirm these predictions in two new experiments. Results of the current study thus highlight similarities and differences in the processes engaged during exposure to novel versus familiar dynamics. In both cases, adaptation is mediated by multiple context-specific representations. In the case of familiar object dynamics, however, the representations can be engaged based on visual context, and are updated by a single-rate process.'),
(85147, 2011, 'plos', 'Time scale hierarchies in the functional organization of complex behaviors', 'Perdikis, Dionysios|Huys, Raoul|Jirsa, Viktor K', 'Theoretical Neuroscience Group, UMR6233, Institut Science du Mouvement, University of the Mediterranean, Marseille, France. dionperd@gmail.com|Theoretical Neuroscience Group, UMR6233, Institut Science du Mouvement, University of the Mediterranean, Marseille, France. dionperd@gmail.com|Theoretical Neuroscience Group, UMR6233, Institut Science du Mouvement, University of the Mediterranean, Marseille, France. dionperd@gmail.com', 'France|France|France', 26, 'Behavior|Cognition|Computational Biology|Computer Simulation|Feedback, Sensory|Handwriting|Humans|Learning|Models, Biological|Models, Neurological|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1002198', '21980278', 'Traditional approaches to cognitive modelling generally portray cognitive events in terms of discrete states (point attractor dynamics) rather than in terms of processes, thereby neglecting the time structure of cognition. In contrast, more recent approaches explicitly address this temporal dimension, but typically provide no entry points into cognitive categorization of events and experiences. With the aim to incorporate both these aspects, we propose a framework for functional architectures. Our approach is grounded in the notion that arbitrary complex (human) behaviour is decomposable into functional modes (elementary units), which we conceptualize as low-dimensional dynamical objects (structured flows on manifolds). The ensemble of modes at an agents disposal constitutes his/her functional repertoire. The modes may be subjected to additional dynamics (termed operational signals), in particular, instantaneous inputs, and a mechanism that sequentially selects a mode so that it temporarily dominates the functional dynamics. The inputs and selection mechanisms act on faster and slower time scales then that inherent to the modes, respectively. The dynamics across the three time scales are coupled via feedback, rendering the entire architecture autonomous. We illustrate the functional architecture in the context of serial behaviour, namely cursive handwriting. Subsequently, we investigate the possibility of recovering the contributions of functional modes and operational signals from the output, which appears to be possible only when examining the output phase flow (i.e., not from trajectories in phase space or time).'),
(85148, 2011, 'plos', 'Changes in dynamics upon oligomerization regulate substrate binding and allostery in amino acid kinase family members', 'Marcos, Enrique|Crehuet, Ramon|Bahar, Ivet', 'Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain.|Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain.|Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain.', 'Spain|Spain|Spain', 35, 'Allosteric Regulation|Allosteric Site|Amino Acids|Catalytic Domain|Computational Biology|Computer Simulation|Dimerization|Models, Molecular|Molecular Dynamics Simulation|Nucleoside-Phosphate Kinase|Phosphotransferases|Phosphotransferases (Carboxyl Group Acceptor)|Protein Binding|Protein Multimerization|Protein Structure, Quaternary|Substrate Specificity|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002201', '21980279', 'Oligomerization is a functional requirement for many proteins. The interfacial interactions and the overall packing geometry of the individual monomers are viewed as important determinants of the thermodynamic stability and allosteric regulation of oligomers. The present study focuses on the role of the interfacial interactions and overall contact topology in the dynamic features acquired in the oligomeric state. To this aim, the collective dynamics of enzymes belonging to the amino acid kinase family both in dimeric and hexameric forms are examined by means of an elastic network model, and the softest collective motions (i.e., lowest frequency or global modes of motions) favored by the overall architecture are analyzed. Notably, the lowest-frequency modes accessible to the individual subunits in the absence of multimerization are conserved to a large extent in the oligomer, suggesting that the oligomer takes advantage of the intrinsic dynamics of the individual monomers. At the same time, oligomerization stiffens the interfacial regions of the monomers and confers new cooperative modes that exploit the rigid-body translational and rotational degrees of freedom of the intact monomers. The present study sheds light on the mechanism of cooperative inhibition of hexameric N-acetyl-L-glutamate kinase by arginine and on the allosteric regulation of UMP kinases. It also highlights the significance of the particular quaternary design in selectively determining the oligomer dynamics congruent with required ligand-binding and allosteric activities.'),
(85149, 2011, 'plos', 'Ten simple rules for getting help from online scientific communities', 'DallOlio, Giovanni M|Marino, Jacopo|Schubert, Michael|Keys, Kevin L|Stefan, Melanie I|Gillespie, Colin S|Poulain, Pierre|Shameer, Khader|Sugar, Robert|Invergo, Brandon M|Jensen, Lars J|Bertranpetit, Jaume|Laayouni, Hafid', 'Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain.|Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain.|Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain.|Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain.|Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain.|Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain.|Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain.|Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain.|Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain.|Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain.|Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain.|Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain.|Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain.', 'Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain', 0, 'Communication|Computational Biology|Helping Behavior|Humans|Internet|Online Systems|Research', 'Editorial', '10.1371/journal.pcbi.1002202', '21980280', '-'),
(85150, 2011, 'plos', 'Determinants of the spatiotemporal dynamics of the 2009 H1N1 pandemic in Europe: implications for real-time modelling', 'Merler, Stefano|Ajelli, Marco|Pugliese, Andrea|Ferguson, Neil M', 'Bruno Kessler Foundation, Trento Povo, Italy. merler@fbk.eu|Bruno Kessler Foundation, Trento Povo, Italy. merler@fbk.eu|Bruno Kessler Foundation, Trento Povo, Italy. merler@fbk.eu|Bruno Kessler Foundation, Trento Povo, Italy. merler@fbk.eu', 'Italy|Italy|Italy|Italy', 79, 'Computational Biology|Computer Simulation|Computer Systems|Epidemiologic Factors|Europe|History, 21st Century|Humans|Influenza A Virus, H1N1 Subtype|Influenza, Human|Pandemics|Travel', 'Historical Article', '10.1371/journal.pcbi.1002205', '21980281', 'Influenza pandemics in the last century were characterized by successive waves and differences in impact and timing between different regions, for reasons not clearly understood. The 2009 H1N1 pandemic showed rapid global spread, but with substantial heterogeneity in timing within each hemisphere. Even within Europe substantial variation was observed, with the UK being unique in experiencing a major first wave of transmission in early summer and all other countries having a single major epidemic in the autumn/winter, with a West to East pattern of spread. Here we show that a microsimulation model, parameterised using data about H1N1pdm collected by the beginning of June 2009, explains the occurrence of two waves in UK and a single wave in the rest of Europe as a consequence of timing of H1N1pdm spread, fluxes of travels from US and Mexico, and timing of school vacations. The model provides a description of pandemic spread through Europe, depending on intra-European mobility patterns and socio-demographic structure of the European populations, which is in broad agreement with observed timing of the pandemic in different countries. Attack rates are predicted to depend on the socio-demographic structure, with age dependent attack rates broadly agreeing with available serological data. Results suggest that the observed heterogeneity can be partly explained by the between country differences in Europe: marked differences in school calendars, mobility patterns and sociodemographic structures. Moreover, higher susceptibility of children to infection played a key role in determining the epidemiology of the 2009 pandemic. Our work shows that it would have been possible to obtain a broad-brush prediction of timing of the European pandemic well before the autumn of 2009, much more difficult to achieve with simpler models or pre-pandemic parameterisation. This supports the use of models accounting for the structure of complex modern societies for giving insight to policy makers.'),
(85151, 2011, 'plos', 'Why dont CD8+ T cells reduce the lifespan of SIV-infected cells in vivo?', 'Elemans, Marjet|Seich Al Basatena, Nafisa-Katrin|Klatt, Nichole R|Gkekas, Christos|Silvestri, Guido|Asquith, Becca', 'Department of Immunology, Imperial College London, London, United Kingdom. m.elemans@imperial.ac.uk|Department of Immunology, Imperial College London, London, United Kingdom. m.elemans@imperial.ac.uk|Department of Immunology, Imperial College London, London, United Kingdom. m.elemans@imperial.ac.uk|Department of Immunology, Imperial College London, London, United Kingdom. m.elemans@imperial.ac.uk|Department of Immunology, Imperial College London, London, United Kingdom. m.elemans@imperial.ac.uk|Department of Immunology, Imperial College London, London, United Kingdom. m.elemans@imperial.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 26, 'Animals|CD8-Positive T-Lymphocytes|Cell Survival|Computational Biology|Lymphocyte Depletion|Macaca|Models, Theoretical|Simian Acquired Immunodeficiency Syndrome|Simian Immunodeficiency Virus|Viral Load|Viremia', 'Journal Article', '10.1371/journal.pcbi.1002200', '21990968', 'In January 2010 two groups independently published the observation that the depletion of CD8+ cells in SIV-infected macaques had no detectable impact on the lifespan of productively infected cells. This unexpected observation led the authors to suggest that CD8+ T cells control SIV viraemia via non-lytic mechanisms. However, a number of alternative plausible explanations, compatible with a lytic model of CD8+ T cell control, were proposed. This left the field with no consensus on how to interpret these experiments and no clear indication whether CD8+ T cells operated primarily via a lytic or a non-lytic mechanism. The aim of this work was to investigate why CD8+ T cells do not appear to reduce the lifespan of SIV-infected cells in vivo.'),
(85152, 2011, 'plos', 'Conflicting biomedical assumptions for mathematical modeling: the case of cancer metastasis', 'Divoli, Anna|Mendonça, Eneida A|Evans, James A|Rzhetsky, Andrey', 'Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.|Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.|Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.|Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.', 'United States|United States|United States|United States', 0, 'Computational Biology|Disease Progression|Expert Testimony|Humans|Markov Chains|Models, Biological|Neoplasm Metastasis', 'Journal Article', '10.1371/journal.pcbi.1002132', '21998558', 'Computational models in biomedicine rely on biological and clinical assumptions. The selection of these assumptions contributes substantially to modeling success or failure. Assumptions used by experts at the cutting edge of research, however, are rarely explicitly described in scientific publications. One can directly collect and assess some of these assumptions through interviews and surveys. Here we investigate diversity in expert views about a complex biological phenomenon, the process of cancer metastasis. We harvested individual viewpoints from 28 experts in clinical and molecular aspects of cancer metastasis and summarized them computationally. While experts predominantly agreed on the definition of individual steps involved in metastasis, no two expert scenarios for metastasis were identical. We computed the probability that any two experts would disagree on k or fewer metastatic stages and found that any two randomly selected experts are likely to disagree about several assumptions. Considering the probability that two or more of these experts review an article or a proposal about metastatic cascades, the probability that they will disagree with elements of a proposed model approaches 1. This diversity of conceptions has clear consequences for advance and deadlock in the field. We suggest that strong, incompatible views are common in biomedicine but largely invisible to biomedical experts themselves. We built a formal Markov model of metastasis to encapsulate expert convergence and divergence regarding the entire sequence of metastatic stages. This model revealed stages of greatest disagreement, including the points at which cancer enters and leaves the bloodstream. The model provides a formal probabilistic hypothesis against which researchers can evaluate data on the process of metastasis. This would enable subsequent improvement of the model through Bayesian probabilistic update. Practically, we propose that model assumptions and hunches be harvested systematically and made available for modelers and scientists.'),
(85153, 2011, 'plos', 'Change in allosteric network affects binding affinities of PDZ domains: analysis through perturbation response scanning', 'Gerek, Z Nevin|Ozkan, S Banu', 'Center for Biological Physics, Arizona State University, Tempe, Arizona, United States of America.|Center for Biological Physics, Arizona State University, Tempe, Arizona, United States of America.', 'United States|United States', 92, 'Allosteric Regulation|Amino Acid Sequence|Computational Biology|Humans|Models, Biological|Models, Molecular|Molecular Sequence Data|Nuclear Magnetic Resonance, Biomolecular|PDZ Domains|Protein Tyrosine Phosphatase, Non-Receptor Type 13|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002154', '21998559', 'The allosteric mechanism plays a key role in cellular functions of several PDZ domain proteins (PDZs) and is directly linked to pharmaceutical applications, however, it is a challenge to elaborate the nature and extent of these allosteric interactions. One solution to this problem is to explore the dynamics of PDZs, which may provide insights about how intramolecular communication occurs within a single domain. Here, we develop an advancement of perturbation response scanning (PRS) that couples elastic network models with linear response theory (LRT) to predict key residues in allosteric transitions of the two most studied PDZs (PSD-95 PDZ3 domain and hPTP1E PDZ2 domain). With PRS, we first identify the residues that give the highest mean square fluctuation response upon perturbing the binding sites. Strikingly, we observe that the residues with the highest mean square fluctuation response agree with experimentally determined residues involved in allosteric transitions. Second, we construct the allosteric pathways by linking the residues giving the same directional response upon perturbation of the binding sites. The predicted intramolecular communication pathways reveal that PSD-95 and hPTP1E have different pathways through the dynamic coupling of different residue pairs. Moreover, our analysis provides a molecular understanding of experimentally observed hidden allostery of PSD-95. We show that removing the distal third alpha helix from the binding site alters the allosteric pathway and decreases the binding affinity. Overall, these results indicate that (i) dynamics plays a key role in allosteric regulations of PDZs, (ii) the local changes in the residue interactions can lead to significant changes in the dynamics of allosteric regulations, and (iii) this might be the mechanism that each PDZ uses to tailor their binding specificities regulation.'),
(85154, 2011, 'plos', 'A multi-cell, multi-scale model of vertebrate segmentation and somite formation', 'Hester, Susan D|Belmonte, Julio M|Gens, J Scott|Clendenon, Sherry G|Glazier, James A', 'Biocomplexity Institute and Department of Physics, Indiana University Bloomington, Bloomington, Indiana, United States of America. sdhester@umail.iu.edu|Biocomplexity Institute and Department of Physics, Indiana University Bloomington, Bloomington, Indiana, United States of America. sdhester@umail.iu.edu|Biocomplexity Institute and Department of Physics, Indiana University Bloomington, Bloomington, Indiana, United States of America. sdhester@umail.iu.edu|Biocomplexity Institute and Department of Physics, Indiana University Bloomington, Bloomington, Indiana, United States of America. sdhester@umail.iu.edu|Biocomplexity Institute and Department of Physics, Indiana University Bloomington, Bloomington, Indiana, United States of America. sdhester@umail.iu.edu', 'India|India|India|India|India', 0, 'Animals|Biological Clocks|Body Patterning|Cell Adhesion|Cell Adhesion Molecules|Cell Division|Cell Movement|Computational Biology|Fibroblast Growth Factor 8|Gene Expression Regulation|Intracellular Signaling Peptides and Proteins|Membrane Proteins|Mesoderm|Models, Biological|RNA, Messenger|Receptors, Notch|Signal Transduction|Somites|Wnt3A Protein', 'Journal Article', '10.1371/journal.pcbi.1002155', '21998560', 'Somitogenesis, the formation of the bodys primary segmental structure common to all vertebrate development, requires coordination between biological mechanisms at several scales. Explaining how these mechanisms interact across scales and how events are coordinated in space and time is necessary for a complete understanding of somitogenesis and its evolutionary flexibility. So far, mechanisms of somitogenesis have been studied independently. To test the consistency, integrability and combined explanatory power of current prevailing hypotheses, we built an integrated clock-and-wavefront model including submodels of the intracellular segmentation clock, intercellular segmentation-clock coupling via Delta/Notch signaling, an FGF8 determination front, delayed differentiation, clock-wavefront readout, and differential-cell-cell-adhesion-driven cell sorting. We identify inconsistencies between existing submodels and gaps in the current understanding of somitogenesis mechanisms, and propose novel submodels and extensions of existing submodels where necessary. For reasonable initial conditions, 2D simulations of our model robustly generate spatially and temporally regular somites, realistic dynamic morphologies and spontaneous emergence of anterior-traveling stripes of Lfng. We show that these traveling stripes are pseudo-waves rather than true propagating waves. Our model is flexible enough to generate interspecies-like variation in somite size in response to changes in the PSM growth rate and segmentation-clock period, and in the number and width of Lfng stripes in response to changes in the PSM growth rate, segmentation-clock period and PSM length.'),
(85155, 2011, 'plos', 'Coexistence of lateral and co-tuned inhibitory configurations in cortical networks', 'Levy, Robert B|Reyes, Alex D', 'Center for Neural Science, New York University, New York, New York, United States of America. rbl2@nyu.edu|Center for Neural Science, New York University, New York, New York, United States of America. rbl2@nyu.edu', 'United States|United States', 22, 'Animals|Cerebral Cortex|Computational Biology|Electrophysiological Phenomena|Models, Neurological|Nerve Net|Sensory Receptor Cells|Synapses', 'Journal Article', '10.1371/journal.pcbi.1002161', '21998561', 'The responses of neurons in sensory cortex depend on the summation of excitatory and inhibitory synaptic inputs. How the excitatory and inhibitory inputs scale with stimulus depends on the network architecture, which ranges from the lateral inhibitory configuration where excitatory inputs are more narrowly tuned than inhibitory inputs, to the co-tuned configuration where both are tuned equally. The underlying circuitry that gives rise to lateral inhibition and co-tuning is yet unclear. Using large-scale network simulations with experimentally determined connectivity patterns and simulations with rate models, we show that the spatial extent of the input determined the configuration: there was a smooth transition from lateral inhibition with narrow input to co-tuning with broad input. The transition from lateral inhibition to co-tuning was accompanied by shifts in overall gain (reduced), output firing pattern (from tonic to phasic) and rate-level functions (from non-monotonic to monotonically increasing). The results suggest that a single cortical network architecture could account for the extended range of experimentally observed response types between the extremes of lateral inhibitory versus co-tuned configurations.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85156, 2011, 'plos', 'Model cortical association fields account for the time course and dependence on target complexity of human contour perception', 'Gintautas, Vadas|Ham, Michael I|Kunsberg, Benjamin|Barr, Shawn|Brumby, Steven P|Rasmussen, Craig|George, John S|Nemenman, Ilya|Bettencourt, Luís M A|Kenyon, Garrett T|Kenyon, Garret T', 'Center for Nonlinear Studies and T-5, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. vgintautas@chatham.edu|Center for Nonlinear Studies and T-5, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. vgintautas@chatham.edu|Center for Nonlinear Studies and T-5, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. vgintautas@chatham.edu|Center for Nonlinear Studies and T-5, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. vgintautas@chatham.edu|Center for Nonlinear Studies and T-5, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. vgintautas@chatham.edu|Center for Nonlinear Studies and T-5, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. vgintautas@chatham.edu|Center for Nonlinear Studies and T-5, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. vgintautas@chatham.edu|Center for Nonlinear Studies and T-5, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. vgintautas@chatham.edu|Center for Nonlinear Studies and T-5, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. vgintautas@chatham.edu|Center for Nonlinear Studies and T-5, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. vgintautas@chatham.edu|Center for Nonlinear Studies and T-5, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. vgintautas@chatham.edu', 'Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico|Mexico', 8, 'Computational Biology|Form Perception|Humans|Models, Neurological|Photic Stimulation|Psychophysics|Reaction Time|Time Factors|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1002162', '21998562', 'Can lateral connectivity in the primary visual cortex account for the time dependence and intrinsic task difficulty of human contour detection? To answer this question, we created a synthetic image set that prevents sole reliance on either low-level visual features or high-level context for the detection of target objects. Rendered images consist of smoothly varying, globally aligned contour fragments (amoebas) distributed among groups of randomly rotated fragments (clutter). The time course and accuracy of amoeba detection by humans was measured using a two-alternative forced choice protocol with self-reported confidence and variable image presentation time (20-200 ms), followed by an image mask optimized so as to interrupt visual processing. Measured psychometric functions were well fit by sigmoidal functions with exponential time constants of 30-91 ms, depending on amoeba complexity. Key aspects of the psychophysical experiments were accounted for by a computational network model, in which simulated responses across retinotopic arrays of orientation-selective elements were modulated by cortical association fields, represented as multiplicative kernels computed from the differences in pairwise edge statistics between target and distractor images. Comparing the experimental and the computational results suggests that each iteration of the lateral interactions takes at least [Formula: see text] ms of cortical processing time. Our results provide evidence that cortical association fields between orientation selective elements in early visual areas can account for important temporal and task-dependent aspects of the psychometric curves characterizing human contour perception, with the remaining discrepancies postulated to arise from the influence of higher cortical areas.'),
(85157, 2011, 'plos', 'Hydrophobicity and charge shape cellular metabolite concentrations', 'Bar-Even, Arren|Noor, Elad|Flamholz, Avi|Buescher, Joerg M|Milo, Ron', 'Department of Plant Sciences, The Weizmann Institute of Science, Rehovot, Israel.|Department of Plant Sciences, The Weizmann Institute of Science, Rehovot, Israel.|Department of Plant Sciences, The Weizmann Institute of Science, Rehovot, Israel.|Department of Plant Sciences, The Weizmann Institute of Science, Rehovot, Israel.|Department of Plant Sciences, The Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel|Israel|Israel|Israel', 0, 'Bacillus subtilis|Cells|Chemical Phenomena|Computational Biology|Databases, Factual|Electrochemistry|Escherichia coli|Humans|Hydrophobic and Hydrophilic Interactions|Metabolic Networks and Pathways|Models, Biological|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1002166', '21998563', 'What governs the concentrations of metabolites within living cells? Beyond specific metabolic and enzymatic considerations, are there global trends that affect their values? We hypothesize that the physico-chemical properties of metabolites considerably affect their in-vivo concentrations. The recently achieved experimental capability to measure the concentrations of many metabolites simultaneously has made the testing of this hypothesis possible. Here, we analyze such recently available data sets of metabolite concentrations within E. coli, S. cerevisiae, B. subtilis and human. Overall, these data sets encompass more than twenty conditions, each containing dozens (28-108) of simultaneously measured metabolites. We test for correlations with various physico-chemical properties and find that the number of charged atoms, non-polar surface area, lipophilicity and solubility consistently correlate with concentration. In most data sets, a change in one of these properties elicits a ~100 fold increase in metabolite concentrations. We find that the non-polar surface area and number of charged atoms account for almost half of the variation in concentrations in the most reliable and comprehensive data set. Analyzing specific groups of metabolites, such as amino-acids or phosphorylated nucleotides, reveals even a higher dependence of concentration on hydrophobicity. We suggest that these findings can be explained by evolutionary constraints imposed on metabolite concentrations and discuss possible selective pressures that can account for them. These include the reduction of solute leakage through the lipid membrane, avoidance of deleterious aggregates and reduction of non-specific hydrophobic binding. By highlighting the global constraints imposed on metabolic pathways, future research could shed light onto aspects of biochemical evolution and the chemical constraints that bound metabolic engineering efforts.'),
(85158, 2011, 'plos', 'Formation of regulatory modules by local sequence duplication', 'Nourmohammad, Armita|Lässig, Michael', 'Institute for Theoretical Physics, University of Cologne, Köln, Germany.|Institute for Theoretical Physics, University of Cologne, Köln, Germany.', 'Germany|Germany', 0, 'Animals|Binding Sites|Computational Biology|DNA|DNA, Intergenic|Drosophila melanogaster|Evolution, Molecular|Genome, Fungal|Genome, Insect|Models, Genetic|Regulatory Sequences, Nucleic Acid|Saccharomyces cerevisiae|Segmental Duplications, Genomic', 'Journal Article', '10.1371/journal.pcbi.1002167', '21998564', 'Turnover of regulatory sequence and function is an important part of molecular evolution. But what are the modes of sequence evolution leading to rapid formation and loss of regulatory sites? Here we show that a large fraction of neighboring transcription factor binding sites in the fly genome have formed from a common sequence origin by local duplications. This mode of evolution is found to produce regulatory information: duplications can seed new sites in the neighborhood of existing sites. Duplicate seeds evolve subsequently by point mutations, often towards binding a different factor than their ancestral neighbor sites. These results are based on a statistical analysis of 346 cis-regulatory modules in the Drosophila melanogaster genome, and a comparison set of intergenic regulatory sequence in Saccharomyces cerevisiae. In fly regulatory modules, pairs of binding sites show significantly enhanced sequence similarity up to distances of about 50 bp. We analyze these data in terms of an evolutionary model with two distinct modes of site formation: (i) evolution from independent sequence origin and (ii) divergent evolution following duplication of a common ancestor sequence. Our results suggest that pervasive formation of binding sites by local sequence duplications distinguishes the complex regulatory architecture of higher eukaryotes from the simpler architecture of unicellular organisms.'),
(85159, 2011, 'plos', 'Identification of a novel class of farnesylation targets by structure-based modeling of binding specificity', 'London, Nir|Lamphear, Corissa L|Hougland, James L|Fierke, Carol A|Schueler-Furman, Ora', 'Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Hadassah Medical School, The Hebrew University, Jerusalem, Israel.|Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Hadassah Medical School, The Hebrew University, Jerusalem, Israel.|Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Hadassah Medical School, The Hebrew University, Jerusalem, Israel.|Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Hadassah Medical School, The Hebrew University, Jerusalem, Israel.|Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Hadassah Medical School, The Hebrew University, Jerusalem, Israel.', 'Canada|Canada|Canada|Canada|Canada', 0, 'Alternative Splicing|Amino Acid Sequence|Binding Sites|Catalytic Domain|Computational Biology|Databases, Protein|Farnesyltranstransferase|Humans|In Vitro Techniques|Models, Molecular|Peptides|Protein Prenylation|Protein Processing, Post-Translational|Substrate Specificity', 'Journal Article', '10.1371/journal.pcbi.1002170', '21998565', 'Farnesylation is an important post-translational modification catalyzed by farnesyltransferase (FTase). Until recently it was believed that a C-terminal CaaX motif is required for farnesylation, but recent experiments have revealed larger substrate diversity. In this study, we propose a general structural modeling scheme to account for peptide binding specificity and recapitulate the experimentally derived selectivity profile of FTase in vitro. In addition to highly accurate recovery of known FTase targets, we also identify a range of novel potential targets in the human genome, including a new substrate class with an acidic C-terminal residue (CxxD/E). In vitro experiments verified farnesylation of 26/29 tested peptides, including both novel human targets, as well as peptides predicted to tightly bind FTase. This study extends the putative range of biological farnesylation substrates. Moreover, it suggests that the ability of a peptide to bind FTase is a main determinant for the farnesylation reaction. Finally, simple adaptation of our approach can contribute to more accurate and complete elucidation of peptide-mediated interactions and modifications in the cell.'),
(85160, 2011, 'plos', 'High-precision, in vitro validation of the sequestration mechanism for generating ultrasensitive dose-response curves in regulatory networks', 'Ricci, Francesco|Vallée-Bélisle, Alexis|Plaxco, Kevin W', 'Department of Chemistry and Biochemistry, University of California, Santa Barbara, California, United States of America.|Department of Chemistry and Biochemistry, University of California, Santa Barbara, California, United States of America.|Department of Chemistry and Biochemistry, University of California, Santa Barbara, California, United States of America.', 'United States|United States|United States', 0, 'Base Sequence|Biosensing Techniques|Computational Biology|DNA Probes|Dose-Response Relationship, Drug|Gene Regulatory Networks|In Vitro Techniques|Metabolic Networks and Pathways|Models, Biological|Synthetic Biology', 'Journal Article', '10.1371/journal.pcbi.1002171', '21998566', 'Our ability to recreate complex biochemical mechanisms in designed, artificial systems provides a stringent test of our understanding of these mechanisms and opens the door to their exploitation in artificial biotechnologies. Motivated by this philosophy, here we have recapitulated in vitro the target sequestration mechanism used by nature to improve the sensitivity (the steepness of the input/output curve) of many regulatory cascades. Specifically, we have employed molecular beacons, a commonly employed optical DNA sensor, to recreate the sequestration mechanism and performed an exhaustive, quantitative study of its key determinants (e.g., the relative concentrations and affinities of probe and depletant). We show that, using sequestration, we can narrow the pseudo-linear range of a traditional molecular beacon from 81-fold (i.e., the transition from 10% to 90% target occupancy spans an 81-fold change in target concentration) to just 1.5-fold. This narrowing of the dynamic range improves the sensitivity of molecular beacons to that equivalent of an oligomeric, allosteric receptor with a Hill coefficient greater than 9. Following this we have adapted the sequestration mechanism to steepen the binding-site occupancy curve of a common transcription factor by an order of magnitude over the sensitivity observed in the absence of sequestration. Given the success with which the sequestration mechanism has been employed by nature, we believe that this strategy could dramatically improve the performance of synthetic biological systems and artificial biosensors.'),
(85161, 2011, 'plos', 'Using structure to explore the sequence alignment space of remote homologs', 'Kuziemko, Andrew|Honig, Barry|Petrey, Donald', 'Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, United States of America.|Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, United States of America.|Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, United States of America.', 'United States|United States|United States', 7, 'Algorithms|Computational Biology|Databases, Protein|Models, Molecular|Sequence Alignment|Software Design|Structural Homology, Protein', 'Journal Article', '10.1371/journal.pcbi.1002175', '21998567', 'Protein structure modeling by homology requires an accurate sequence alignment between the query protein and its structural template. However, sequence alignment methods based on dynamic programming (DP) are typically unable to generate accurate alignments for remote sequence homologs, thus limiting the applicability of modeling methods. A central problem is that the alignment that is optimal in terms of the DP score does not necessarily correspond to the alignment that produces the most accurate structural model. That is, the correct alignment based on structural superposition will generally have a lower score than the optimal alignment obtained from sequence. Variations of the DP algorithm have been developed that generate alternative alignments that are suboptimal in terms of the DP score, but these still encounter difficulties in detecting the correct structural alignment. We present here a new alternative sequence alignment method that relies heavily on the structure of the template. By initially aligning the query sequence to individual fragments in secondary structure elements and combining high-scoring fragments that pass basic tests for modelability, we can generate accurate alignments within a small ensemble. Our results suggest that the set of sequences that can currently be modeled by homology can be greatly extended.'),
(85162, 2011, 'plos', 'Synchronous chaos and broad band gamma rhythm in a minimal multi-layer model of primary visual cortex', 'Battaglia, Demian|Hansel, David', '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', 0, 'Animals|Computational Biology|Contrast Sensitivity|Electroencephalography|Electrophysiological Phenomena|Feedback, Physiological|Models, Neurological|Nerve Net|Nonlinear Dynamics|Photic Stimulation|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1002176', '21998568', 'Visually induced neuronal activity in V1 displays a marked gamma-band component which is modulated by stimulus properties. It has been argued that synchronized oscillations contribute to these gamma-band activity. However, analysis of Local Field Potentials (LFPs) across different experiments reveals considerable diversity in the degree of oscillatory behavior of this induced activity. Contrast-dependent power enhancements can indeed occur over a broad band in the gamma frequency range and spectral peaks may not arise at all. Furthermore, even when oscillations are observed, they undergo temporal decorrelation over very few cycles. This is not easily accounted for in previous network modeling of gamma oscillations. We argue here that interactions between cortical layers can be responsible for this fast decorrelation. We study a model of a V1 hypercolumn, embedding a simplified description of the multi-layered structure of the cortex. When the stimulus contrast is low, the induced activity is only weakly synchronous and the network resonates transiently without developing collective oscillations. When the contrast is high, on the other hand, the induced activity undergoes synchronous oscillations with an irregular spatiotemporal structure expressing a synchronous chaotic state. As a consequence the population activity undergoes fast temporal decorrelation, with concomitant rapid damping of the oscillations in LFPs autocorrelograms and peak broadening in LFPs power spectra. We show that the strength of the inter-layer coupling crucially affects this spatiotemporal structure. We predict that layer VI inactivation should induce global changes in the spectral properties of induced LFPs, reflecting their slower temporal decorrelation in the absence of inter-layer feedback. Finally, we argue that the mechanism underlying the emergence of synchronous chaos in our model is in fact very general. It stems from the fact that gamma oscillations induced by local delayed inhibition tend to develop chaos when coupled by sufficiently strong excitation.'),
(85163, 2011, 'plos', 'Computational modeling of allosteric communication reveals organizing principles of mutation-induced signaling in ABL and EGFR kinases', 'Dixit, Anshuman|Verkhivker, Gennady M', 'Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas, United States of America.|Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas, United States of America.', 'United States|United States', 0, 'Allosteric Regulation|Catalytic Domain|Computational Biology|Dimerization|Enzyme Activation|ErbB Receptors|Humans|Models, Molecular|Molecular Dynamics Simulation|Mutation|Principal Component Analysis|Protein Interaction Domains and Motifs|Protein Structure, Quaternary|Protein Structure, Secondary|Proto-Oncogene Proteins c-abl|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002179', '21998569', 'The emerging structural information about allosteric kinase complexes and the growing number of allosteric inhibitors call for a systematic strategy to delineate and classify mechanisms of allosteric regulation and long-range communication that control kinase activity. In this work, we have investigated mechanistic aspects of long-range communications in ABL and EGFR kinases based on the results of multiscale simulations of regulatory complexes and computational modeling of signal propagation in proteins. These approaches have been systematically employed to elucidate organizing molecular principles of allosteric signaling in the ABL and EGFR multi-domain regulatory complexes and analyze allosteric signatures of the gate-keeper cancer mutations. We have presented evidence that mechanisms of allosteric activation may have universally evolved in the ABL and EGFR regulatory complexes as a product of a functional cross-talk between the organizing xcexb1F-helix and conformationally adaptive xcexb1I-helix and xcexb1C-helix. These structural elements form a dynamic network of efficiently communicated clusters that may control the long-range interdomain coupling and allosteric activation. The results of this study have unveiled a unifying effect of the gate-keeper cancer mutations as catalysts of kinase activation, leading to the enhanced long-range communication among allosterically coupled segments and stabilization of the active kinase form. The results of this study can reconcile recent experimental studies of allosteric inhibition and long-range cooperativity between binding sites in protein kinases. The presented study offers a novel molecular insight into mechanistic aspects of allosteric kinase signaling and provides a quantitative picture of activation mechanisms in protein kinases at the atomic level.'),
(85164, 2011, 'plos', 'Three people can synchronize as coupled oscillators during sports activities', 'Yokoyama, Keiko|Yamamoto, Yuji', 'Graduate School of Education and Human Development, Nagoya University, Furo-cho, Chikusa, Nagoya, Japan. yokoyama@htc.nagoya-u.ac.jp|Graduate School of Education and Human Development, Nagoya University, Furo-cho, Chikusa, Nagoya, Japan. yokoyama@htc.nagoya-u.ac.jp', 'Japan|Japan', 0, 'Animals|Athletic Performance|Biological Clocks|Communication|Computational Biology|Female|Humans|Male|Models, Biological|Movement|Nonlinear Dynamics|Soccer|Sports|Time Factors|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1002181', '21998570', 'We experimentally investigated the synchronized patterns of three people during sports activities and found that the activity corresponded to spatiotemporal patterns in rings of coupled biological oscillators derived from symmetric Hopf bifurcation theory, which is based on group theory. This theory can provide catalogs of possible generic spatiotemporal patterns irrespective of their internal models. Instead, they are simply based on the geometrical symmetries of the systems. We predicted the synchronization patterns of rings of three coupled oscillators as trajectories on the phase plane. The interactions among three people during a 3 vs. 1 ball possession task were plotted on the phase plane. We then demonstrated that two patterns conformed to two of the three patterns predicted by the theory. One of these patterns was a rotation pattern (R) in which phase differences between adjacent oscillators were almost 2xcfx80/3. The other was a partial anti-phase pattern (PA) in which the two oscillators were anti-phase and the third oscillator frequency was dead. These results suggested that symmetric Hopf bifurcation theory could be used to understand synchronization phenomena among three people who communicate via perceptual information, not just physically connected systems such as slime molds, chemical reactions, and animal gaits. In addition, the skill level in human synchronization may play the role of the bifurcation parameter.'),
(85165, 2011, 'plos', 'Local orientation and the evolution of foraging: changes in decision making can eliminate evolutionary trade-offs', 'van der Post, Daniel J|Semmann, Dirk', 'Courant Research Center Evolution of Social Behaviour, Georg-August Universität Göttingen, Göttingen, Germany. d.j.vanderpost@gmail.com|Courant Research Center Evolution of Social Behaviour, Georg-August Universität Göttingen, Göttingen, Germany. d.j.vanderpost@gmail.com', 'Germany|Germany', 8, 'Animals|Behavior, Animal|Biological Evolution|Computational Biology|Decision Making|Food|Models, Biological|Models, Psychological|Orientation', 'Journal Article', '10.1371/journal.pcbi.1002186', '21998571', 'Information processing is a major aspect of the evolution of animal behavior. In foraging, responsiveness to local feeding opportunities can generate patterns of behavior which reflect or recognize patterns in the environment beyond the perception of individuals. Theory on the evolution of behavior generally neglects such opportunity-based adaptation. Using a spatial individual-based model we study the role of opportunity-based adaptation in the evolution of foraging, and how it depends on local decision making. We compare two model variants which differ in the individual decision making that can evolve (restricted and extended model), and study the evolution of simple foraging behavior in environments where food is distributed either uniformly or in patches. We find that opportunity-based adaptation and the pattern recognition it generates, plays an important role in foraging success, particularly in patchy environments where one of the main challenges is staying in patches. In the restricted model this is achieved by genetic adaptation of move and search behavior, in light of a trade-off on within- and between-patch behavior. In the extended model this trade-off does not arise because decision making capabilities allow for differentiated behavioral patterns. As a consequence, it becomes possible for properties of movement to be specialized for detection of patches with more food, a larger scale information processing not present in the restricted model. Our results show that changes in decision making abilities can alter what kinds of pattern recognition are possible, eliminate an evolutionary trade-off and change the adaptive landscape.'),
(85166, 2011, 'plos', 'B cell activation triggered by the formation of the small receptor cluster: a computational study', 'Hat, Beata|Kazmierczak, Bogdan|Lipniacki, Tomasz', 'Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.|Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.|Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.', 'Poland|Poland|Poland', 24, 'B-Lymphocytes|Cell Membrane|Computational Biology|Humans|Immunological Synapses|Lymphocyte Activation|Models, Immunological|Receptor Aggregation|Receptors, Antigen, B-Cell|src-Family Kinases', 'Journal Article', '10.1371/journal.pcbi.1002197', '21998572', 'We proposed a spatially extended model of early events of B cell receptors (BCR) activation, which is based on mutual kinase-receptor interactions that are characteristic for the immune receptors and the Src family kinases. These interactions lead to the positive feedback which, together with two nonlinearities resulting from the double phosphorylation of receptors and Michaelis-Menten dephosphorylation kinetics, are responsible for the system bistability. We demonstrated that B cell can be activated by a formation of a tiny cluster of receptors or displacement of the nucleus. The receptors and Src kinases are activated, first locally, in the locus of the receptor cluster or the region where the cytoplasm is the thinnest. Then the traveling wave of activation propagates until activity spreads over the whole cell membrane. In the models in which we assume that the kinases are free to diffuse in the cytoplasm, we found that the fraction of aggregated receptors, capable to initiate B cell activation decreases with the decreasing thickness of cytoplasm and decreasing kinase diffusion. When kinases are restricted to the cell membrane - which is the case for most of the Src family kinases - even a cluster consisting of a tiny fraction of total receptors becomes activatory. Interestingly, the system remains insensitive to the modest changes of total receptor level. The model provides a plausible mechanism of B cells activation due to the formation of small receptors clusters collocalized by binding of polyvalent antigens or arising during the immune synapse formation.'),
(85167, 2011, 'plos', 'Evolution of networks for body plan patterning, interplay of modularity, robustness and evolvability', 'Ten Tusscher, Kirsten H|Hogeweg, Paulien', 'Theoretical Biology and Bioinformatics Group, Department of Biology, Utrecht University, Utrecht, The Netherlands. K.H.W.J.tenTusscher@uu.nl|Theoretical Biology and Bioinformatics Group, Department of Biology, Utrecht University, Utrecht, The Netherlands. K.H.W.J.tenTusscher@uu.nl', 'Netherlands|Netherlands', 0, 'Animals|Biological Evolution|Body Patterning|Computational Biology|Computer Simulation|Gene Expression Regulation, Developmental|Gene Regulatory Networks|Models, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002208', '21998573', 'A major goal of evolutionary developmental biology (evo-devo) is to understand how multicellular body plans of increasing complexity have evolved, and how the corresponding developmental programs are genetically encoded. It has been repeatedly argued that key to the evolution of increased body plan complexity is the modularity of the underlying developmental gene regulatory networks (GRNs). This modularity is considered essential for network robustness and evolvability. In our opinion, these ideas, appealing as they may sound, have not been sufficiently tested. Here we use computer simulations to study the evolution of GRNs underlying body plan patterning. We select for body plan segmentation and differentiation, as these are considered to be major innovations in metazoan evolution. To allow modular networks to evolve, we independently select for segmentation and differentiation. We study both the occurrence and relation of robustness, evolvability and modularity of evolved networks. Interestingly, we observed two distinct evolutionary strategies to evolve a segmented, differentiated body plan. In the first strategy, first segments and then differentiation domains evolve (SF strategy). In the second scenario segments and domains evolve simultaneously (SS strategy). We demonstrate that under indirect selection for robustness the SF strategy becomes dominant. In addition, as a byproduct of this larger robustness, the SF strategy is also more evolvable. Finally, using a combined functional and architectural approach, we determine network modularity. We find that while SS networks generate segments and domains in an integrated manner, SF networks use largely independent modules to produce segments and domains. Surprisingly, we find that widely used, purely architectural methods for determining network modularity completely fail to establish this higher modularity of SF networks. Finally, we observe that, as a free side effect of evolving segmentation and differentiation in combination, we obtained in-silico developmental mechanisms resembling mechanisms used in vertebrate development.'),
(85168, 2011, 'plos', 'Estimating the relevance of world disturbances to explain savings, interference and long-term motor adaptation effects', 'Berniker, Max|Kording, Konrad P', 'Department of Physical Medicine and Rehabilitation, Northwestern University and Rehabilitation Institute of Chicago, Chicago, Illinois, United States of America. mbernike@northwestern.edu|Department of Physical Medicine and Rehabilitation, Northwestern University and Rehabilitation Institute of Chicago, Chicago, Illinois, United States of America. mbernike@northwestern.edu', 'United States|United States', 0, 'Adaptation, Physiological|Computational Biology|Feedback, Physiological|Humans|Linear Models|Models, Neurological|Motor Skills|Movement|Nervous System Physiological Phenomena|Psychomotor Performance|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1002210', '21998574', 'Recent studies suggest that motor adaptation is the result of multiple, perhaps linear processes each with distinct time scales. While these models are consistent with some motor phenomena, they can neither explain the relatively fast re-adaptation after a long washout period, nor savings on a subsequent day. Here we examined if these effects can be explained if we assume that the CNS stores and retrieves movement parameters based on their possible relevance. We formalize this idea with a model that infers not only the sources of potential motor errors, but also their relevance to the current motor circumstances. In our model adaptation is the process of re-estimating parameters that represent the body and the world. The likelihood of a world parameter being relevant is then based on the mismatch between an observed movement and that predicted when not compensating for the estimated world disturbance. As such, adapting to large motor errors in a laboratory setting should alert subjects that disturbances are being imposed on them, even after motor performance has returned to baseline. Estimates of this external disturbance should be relevant both now and in future laboratory settings. Estimated properties of our bodies on the other hand should always be relevant. Our model demonstrates savings, interference, spontaneous rebound and differences between adaptation to sudden and gradual disturbances. We suggest that many issues concerning savings and interference can be understood when adaptation is conditioned on the relevance of parameters.'),
(85169, 2011, 'plos', 'Automatic morphological subtyping reveals new roles of caspases in mitochondrial dynamics', 'Peng, Jyh-Ying|Lin, Chung-Chih|Chen, Yen-Jen|Kao, Lung-Sen|Liu, Young-Chau|Chou, Chung-Chien|Huang, Yi-Hung|Chang, Fang-Rong|Wu, Yang-Chang|Tsai, Yuh-Show|Hsu, Chun-Nan', 'Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan. jypeng@ym.edu.tw|Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan. jypeng@ym.edu.tw|Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan. jypeng@ym.edu.tw|Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan. jypeng@ym.edu.tw|Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan. jypeng@ym.edu.tw|Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan. jypeng@ym.edu.tw|Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan. jypeng@ym.edu.tw|Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan. jypeng@ym.edu.tw|Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan. jypeng@ym.edu.tw|Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan. jypeng@ym.edu.tw|Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan. jypeng@ym.edu.tw', '-|-|-|-|-|-|-|-|-|-|-', 66, 'Animals|CHO Cells|Caspase Inhibitors|Caspases|Computational Biology|Cricetinae|Cricetulus|Cysteine Proteinase Inhibitors|Dimethyl Sulfoxide|Furans|Lactones|Mitochondria|Models, Biological|Oligopeptides|Pattern Recognition, Automated', 'Journal Article', '10.1371/journal.pcbi.1002212', '21998575', 'Morphological dynamics of mitochondria is associated with key cellular processes related to aging and neuronal degenerative diseases, but the lack of standard quantification of mitochondrial morphology impedes systematic investigation. This paper presents an automated system for the quantification and classification of mitochondrial morphology. We discovered six morphological subtypes of mitochondria for objective quantification of mitochondrial morphology. These six subtypes are small globules, swollen globules, straight tubules, twisted tubules, branched tubules and loops. The subtyping was derived by applying consensus clustering to a huge collection of more than 200 thousand mitochondrial images extracted from 1422 micrographs of Chinese hamster ovary (CHO) cells treated with different drugs, and was validated by evidence of functional similarity reported in the literature. Quantitative statistics of subtype compositions in cells is useful for correlating drug response and mitochondrial dynamics. Combining the quantitative results with our biochemical studies about the effects of squamocin on CHO cells reveals new roles of Caspases in the regulatory mechanisms of mitochondrial dynamics. This system is not only of value to the mitochondrial field, but also applicable to the investigation of other subcellular organelle morphology.'),
(85170, 2011, 'plos', 'Monkeys and humans share a common computation for face/voice integration', 'Chandrasekaran, Chandramouli|Lemus, Luis|Trubanova, Andrea|Gondan, Matthias|Ghazanfar, Asif A', 'Neuroscience Institute, Princeton University, Princeton, NJ, USA.|Neuroscience Institute, Princeton University, Princeton, NJ, USA.|Neuroscience Institute, Princeton University, Princeton, NJ, USA.|Neuroscience Institute, Princeton University, Princeton, NJ, USA.|Neuroscience Institute, Princeton University, Princeton, NJ, USA.', 'United States|United States|United States|United States|United States', 0, 'Acoustic Stimulation|Animals|Computational Biology|Face|Female|Humans|Macaca fascicularis|Male|Models, Neurological|Models, Psychological|Photic Stimulation|Reaction Time|Species Specificity|Speech Perception|Visual Perception|Vocalization, Animal', 'Comparative Study', '10.1371/journal.pcbi.1002165', '21998576', 'Speech production involves the movement of the mouth and other regions of the face resulting in visual motion cues. These visual cues enhance intelligibility and detection of auditory speech. As such, face-to-face speech is fundamentally a multisensory phenomenon. If speech is fundamentally multisensory, it should be reflected in the evolution of vocal communication: similar behavioral effects should be observed in other primates. Old World monkeys share with humans vocal production biomechanics and communicate face-to-face with vocalizations. It is unknown, however, if they, too, combine faces and voices to enhance their perception of vocalizations. We show that they do: monkeys combine faces and voices in noisy environments to enhance their detection of vocalizations. Their behavior parallels that of humans performing an identical task. We explored what common computational mechanism(s) could explain the pattern of results we observed across species. Standard explanations or models such as the principle of inverse effectiveness and a race model failed to account for their behavior patterns. Conversely, a superposition model, positing the linear summation of activity patterns in response to visual and auditory components of vocalizations, served as a straightforward but powerful explanatory mechanism for the observed behaviors in both species. As such, it represents a putative homologous mechanism for integrating faces and voices across primates.'),
(85171, 2011, 'plos', 'A peptide filtering relation quantifies MHC class I peptide optimization', 'Dalchau, Neil|Phillips, Andrew|Goldstein, Leonard D|Howarth, Mark|Cardelli, Luca|Emmott, Stephen|Elliott, Tim|Werner, Joern M', 'Biological Computation Group, Microsoft Research, Cambridge, United Kingdom. ndalchau@microsoft.com|Biological Computation Group, Microsoft Research, Cambridge, United Kingdom. ndalchau@microsoft.com|Biological Computation Group, Microsoft Research, Cambridge, United Kingdom. ndalchau@microsoft.com|Biological Computation Group, Microsoft Research, Cambridge, United Kingdom. ndalchau@microsoft.com|Biological Computation Group, Microsoft Research, Cambridge, United Kingdom. ndalchau@microsoft.com|Biological Computation Group, Microsoft Research, Cambridge, United Kingdom. ndalchau@microsoft.com|Biological Computation Group, Microsoft Research, Cambridge, United Kingdom. ndalchau@microsoft.com|Biological Computation Group, Microsoft Research, Cambridge, United Kingdom. ndalchau@microsoft.com', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Bayes Theorem|Histocompatibility Antigens Class I|Humans|Models, Theoretical|Peptides|T-Lymphocytes', 'Journal Article', '10.1371/journal.pcbi.1002144', '22022238', 'Major Histocompatibility Complex (MHC) class I molecules enable cytotoxic T lymphocytes to destroy virus-infected or cancerous cells, thereby preventing disease progression. MHC class I molecules provide a snapshot of the contents of a cell by binding to protein fragments arising from intracellular protein turnover and presenting these fragments at the cell surface. Competing fragments (peptides) are selected for cell-surface presentation on the basis of their ability to form a stable complex with MHC class I, by a process known as peptide optimization. A better understanding of the optimization process is important for our understanding of immunodominance, the predominance of some T lymphocyte specificities over others, which can determine the efficacy of an immune response, the danger of immune evasion, and the success of vaccination strategies. In this paper we present a dynamical systems model of peptide optimization by MHC class I. We incorporate the chaperone molecule tapasin, which has been shown to enhance peptide optimization to different extents for different MHC class I alleles. Using a combination of published and novel experimental data to parameterize the model, we arrive at a relation of peptide filtering, which quantifies peptide optimization as a function of peptide supply and peptide unbinding rates. From this relation, we find that tapasin enhances peptide unbinding to improve peptide optimization without significantly delaying the transit of MHC to the cell surface, and differences in peptide optimization across MHC class I alleles can be explained by allele-specific differences in peptide binding. Importantly, our filtering relation may be used to dynamically predict the cell surface abundance of any number of competing peptides by MHC class I alleles, providing a quantitative basis to investigate viral infection or disease at the cellular level. We exemplify this by simulating optimization of the distribution of peptides derived from Human Immunodeficiency Virus Gag-Pol polyprotein.'),
(85172, 2011, 'plos', 'Inversion of the balance between hydrophobic and hydrogen bonding interactions in protein folding and aggregation', 'Fitzpatrick, Anthony W|Knowles, Tuomas P J|Waudby, Christopher A|Vendruscolo, Michele|Dobson, Christopher M', 'Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Alzheimer Disease|Diabetes Mellitus, Type 2|Humans|Hydrogen Bonding|Parkinson Disease|Protein Folding', 'Journal Article', '10.1371/journal.pcbi.1002169', '22022239', 'Identifying the forces that drive proteins to misfold and aggregate, rather than to fold into their functional states, is fundamental to our understanding of living systems and to our ability to combat protein deposition disorders such as Alzheimers disease and the spongiform encephalopathies. We report here the finding that the balance between hydrophobic and hydrogen bonding interactions is different for proteins in the processes of folding to their native states and misfolding to the alternative amyloid structures. We find that the minima of the protein free energy landscape for folding and misfolding tend to be respectively dominated by hydrophobic and by hydrogen bonding interactions. These results characterise the nature of the interactions that determine the competition between folding and misfolding of proteins by revealing that the stability of native proteins is primarily determined by hydrophobic interactions between side-chains, while the stability of amyloid fibrils depends more on backbone intermolecular hydrogen bonding interactions.'),
(85173, 2011, 'plos', 'Large-scale conformational changes of Trypanosoma cruzi proline racemase predicted by accelerated molecular dynamics simulation', 'de Oliveira, César Augusto F|Grant, Barry J|Zhou, Michelle|McCammon, J Andrew', 'Departments of Chemistry and Biochemistry, Howard Hughes Medical Institute, Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, California, United States of America. cesar@mccammon.ucsd.edu|Departments of Chemistry and Biochemistry, Howard Hughes Medical Institute, Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, California, United States of America. cesar@mccammon.ucsd.edu|Departments of Chemistry and Biochemistry, Howard Hughes Medical Institute, Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, California, United States of America. cesar@mccammon.ucsd.edu|Departments of Chemistry and Biochemistry, Howard Hughes Medical Institute, Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, California, United States of America. cesar@mccammon.ucsd.edu', 'United States|United States|United States|United States', 0, 'Amino Acid Isomerases|Animals|B-Lymphocytes|Models, Molecular|Molecular Dynamics Simulation|Principal Component Analysis|Protein Conformation|Protozoan Proteins|Trypanosoma cruzi', 'Journal Article', '10.1371/journal.pcbi.1002178', '22022240', 'Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is a life-threatening illness affecting 11-18 million people. Currently available treatments are limited, with unacceptable efficacy and safety profiles. Recent studies have revealed an essential T. cruzi proline racemase enzyme (TcPR) as an attractive candidate for improved chemotherapeutic intervention. Conformational changes associated with substrate binding to TcPR are believed to expose critical residues that elicit a host mitogenic B-cell response, a process contributing to parasite persistence and immune system evasion. Characterization of the conformational states of TcPR requires access to long-time-scale motions that are currently inaccessible by standard molecular dynamics simulations. Here we describe advanced accelerated molecular dynamics that extend the effective simulation time and capture large-scale motions of functional relevance. Conservation and fragment mapping analyses identified potential conformational epitopes located in the vicinity of newly identified transient binding pockets. The newly identified open TcPR conformations revealed by this study along with knowledge of the closed to open interconversion mechanism advances our understanding of TcPR function. The results and the strategy adopted in this work constitute an important step toward the rationalization of the molecular basis behind the mitogenic B-cell response of TcPR and provide new insights for future structure-based drug discovery.'),
(85174, 2011, 'plos', 'Barriers to diffusion in dendrites and estimation of calcium spread following synaptic inputs', 'Biess, Armin|Korkotian, Eduard|Holcman, David', 'Bernstein Center for Computational Neuroscience, Gxc3xb6ttingen, Germany. armin@nld.ds.mpg.de|Bernstein Center for Computational Neuroscience, Gxc3xb6ttingen, Germany. armin@nld.ds.mpg.de|Bernstein Center for Computational Neuroscience, Gxc3xb6ttingen, Germany. armin@nld.ds.mpg.de', 'Germany|Germany|Germany', 30, 'Calcium|Cytoplasm|Dendrites|Diffusion|Models, Theoretical|Synapses', 'Journal Article', '10.1371/journal.pcbi.1002182', '22022241', 'The motion of ions, molecules or proteins in dendrites is restricted by cytoplasmic obstacles such as organelles, microtubules and actin network. To account for molecular crowding, we study the effect of diffusion barriers on local calcium spread in a dendrite. We first present a model based on a dimension reduction approach to approximate a three dimensional diffusion in a cylindrical dendrite by a one-dimensional effective diffusion process. By comparing uncaging experiments of an inert dye in a spiny dendrite and in a thin glass tube, we quantify the change in diffusion constants due to molecular crowding as D(cyto)/D(water)xe2x80x8a=xe2x80x8a1/20. We validate our approach by reconstructing the uncaging experiments using Brownian simulations in a realistic 3D model dendrite. Finally, we construct a reduced reaction-diffusion equation to model calcium spread in a dendrite under the presence of additional buffers, pumps and synaptic input. We find that for moderate crowding, calcium dynamics is mainly regulated by the buffer concentration, but not by the cytoplasmic crowding, dendritic spines or synaptic inputs. Following high frequency stimulations, we predict that calcium spread in dendrites is limited to small microdomains of the order of a few microns (<5 xcexbcm).');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85175, 2011, 'plos', 'Evidence for composite cost functions in arm movement planning: an inverse optimal control approach', 'Berret, Bastien|Chiovetto, Enrico|Nori, Francesco|Pozzo, Thierry', 'Italian Institute of Technology, Department of Robotics, Brain and Cognitive Sciences, Genoa, Italy. bastien.berret@iit.it|Italian Institute of Technology, Department of Robotics, Brain and Cognitive Sciences, Genoa, Italy. bastien.berret@iit.it|Italian Institute of Technology, Department of Robotics, Brain and Cognitive Sciences, Genoa, Italy. bastien.berret@iit.it|Italian Institute of Technology, Department of Robotics, Brain and Cognitive Sciences, Genoa, Italy. bastien.berret@iit.it', 'Italy|Italy|Italy|Italy', 0, 'Adolescent|Adult|Arm|Female|Humans|Male|Models, Anatomic|Movement|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1002183', '22022242', 'An important issue in motor control is understanding the basic principles underlying the accomplishment of natural movements. According to optimal control theory, the problem can be stated in these terms: what cost function do we optimize to coordinate the many more degrees of freedom than necessary to fulfill a specific motor goal? This question has not received a final answer yet, since what is optimized partly depends on the requirements of the task. Many cost functions were proposed in the past, and most of them were found to be in agreement with experimental data. Therefore, the actual principles on which the brain relies to achieve a certain motor behavior are still unclear. Existing results might suggest that movements are not the results of the minimization of single but rather of composite cost functions. In order to better clarify this last point, we consider an innovative experimental paradigm characterized by arm reaching with target redundancy. Within this framework, we make use of an inverse optimal control technique to automatically infer the (combination of) optimality criteria that best fit the experimental data. Results show that the subjects exhibited a consistent behavior during each experimental condition, even though the target point was not prescribed in advance. Inverse and direct optimal control together reveal that the average arm trajectories were best replicated when optimizing the combination of two cost functions, nominally a mix between the absolute work of torques and the integrated squared joint acceleration. Our results thus support the cost combination hypothesis and demonstrate that the recorded movements were closely linked to the combination of two complementary functions related to mechanical energy expenditure and joint-level smoothness.'),
(85176, 2011, 'plos', 'Transmission selects for HIV-1 strains of intermediate virulence: a modelling approach', 'Shirreff, George|Pellis, Lorenzo|Laeyendecker, Oliver|Fraser, Christophe', 'Medical Research Council Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College, London, United Kingdom.|Medical Research Council Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College, London, United Kingdom.|Medical Research Council Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College, London, United Kingdom.|Medical Research Council Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 27, 'Genes, Viral|Genotype|HIV Infections|HIV-1|Humans|Likelihood Functions|Models, Theoretical|Mutation|Virulence', 'Journal Article', '10.1371/journal.pcbi.1002185', '22022243', 'Recent data shows that HIV-1 is characterised by variation in viral virulence factors that is heritable between infections, which suggests that viral virulence can be naturally selected at the population level. A trade-off between transmissibility and duration of infection appears to favour viruses of intermediate virulence. We developed a mathematical model to simulate the dynamics of putative viral genotypes that differ in their virulence. As a proxy for virulence, we use set-point viral load (SPVL), which is the steady density of viral particles in blood during asymptomatic infection. Mutation, the dependency of survival and transmissibility on SPVL, and host effects were incorporated into the model. The model was fitted to data to estimate unknown parameters, and was found to fit existing data well. The maximum likelihood estimates of the parameters produced a model in which SPVL converged from any initial conditions to observed values within 100-150 years of first emergence of HIV-1. We estimated the 1) host effect and 2) the extent to which the viral virulence genotype mutates from one infection to the next, and found a trade-off between these two parameters in explaining the variation in SPVL. The model confirms that evolution of virulence towards intermediate levels is sufficiently rapid for it to have happened in the early stages of the HIV epidemic, and confirms that existing viral loads are nearly optimal given the assumed constraints on evolution. The model provides a useful framework under which to examine the future evolution of HIV-1 virulence.'),
(85177, 2011, 'plos', 'Heat shock partially dissociates the overlapping modules of the yeast protein-protein interaction network: a systems level model of adaptation', 'Mihalik, Ágoston|Csermely, Peter', 'Department of Medical Chemistry, Semmelweis University, Budapest, Hungary.|Department of Medical Chemistry, Semmelweis University, Budapest, Hungary.', 'Hungary|Hungary', 0, 'Adaptation, Physiological|Heat-Shock Response|Models, Biological|Oligonucleotide Array Sequence Analysis|RNA, Messenger|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins', 'Journal Article', '10.1371/journal.pcbi.1002187', '22022244', 'Network analysis became a powerful tool giving new insights to the understanding of cellular behavior. Heat shock, the archetype of stress responses, is a well-characterized and simple model of cellular dynamics. S. cerevisiae is an appropriate model organism, since both its protein-protein interaction network (interactome) and stress response at the gene expression level have been well characterized. However, the analysis of the reorganization of the yeast interactome during stress has not been investigated yet. We calculated the changes of the interaction-weights of the yeast interactome from the changes of mRNA expression levels upon heat shock. The major finding of our study is that heat shock induced a significant decrease in both the overlaps and connections of yeast interactome modules. In agreement with this the weighted diameter of the yeast interactome had a 4.9-fold increase in heat shock. Several key proteins of the heat shock response became centers of heat shock-induced local communities, as well as bridges providing a residual connection of modules after heat shock. The observed changes resemble to a stratus-cumulus type transition of the interactome structure, since the unstressed yeast interactome had a globally connected organization, similar to that of stratus clouds, whereas the heat shocked interactome had a multifocal organization, similar to that of cumulus clouds. Our results showed that heat shock induces a partial disintegration of the global organization of the yeast interactome. This change may be rather general occurring in many types of stresses. Moreover, other complex systems, such as single proteins, social networks and ecosystems may also decrease their inter-modular links, thus develop more compact modules, and display a partial disintegration of their global structure in the initial phase of crisis. Thus, our work may provide a model of a general, system-level adaptation mechanism to environmental changes.'),
(85178, 2011, 'plos', 'Neural computation via neural geometry: a place code for inter-whisker timing in the barrel cortex?', 'Wilson, Stuart P|Bednar, James A|Prescott, Tony J|Mitchinson, Ben', 'Active Touch Laboratory, Department of Psychology, The University of Sheffield, Sheffield, United Kingdom. S.P.Wilson@Sheffield.ac.uk|Active Touch Laboratory, Department of Psychology, The University of Sheffield, Sheffield, United Kingdom. S.P.Wilson@Sheffield.ac.uk|Active Touch Laboratory, Department of Psychology, The University of Sheffield, Sheffield, United Kingdom. S.P.Wilson@Sheffield.ac.uk|Active Touch Laboratory, Department of Psychology, The University of Sheffield, Sheffield, United Kingdom. S.P.Wilson@Sheffield.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 3, 'Action Potentials|Animals|Models, Theoretical|Neurons|Rats|Vibrissae', 'Journal Article', '10.1371/journal.pcbi.1002188', '22022245', 'The place theory proposed by Jeffress (1948) is still the dominant model of how the brain represents the movement of sensory stimuli between sensory receptors. According to the place theory, delays in signalling between neurons, dependent on the distances between them, compensate for time differences in the stimulation of sensory receptors. Hence the location of neurons, activated by the coincident arrival of multiple signals, reports the stimulus movement velocity. Despite its generality, most evidence for the place theory has been provided by studies of the auditory system of auditory specialists like the barn owl, but in the study of mammalian auditory systems the evidence is inconclusive. We ask to what extent the somatosensory systems of tactile specialists like rats and mice use distance dependent delays between neurons to compute the motion of tactile stimuli between the facial whiskers (or vibrissae). We present a model in which synaptic inputs evoked by whisker deflections arrive at neurons in layer 2/3 (L2/3) somatosensory barrel cortex at different times. The timing of synaptic inputs to each neuron depends on its location relative to sources of input in layer 4 (L4) that represent stimulation of each whisker. Constrained by the geometry and timing of projections from L4 to L2/3, the model can account for a range of experimentally measured responses to two-whisker stimuli. Consistent with that data, responses of model neurons located between the barrels to paired stimulation of two whiskers are greater than the sum of the responses to either whisker input alone. The model predicts that for neurons located closer to either barrel these supralinear responses are tuned for longer inter-whisker stimulation intervals, yielding a topographic map for the inter-whisker deflection interval across the surface of L2/3. This map constitutes a neural place code for the relative timing of sensory stimuli.'),
(85179, 2011, 'plos', 'Identification of potent EGFR inhibitors from TCM Database@Taiwan', 'Yang, Shun-Chieh|Chang, Su-Sen|Chen, Hsin-Yi|Chen, Calvin Yu-Chian', 'Laboratory of Computational and Systems Biology, School of Chinese Medicine, China Medical University, Taichung, Taiwan. ycc929@MIT.EDU|Laboratory of Computational and Systems Biology, School of Chinese Medicine, China Medical University, Taichung, Taiwan. ycc929@MIT.EDU|Laboratory of Computational and Systems Biology, School of Chinese Medicine, China Medical University, Taichung, Taiwan. ycc929@MIT.EDU|Laboratory of Computational and Systems Biology, School of Chinese Medicine, China Medical University, Taichung, Taiwan. ycc929@MIT.EDU', 'China|China|China|China', 0, 'Algorithms|Databases, Factual|ErbB Receptors|Hydrogen Bonding|Ligands|Models, Molecular|Molecular Dynamics Simulation|Protein Conformation|Quantitative Structure-Activity Relationship|Taiwan', 'Journal Article', '10.1371/journal.pcbi.1002189', '22022246', 'Overexpression of epidermal growth factor receptor (EGFR) has been associated with cancer. Targeted inhibition of the EGFR pathway has been shown to limit proliferation of cancerous cells. Hence, we employed Traditional Chinese Medicine Database (TCM Database@Taiwan) (http://tcm.cmu.edu.tw) to identify potential EGFR inhibitor. Multiple Linear Regression (MLR), Support Vector Machine (SVM), Comparative Molecular Field Analysis (CoMFA), and Comparative Molecular Similarities Indices Analysis (CoMSIA) models were generated using a training set of EGFR ligands of known inhibitory activities. The top four TCM candidates based on DockScore were 2-O-caffeoyl tartaric acid, Emitine, Rosmaricine, and 2-O-feruloyl tartaric acid, and all had higher binding affinities than the control Iressaxc2xae. The TCM candidates had interactions with Asp855, Lys716, and Lys728, all which are residues of the protein kinase binding site. Validated MLR (rxc2xb2xe2x80x8a=xe2x80x8a0.7858) and SVM (rxc2xb2xe2x80x8a=xe2x80x8a0.8754) models predicted good bioactivity for the TCM candidates. In addition, the TCM candidates contoured well to the 3D-Quantitative Structure-Activity Relationship (3D-QSAR) map derived from the CoMFA (qxc2xb2xe2x80x8a=xe2x80x8a0.721, rxc2xb2xe2x80x8a=xe2x80x8a0.986) and CoMSIA (qxc2xb2xe2x80x8a=xe2x80x8a0.662, rxc2xb2xe2x80x8a=xe2x80x8a0.988) models. The steric field, hydrophobic field, and H-bond of the 3D-QSAR map were well matched by each TCM candidate. Molecular docking indicated that all TCM candidates formed H-bonds within the EGFR protein kinase domain. Based on the different structures, H-bonds were formed at either Asp855 or Lys716/Lys728. The compounds remained stable throughout molecular dynamics (MD) simulation. Based on the results of this study, 2-O-caffeoyl tartaric acid, Emitine, Rosmaricine, and 2-O-feruloyl tartaric acid are suggested to be potential EGFR inhibitors.'),
(85180, 2011, 'plos', 'Quantifying intramolecular binding in multivalent interactions: a structure-based synergistic study on Grb2-Sos1 complex', 'Sethi, Anurag|Goldstein, Byron|Gnanakaran, S', 'Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.', 'Mexico|Mexico|Mexico', 13, 'Amino Acid Sequence|Animals|GRB2 Adaptor Protein|Humans|Models, Molecular|Molecular Dynamics Simulation|Molecular Sequence Data|Molecular Structure|Probability|Protein Binding|SOS1 Protein|Sequence Homology, Amino Acid', 'Journal Article', '10.1371/journal.pcbi.1002192', '22022247', 'Numerous signaling proteins use multivalent binding to increase the specificity and affinity of their interactions within the cell. Enhancement arises because the effective binding constant for multivalent binding is larger than the binding constants for each individual interaction. We seek to gain both qualitative and quantitative understanding of the multivalent interactions of an adaptor protein, growth factor receptor bound protein-2 (Grb2), containing two SH3 domains interacting with the nucleotide exchange factor son-of-sevenless 1 (Sos1) containing multiple polyproline motifs separated by flexible unstructured regions. Grb2 mediates the recruitment of Sos1 from the cytosol to the plasma membrane where it activates Ras by inducing the exchange of GDP for GTP. First, using a combination of evolutionary information and binding energy calculations, we predict an additional polyproline motif in Sos1 that binds to the SH3 domains of Grb2. This gives rise to a total of five polyproline motifs in Sos1 that are capable of binding to the two SH3 domains of Grb2. Then, using a hybrid method combining molecular dynamics simulations and polymer models, we estimate the enhancement in local concentration of a polyproline motif on Sos1 near an unbound SH3 domain of Grb2 when its other SH3 domain is bound to a different polyproline motif on Sos1. We show that the local concentration of the Sos1 motifs that a Grb2 SH3 domain experiences is approximately 1000 times greater than the cellular concentration of Sos1. Finally, we calculate the intramolecular equilibrium constants for the crosslinking of Grb2 on Sos1 and use thermodynamic modeling to calculate the stoichiometry. With these equilibrium constants, we are able to predict the distribution of complexes that form at physiological concentrations. We believe this is the first systematic analysis that combines sequence, structure, and thermodynamic analyses to determine the stoichiometry of the complexes that are dominant in the cellular environment.'),
(85181, 2011, 'plos', 'Ligand-induced modulation of the free-energy landscape of G protein-coupled receptors explored by adaptive biasing techniques', 'Provasi, Davide|Artacho, Marta Camacho|Negri, Ana|Mobarec, Juan Carlos|Filizola, Marta', 'Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Ligands|Models, Theoretical|Receptors, G-Protein-Coupled|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002193', '22022248', 'Extensive experimental information supports the formation of ligand-specific conformations of G protein-coupled receptors (GPCRs) as a possible molecular basis for their functional selectivity for signaling pathways. Taking advantage of the recently published inactive and active crystal structures of GPCRs, we have implemented an all-atom computational strategy that combines different adaptive biasing techniques to identify ligand-specific conformations along pre-determined activation pathways. Using the prototypic GPCR xcexb22-adrenergic receptor as a suitable test case for validation, we show that ligands with different efficacies (either inverse agonists, neutral antagonists, or agonists) modulate the free-energy landscape of the receptor by shifting the conformational equilibrium towards active or inactive conformations depending on their elicited physiological response. Notably, we provide for the first time a quantitative description of the thermodynamics of the receptor in an explicit atomistic environment, which accounts for the receptor basal activity and the stabilization of different active-like states by differently potent agonists. Structural inspection of these metastable states reveals unique conformations of the receptor that may have been difficult to retrieve experimentally.'),
(85182, 2011, 'plos', 'Assessing vaccination sentiments with online social media: implications for infectious disease dynamics and control', 'Salathé, Marcel|Khandelwal, Shashank', 'Center for Infectious Disease Dynamics, Department of Biology, Penn State University, University Park, Pennsylvania, United States of America. salathe@psu.edu|Center for Infectious Disease Dynamics, Department of Biology, Penn State University, University Park, Pennsylvania, United States of America. salathe@psu.edu', 'United States|United States', 0, 'Attitude to Health|Centers for Disease Control and Prevention (U.S.)|Disease Outbreaks|Humans|Immunization|Social Media|United States', 'Journal Article', '10.1371/journal.pcbi.1002199', '22022249', 'There is great interest in the dynamics of health behaviors in social networks and how they affect collective public health outcomes, but measuring population health behaviors over time and space requires substantial resources. Here, we use publicly available data from 101,853 users of online social media collected over a time period of almost six months to measure the spatio-temporal sentiment towards a new vaccine. We validated our approach by identifying a strong correlation between sentiments expressed online and CDC-estimated vaccination rates by region. Analysis of the network of opinionated users showed that information flows more often between users who share the same sentiments - and less often between users who do not share the same sentiments - than expected by chance alone. We also found that most communities are dominated by either positive or negative sentiments towards the novel vaccine. Simulations of infectious disease transmission show that if clusters of negative vaccine sentiments lead to clusters of unprotected individuals, the likelihood of disease outbreaks is greatly increased. Online social media provide unprecedented access to data allowing for inexpensive and efficient tools to identify target areas for intervention efforts and to evaluate their effectiveness.'),
(85183, 2011, 'plos', 'The dynamics of supply and demand in mRNA translation', 'Brackley, Chris A|Romano, M Carmen|Thiel, Marco', 'Institute for Complex Systems and Mathematical Biology, SUPA, University of Aberdeen, Aberdeen, United Kingdom. c.a.brackley@abdn.ac.uk|Institute for Complex Systems and Mathematical Biology, SUPA, University of Aberdeen, Aberdeen, United Kingdom. c.a.brackley@abdn.ac.uk|Institute for Complex Systems and Mathematical Biology, SUPA, University of Aberdeen, Aberdeen, United Kingdom. c.a.brackley@abdn.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Genome, Fungal|Monte Carlo Method|Protein Biosynthesis|RNA, Messenger|RNA, Transfer|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1002203', '22022250', 'We study the elongation stage of mRNA translation in eukaryotes and find that, in contrast to the assumptions of previous models, both the supply and the demand for tRNA resources are important for determining elongation rates. We find that increasing the initiation rate of translation can lead to the depletion of some species of aa-tRNA, which in turn can lead to slow codons and queueing. Particularly striking competition effects are observed in simulations of multiple species of mRNA which are reliant on the same pool of tRNA resources. These simulations are based on a recent model of elongation which we use to study the translation of mRNA sequences from the Saccharomyces cerevisiae genome. This model includes the dynamics of the use and recharging of amino acid tRNA complexes, and we show via Monte Carlo simulation that this has a dramatic effect on the protein production behaviour of the system.'),
(85184, 2011, 'plos', 'Brain rhythms reveal a hierarchical network organization', 'Steinke, G Karl|Galán, Roberto F', 'Department of Biomedical Engineering, School of Engineering, Case Western Reserve University, Cleveland, Ohio, United States of America.|Department of Biomedical Engineering, School of Engineering, Case Western Reserve University, Cleveland, Ohio, United States of America.', 'United States|United States', 0, 'Brain|Electroencephalography|Humans|Models, Theoretical|Probability', 'Journal Article', '10.1371/journal.pcbi.1002207', '22022251', 'Recordings of ongoing neural activity with EEG and MEG exhibit oscillations of specific frequencies over a non-oscillatory background. The oscillations appear in the power spectrum as a collection of frequency bands that are evenly spaced on a logarithmic scale, thereby preventing mutual entrainment and cross-talk. Over the last few years, experimental, computational and theoretical studies have made substantial progress on our understanding of the biophysical mechanisms underlying the generation of network oscillations and their interactions, with emphasis on the role of neuronal synchronization. In this paper we ask a very different question. Rather than investigating how brain rhythms emerge, or whether they are necessary for neural function, we focus on what they tell us about functional brain connectivity. We hypothesized that if we were able to construct abstract networks, or virtual brains, whose dynamics were similar to EEG/MEG recordings, those networks would share structural features among themselves, and also with real brains. Applying mathematical techniques for inverse problems, we have reverse-engineered network architectures that generate characteristic dynamics of actual brains, including spindles and sharp waves, which appear in the power spectrum as frequency bands superimposed on a non-oscillatory background dominated by low frequencies. We show that all reconstructed networks display similar topological features (e.g. structural motifs) and dynamics. We have also reverse-engineered putative diseased brains (epileptic and schizophrenic), in which the oscillatory activity is altered in different ways, as reported in clinical studies. These reconstructed networks show consistent alterations of functional connectivity and dynamics. In particular, we show that the complexity of the network, quantified as proposed by Tononi, Sporns and Edelman, is a good indicator of brain fitness, since virtual brains modeling diseased states display lower complexity than virtual brains modeling normal neural function. We finally discuss the implications of our results for the neurobiology of health and disease.'),
(85185, 2011, 'plos', 'Computation of steady-state probability distributions in stochastic models of cellular networks', 'Hallen, Mark|Li, Bochong|Tanouchi, Yu|Tan, Cheemeng|West, Mike|You, Lingchong', 'Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America.|Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America.|Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America.|Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America.|Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America.|Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America.', 'United States|United States|United States|United States|United States|United States', 11, 'Models, Biological|Probability|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002209', '22022252', 'Cellular processes are noisy. In each cell, concentrations of molecules are subject to random fluctuations due to the small numbers of these molecules and to environmental perturbations. While noise varies with time, it is often measured at steady state, for example by flow cytometry. When interrogating aspects of a cellular network by such steady-state measurements of network components, a key need is to develop efficient methods to simulate and compute these distributions. We describe innovations in stochastic modeling coupled with approaches to this computational challenge: first, an approach to modeling intrinsic noise via solution of the chemical master equation, and second, a convolution technique to account for contributions of extrinsic noise. We show how these techniques can be combined in a streamlined procedure for evaluation of different sources of variability in a biochemical network. Evaluation and illustrations are given in analysis of two well-characterized synthetic gene circuits, as well as a signaling network underlying the mammalian cell cycle entry.'),
(85186, 2011, 'plos', 'Number and size distribution of colorectal adenomas under the multistage clonal expansion model of cancer', 'Dewanji, Anup|Jeon, Jihyoun|Meza, Rafael|Luebeck, E Georg', 'Applied Statistics Division, Indian Statistical Institute, Kolkata, India.|Applied Statistics Division, Indian Statistical Institute, Kolkata, India.|Applied Statistics Division, Indian Statistical Institute, Kolkata, India.|Applied Statistics Division, Indian Statistical Institute, Kolkata, India.', 'India|India|India|India', 0, 'Adenoma|Colorectal Neoplasms|Humans|Likelihood Functions|Models, Biological|Neoplastic Stem Cells|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002213', '22022253', 'Colorectal cancer (CRC) is believed to arise from mutant stem cells in colonic crypts that undergo a well-characterized progression involving benign adenoma, the precursor to invasive carcinoma. Although a number of (epi)genetic events have been identified as drivers of this process, little is known about the dynamics involved in the stage-wise progression from the first appearance of an adenoma to its ultimate conversion to malignant cancer. By the time adenomas become endoscopically detectable (i.e., are in the range of 1-2 mm in diameter), adenomas are already comprised of hundreds of thousands of cells and may have been in existence for several years if not decades. Thus, a large fraction of adenomas may actually remain undetected during endoscopic screening and, at least in principle, could give rise to cancer before they are detected. It is therefore of importance to establish what fraction of adenomas is detectable, both as a function of when the colon is screened for neoplasia and as a function of the achievable detection limit. To this end, we have derived mathematical expressions for the detectable adenoma number and size distributions based on a recently developed stochastic model of CRC. Our results and illustrations using these expressions suggest (1) that screening efficacy is critically dependent on the detection threshold and implicit knowledge of the relevant stem cell fraction in adenomas, (2) that a large fraction of non-extinct adenomas remains likely undetected assuming plausible detection thresholds and cell division rates, and (3), under a realistic description of adenoma initiation, growth and progression to CRC, the empirical prevalence of adenomas is likely inflated with lesions that are not on the pathway to cancer.'),
(85187, 2011, 'plos', 'Chemical basis of metabolic network organization', 'Zhu, Qiang|Qin, Tao|Jiang, Ying-Ying|Ji, Cong|Kong, De-Xin|Ma, Bin-Guang|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.|National Key Laboratory of Crop Genetic Improvement, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China.', 'China|China|China|China|China|China|China', 9, 'Escherichia coli|Escherichia coli Proteins|Metabolic Networks and Pathways|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1002214', '22022254', 'Although the metabolic networks of the three domains of life consist of different constituents and metabolic pathways, they exhibit the same scale-free organization. This phenomenon has been hypothetically explained by preferential attachment principle that the new-recruited metabolites attach preferentially to those that are already well connected. However, since metabolites are usually small molecules and metabolic processes are basically chemical reactions, we speculate that the metabolic network organization may have a chemical basis. In this paper, chemoinformatic analyses on metabolic networks of Kyoto Encyclopedia of Genes and Genomes (KEGG), Escherichia coli and Saccharomyces cerevisiae were performed. It was found that there exist qualitative and quantitative correlations between network topology and chemical properties of metabolites. The metabolites with larger degrees of connectivity (hubs) are of relatively stronger polarity. This suggests that metabolic networks are chemically organized to a certain extent, which was further elucidated in terms of high concentrations required by metabolic hubs to drive a variety of reactions. This finding not only provides a chemical explanation to the preferential attachment principle for metabolic network expansion, but also has important implications for metabolic network design and metabolite concentration prediction.'),
(85188, 2011, 'plos', 'Modelling reveals kinetic advantages of co-transcriptional splicing', 'Aitken, Stuart|Alexander, Ross D|Beggs, Jean D', 'Centre for Systems Biology, University of Edinburgh, Edinburgh, United Kingdom. s.aitken@ed.ac.uk|Centre for Systems Biology, University of Edinburgh, Edinburgh, United Kingdom. s.aitken@ed.ac.uk|Centre for Systems Biology, University of Edinburgh, Edinburgh, United Kingdom. s.aitken@ed.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 19, 'Genes, Fungal|Genes, Reporter|Introns|Kinetics|Models, Genetic|RNA Splicing|Saccharomyces cerevisiae|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002215', '22022255', 'Messenger RNA splicing is an essential and complex process for the removal of intron sequences. Whereas the composition of the splicing machinery is mostly known, the kinetics of splicing, the catalytic activity of splicing factors and the interdependency of transcription, splicing and mRNA 3 end formation are less well understood. We propose a stochastic model of splicing kinetics that explains data obtained from high-resolution kinetic analyses of transcription, splicing and 3 end formation during induction of an intron-containing reporter gene in budding yeast. Modelling reveals co-transcriptional splicing to be the most probable and most efficient splicing pathway for the reporter transcripts, due in part to a positive feedback mechanism for co-transcriptional second step splicing. Model comparison is used to assess the alternative representations of reactions. Modelling also indicates the functional coupling of transcription and splicing, because both the rate of initiation of transcription and the probability that step one of splicing occurs co-transcriptionally are reduced, when the second step of splicing is abolished in a mutant reporter.'),
(85189, 2011, 'plos', 'Thousands of rab GTPases for the cell biologist', 'Diekmann, Yoan|Seixas, Elsa|Gouw, Marc|Tavares-Cadete, Filipe|Seabra, Miguel C|Pereira-Leal, José B', 'Instituto Gulbenkian de Ciência, Oeiras, Portugal. ydiekmann@igc.gulbenkian.pt|Instituto Gulbenkian de Ciência, Oeiras, Portugal. ydiekmann@igc.gulbenkian.pt|Instituto Gulbenkian de Ciência, Oeiras, Portugal. ydiekmann@igc.gulbenkian.pt|Instituto Gulbenkian de Ciência, Oeiras, Portugal. ydiekmann@igc.gulbenkian.pt|Instituto Gulbenkian de Ciência, Oeiras, Portugal. ydiekmann@igc.gulbenkian.pt|Instituto Gulbenkian de Ciência, Oeiras, Portugal. ydiekmann@igc.gulbenkian.pt', 'Portugal|Portugal|Portugal|Portugal|Portugal|Portugal', 0, 'Animals|Databases, Protein|Humans|Phylogeny|Protein Transport|rab GTP-Binding Proteins', 'Journal Article', '10.1371/journal.pcbi.1002217', '22022256', 'Rab proteins are small GTPases that act as essential regulators of vesicular trafficking. 44 subfamilies are known in humans, performing specific sets of functions at distinct subcellular localisations and tissues. Rab function is conserved even amongst distant orthologs. Hence, the annotation of Rabs yields functional predictions about the cell biology of trafficking. So far, annotating Rabs has been a laborious manual task not feasible for current and future genomic output of deep sequencing technologies. We developed, validated and benchmarked the Rabifier, an automated bioinformatic pipeline for the identification and classification of Rabs, which achieves up to 90% classification accuracy. We cataloged roughly 8.000 Rabs from 247 genomes covering the entire eukaryotic tree. The full Rab database and a web tool implementing the pipeline are publicly available at www.RabDB.org. For the first time, we describe and analyse the evolution of Rabs in a dataset covering the whole eukaryotic phylogeny. We found a highly dynamic family undergoing frequent taxon-specific expansions and losses. We dated the origin of human subfamilies using phylogenetic profiling, which enlarged the Rab repertoire of the Last Eukaryotic Common Ancestor with Rab14, 32 and RabL4. Furthermore, a detailed analysis of the Choanoflagellate Monosiga brevicollis Rab family pinpointed the changes that accompanied the emergence of Metazoan multicellularity, mainly an important expansion and specialisation of the secretory pathway. Lastly, we experimentally establish tissue specificity in expression of mouse Rabs and show that neo-functionalisation best explains the emergence of new human Rab subfamilies. With the Rabifier and RabDB, we provide tools that easily allows non-bioinformaticians to integrate thousands of Rabs in their analyses. RabDB is designed to enable the cell biology community to keep pace with the increasing number of fully-sequenced genomes and change the scale at which we perform comparative analysis in cell biology.'),
(85190, 2011, 'plos', 'Bacteria modulate the CD8+ T cell epitope repertoire of host cytosol-exposed proteins to manipulate the host immune response', 'Maman, Yaakov|Nir-Paz, Ran|Louzoun, Yoram', 'Department of Mathematics and Gonda Brain Research Center, Bar-Ilan University, Ramat Gan, Israel.|Department of Mathematics and Gonda Brain Research Center, Bar-Ilan University, Ramat Gan, Israel.|Department of Mathematics and Gonda Brain Research Center, Bar-Ilan University, Ramat Gan, Israel.', 'Israel|Israel|Israel', 0, 'Algorithms|Alleles|Bacterial Physiological Phenomena|CD8-Positive T-Lymphocytes|Cytosol|Epitopes|HLA Antigens|Humans|Mutation', 'Journal Article', '10.1371/journal.pcbi.1002220', '22022257', 'The main adaptive immune response to bacteria is mediated by B cells and CD4+ T-cells. However, some bacterial proteins reach the cytosol of host cells and are exposed to the host CD8+ T-cells response. Both gram-negative and gram-positive bacteria can translocate proteins to the cytosol through type III and IV secretion and ESX-1 systems, respectively. The translocated proteins are often essential for the bacterium survival. Once injected, these proteins can be degraded and presented on MHC-I molecules to CD8+ T-cells. The CD8+ T-cells, in turn, can induce cell death and destroy the bacterias habitat. In viruses, escape mutations arise to avoid this detection. The accumulation of escape mutations in bacteria has never been systematically studied. We show for the first time that such mutations are systematically present in most bacteria tested. We combine multiple bioinformatic algorithms to compute CD8+ T-cell epitope libraries of bacteria with secretion systems that translocate proteins to the host cytosol. In all bacteria tested, proteins not translocated to the cytosol show no escape mutations in their CD8+ T-cell epitopes. However, proteins translocated to the cytosol show clear escape mutations and have low epitope densities for most tested HLA alleles. The low epitope densities suggest that bacteria, like viruses, are evolutionarily selected to ensure their survival in the presence of CD8+ T-cells. In contrast with most other translocated proteins examined, Pseudomonas aeruginosas ExoU, which ultimately induces host cell death, was found to have high epitope density. This finding suggests a novel mechanism for the manipulation of CD8+ T-cells by pathogens. The ExoU effector may have evolved to maintain high epitope density enabling it to efficiently induce CD8+ T-cell mediated cell death. These results were tested using multiple epitope prediction algorithms, and were found to be consistent for most proteins tested.'),
(85191, 2011, 'plos', 'Coupled information diffusion--pest dynamics models predict delayed benefits of farmer cooperation in pest management programs', 'Rebaudo, François|Dangles, Olivier', 'UR072, Institut de Recherche pour le Développement (IRD), Gif-sur-Yvette, France.|UR072, Institut de Recherche pour le Développement (IRD), Gif-sur-Yvette, France.', 'France|France', 28, 'Agriculture|Animals|Cooperative Behavior|Costs and Cost Analysis|Insecta|Models, Theoretical|Pest Control|Population Dynamics', 'Journal Article', '10.1371/journal.pcbi.1002222', '22022258', 'Worldwide, the theory and practice of agricultural extension system have been dominated for almost half a century by Rogers diffusion of innovation theory. In particular, the success of integrated pest management (IPM) extension programs depends on the effectiveness of IPM information diffusion from trained farmers to other farmers, an important assumption which underpins funding from development organizations. Here we developed an innovative approach through an agent-based model (ABM) combining social (diffusion theory) and biological (pest population dynamics) models to study the role of cooperation among small-scale farmers to share IPM information for controlling an invasive pest. The model was implemented with field data, including learning processes and control efficiency, from large scale surveys in the Ecuadorian Andes. Our results predict that although cooperation had short-term costs for individual farmers, it paid in the long run as it decreased pest infestation at the community scale. However, the slow learning process placed restrictions on the knowledge that could be generated within farmer communities over time, giving rise to natural lags in IPM diffusion and applications. We further showed that if individuals learn from others about the benefits of early prevention of new pests, then educational effort may have a sustainable long-run impact. Consistent with models of information diffusion theory, our results demonstrate how an integrated approach combining ecological and social systems would help better predict the success of IPM programs. This approach has potential beyond pest management as it could be applied to any resource management program seeking to spread innovations across populations.'),
(85192, 2011, 'plos', 'An integrated disease/pharmacokinetic/pharmacodynamic model suggests improved interleukin-21 regimens validated prospectively for mouse solid cancers', 'Elishmereni, Moran|Kheifetz, Yuri|Søndergaard, Henrik|Overgaard, Rune Viig|Agur, Zvia', 'Institute for Medical Biomathematics, Bene-Ataroth, Israel.|Institute for Medical Biomathematics, Bene-Ataroth, Israel.|Institute for Medical Biomathematics, Bene-Ataroth, Israel.|Institute for Medical Biomathematics, Bene-Ataroth, Israel.|Institute for Medical Biomathematics, Bene-Ataroth, Israel.', 'Israel|Israel|Israel|Israel|Israel', 0, 'Animals|Antineoplastic Agents|Antineoplastic Combined Chemotherapy Protocols|Computer Simulation|Dose-Response Relationship, Drug|Drug Administration Schedule|Interleukins|Mice|Models, Biological|Neoplasms, Experimental|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1002206', '22022259', 'Interleukin (IL)-21 is an attractive antitumor agent with potent immunomodulatory functions. Yet thus far, the cytokine has yielded only partial responses in solid cancer patients, and conditions for beneficial IL-21 immunotherapy remain elusive. The current work aims to identify clinically-relevant IL-21 regimens with enhanced efficacy, based on mathematical modeling of long-term antitumor responses. For this purpose, pharmacokinetic (PK) and pharmacodynamic (PD) data were acquired from a preclinical study applying systemic IL-21 therapy in murine solid cancers. We developed an integrated disease/PK/PD model for the IL-21 anticancer response, and calibrated it using selected training data. The accuracy of the model was verified retrospectively under diverse IL-21 treatment settings, by comparing its predictions to independent validation data in melanoma and renal cell carcinoma-challenged mice (R(2)>0.90). Simulations of the verified model surfaced important therapeutic insights: (1) Fractionating the standard daily regimen (50 µg/dose) into a twice daily schedule (25 µg/dose) is advantageous, yielding a significantly lower tumor mass (45% decrease), (2) A low-dose (12 µg/day) regimen exerts a response similar to that obtained under the 50 µg/day treatment, suggestive of an equally efficacious dose with potentially reduced toxicity. Subsequent experiments in melanoma-bearing mice corroborated both of these predictions with high precision (R(2)>0.89), thus validating the model also prospectively in vivo. Thus, the confirmed PK/PD model rationalizes IL-21 therapy, and pinpoints improved clinically-feasible treatment schedules. Our analysis demonstrates the value of employing mathematical modeling and in silico-guided design of solid tumor immunotherapy in the clinic.'),
(85193, 2011, 'plos', 'Transmembrane helix dynamics of bacterial chemoreceptors supports a piston model of signalling', 'Hall, Benjamin A|Armitage, Judith P|Sansom, Mark S P', 'Oxford Centre for Integrative Systems Biology, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.|Oxford Centre for Integrative Systems Biology, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.|Oxford Centre for Integrative Systems Biology, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 31, 'Amino Acid Sequence|Escherichia coli|Escherichia coli Proteins|Membrane Proteins|Molecular Dynamics Simulation|Molecular Sequence Data|Mutation|Protein Structure, Secondary|Receptors, Cell Surface|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002204', '22028633', 'Transmembrane xcexb1-helices play a key role in many receptors, transmitting a signal from one side to the other of the lipid bilayer membrane. Bacterial chemoreceptors are one of the best studied such systems, with a wealth of biophysical and mutational data indicating a key role for the TM2 helix in signalling. In particular, aromatic (Trp and Tyr) and basic (Arg) residues help to lock xcexb1-helices into a membrane. Mutants in TM2 of E. coli Tar and related chemoreceptors involving these residues implicate changes in helix location and/or orientation in signalling. We have investigated the detailed structural basis of this via high throughput coarse-grained molecular dynamics (CG-MD) of Tar TM2 and its mutants in lipid bilayers. We focus on the position (shift) and orientation (tilt, rotation) of TM2 relative to the bilayer and how these are perturbed in mutants relative to the wildtype. The simulations reveal a clear correlation between small (ca. 1.5 xc3x85) shift in position of TM2 along the bilayer normal and downstream changes in signalling activity. Weaker correlations are seen with helix tilt, and little/none between signalling and helix twist. This analysis of relatively subtle changes was only possible because the high throughput simulation method allowed us to run large (nxe2x80x8a=xe2x80x8a100) ensembles for substantial numbers of different helix sequences, amounting to ca. 2000 simulations in total. Overall, this analysis supports a swinging-piston model of transmembrane signalling by Tar and related chemoreceptors.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85194, 2011, 'plos', 'A neurodynamic account of spontaneous behaviour', 'Namikawa, Jun|Nishimoto, Ryunosuke|Tani, Jun', 'Brain Science Institute, RIKEN, Wako, Japan.|Brain Science Institute, RIKEN, Wako, Japan.|Brain Science Institute, RIKEN, Wako, Japan.', 'Japan|Japan|Japan', 0, 'Behavior|Humans|Models, Neurological|Motor Cortex|Neural Networks (Computer)|Prefrontal Cortex|Psychomotor Performance|Robotics', 'Journal Article', '10.1371/journal.pcbi.1002221', '22028634', 'The current article suggests that deterministic chaos self-organized in cortical dynamics could be responsible for the generation of spontaneous action sequences. Recently, various psychological observations have suggested that humans and primates can learn to extract statistical structures hidden in perceptual sequences experienced during active environmental interactions. Although it has been suggested that such statistical structures involve chunking or compositional primitives, their neuronal implementations in brains have not yet been clarified. Therefore, to reconstruct the phenomena, synthetic neuro-robotics experiments were conducted by using a neural network model, which is characterized by a generative model with intentional states and its multiple timescales dynamics. The experimental results showed that the robot successfully learned to imitate tutored behavioral sequence patterns by extracting the underlying transition probability among primitive actions. An analysis revealed that a set of primitive action patterns was embedded in the fast dynamics part, and the chaotic dynamics of spontaneously sequencing these action primitive patterns was structured in the slow dynamics part, provided that the timescale was adequately set for each part. It was also shown that self-organization of this type of functional hierarchy ensured robust action generation by the robot in its interactions with a noisy environment. This article discusses the correspondence of the synthetic experiments with the known hierarchy of the prefrontal cortex, the supplementary motor area, and the primary motor cortex for action generation. We speculate that deterministic dynamical structures organized in the prefrontal cortex could be essential because they can account for the generation of both intentional behaviors of fixed action sequences and spontaneous behaviors of pseudo-stochastic action sequences by the same mechanism.'),
(85195, 2011, 'plos', 'Replication timing: a fingerprint for cell identity and pluripotency', 'Ryba, Tyrone|Hiratani, Ichiro|Sasaki, Takayo|Battaglia, Dana|Kulik, Michael|Zhang, Jinfeng|Dalton, Stephen|Gilbert, David M', 'Department of Biological Science, Florida State University, Tallahassee, Florida, United States of America.|Department of Biological Science, Florida State University, Tallahassee, Florida, United States of America.|Department of Biological Science, Florida State University, Tallahassee, Florida, United States of America.|Department of Biological Science, Florida State University, Tallahassee, Florida, United States of America.|Department of Biological Science, Florida State University, Tallahassee, Florida, United States of America.|Department of Biological Science, Florida State University, Tallahassee, Florida, United States of America.|Department of Biological Science, Florida State University, Tallahassee, Florida, United States of America.|Department of Biological Science, Florida State University, Tallahassee, Florida, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 60, 'Animals|Cell Line|Chromatin|DNA Fingerprinting|DNA Methylation|DNA Replication Timing|Embryonic Stem Cells|Endoderm|Epigenomics|Gene Expression Regulation, Developmental|Histones|Humans|Mesoderm|Mice|Monte Carlo Method|Muscle, Smooth|Pluripotent Stem Cells', 'Journal Article', '10.1371/journal.pcbi.1002225', '22028635', 'Many types of epigenetic profiling have been used to classify stem cells, stages of cellular differentiation, and cancer subtypes. Existing methods focus on local chromatin features such as DNA methylation and histone modifications that require extensive analysis for genome-wide coverage. Replication timing has emerged as a highly stable cell type-specific epigenetic feature that is regulated at the megabase-level and is easily and comprehensively analyzed genome-wide. Here, we describe a cell classification method using 67 individual replication profiles from 34 mouse and human cell lines and stem cell-derived tissues, including new data for mesendoderm, definitive endoderm, mesoderm and smooth muscle. Using a Monte-Carlo approach for selecting features of replication profiles conserved in each cell type, we identify replication timing fingerprints unique to each cell type and apply a k nearest neighbor approach to predict known and unknown cell types. Our method correctly classifies 67/67 independent replication-timing profiles, including those derived from closely related intermediate stages. We also apply this method to derive fingerprints for pluripotency in human and mouse cells. Interestingly, the mouse pluripotency fingerprint overlaps almost completely with previously identified genomic segments that switch from early to late replication as pluripotency is lost. Thereafter, replication timing and transcription within these regions become difficult to reprogram back to pluripotency, suggesting these regions highlight an epigenetic barrier to reprogramming. In addition, the major histone cluster Hist1 consistently becomes later replicating in committed cell types, and several histone H1 genes in this cluster are downregulated during differentiation, suggesting a possible instrument for the chromatin compaction observed during differentiation. Finally, we demonstrate that unknown samples can be classified independently using site-specific PCR against fingerprint regions. In sum, replication fingerprints provide a comprehensive means for cell characterization and are a promising tool for identifying regions with cell type-specific organization.'),
(85196, 2011, 'plos', 'Patient-specific data fusion defines prognostic cancer subtypes', 'Yuan, Yinyin|Savage, Richard S|Markowetz, Florian', 'Cambridge Research Institute, Cancer Research UK, Cambridge, United Kingdom. yy341@cam.ac.uk|Cambridge Research Institute, Cancer Research UK, Cambridge, United Kingdom. yy341@cam.ac.uk|Cambridge Research Institute, Cancer Research UK, Cambridge, United Kingdom. yy341@cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Bayes Theorem|Breast Neoplasms|DNA Copy Number Variations|Female|Gene Expression Profiling|Humans|Male|Models, Biological|Models, Statistical|Prognosis|Prostatic Neoplasms|Signal Transduction|Statistics, Nonparametric|Survival Analysis', 'Journal Article', '10.1371/journal.pcbi.1002227', '22028636', 'Different data types can offer complementary perspectives on the same biological phenomenon. In cancer studies, for example, data on copy number alterations indicate losses and amplifications of genomic regions in tumours, while transcriptomic data point to the impact of genomic and environmental events on the internal wiring of the cell. Fusing different data provides a more comprehensive model of the cancer cell than that offered by any single type. However, biological signals in different patients exhibit diverse degrees of concordance due to cancer heterogeneity and inherent noise in the measurements. This is a particularly important issue in cancer subtype discovery, where personalised strategies to guide therapy are of vital importance. We present a nonparametric Bayesian model for discovering prognostic cancer subtypes by integrating gene expression and copy number variation data. Our model is constructed from a hierarchy of Dirichlet Processes and addresses three key challenges in data fusion: (i) To separate concordant from discordant signals, (ii) to select informative features, (iii) to estimate the number of disease subtypes. Concordance of signals is assessed individually for each patient, giving us an additional level of insight into the underlying disease structure. We exemplify the power of our model in prostate cancer and breast cancer and show that it outperforms competing methods. In the prostate cancer data, we identify an entirely new subtype with extremely poor survival outcome and show how other analyses fail to detect it. In the breast cancer data, we find subtypes with superior prognostic value by using the concordant results. These discoveries were crucially dependent on our models ability to distinguish concordant and discordant signals within each patient sample, and would otherwise have been missed. We therefore demonstrate the importance of taking a patient-specific approach, using highly-flexible nonparametric Bayesian methods.'),
(85197, 2011, 'plos', 'A semi-quantitative, synteny-based method to improve functional predictions for hypothetical and poorly annotated bacterial and archaeal genes', 'Yelton, Alexis P|Thomas, Brian C|Simmons, Sheri L|Wilmes, Paul|Zemla, Adam|Thelen, Michael P|Justice, Nicholas|Banfield, Jillian F', 'Department of Environmental Science, Policy, and Management, University of California, Berkeley, California, United States of America.|Department of Environmental Science, Policy, and Management, University of California, Berkeley, California, United States of America.|Department of Environmental Science, Policy, and Management, University of California, Berkeley, California, United States of America.|Department of Environmental Science, Policy, and Management, University of California, Berkeley, California, United States of America.|Department of Environmental Science, Policy, and Management, University of California, Berkeley, California, United States of America.|Department of Environmental Science, Policy, and Management, University of California, Berkeley, California, United States of America.|Department of Environmental Science, Policy, and Management, University of California, Berkeley, California, United States of America.|Department of Environmental Science, Policy, and Management, University of California, Berkeley, California, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 25, 'Archaeal Proteins|Bacterial Proteins|Conserved Sequence|Evolution, Molecular|Genes, Archaeal|Genes, Bacterial|Models, Genetic|Molecular Sequence Annotation|Phylogeny|Synteny', 'Journal Article', '10.1371/journal.pcbi.1002230', '22028637', 'During microbial evolution, genome rearrangement increases with increasing sequence divergence. If the relationship between synteny and sequence divergence can be modeled, gene clusters in genomes of distantly related organisms exhibiting anomalous synteny can be identified and used to infer functional conservation. We applied the phylogenetic pairwise comparison method to establish and model a strong correlation between synteny and sequence divergence in all 634 available Archaeal and Bacterial genomes from the NCBI database and four newly assembled genomes of uncultivated Archaea from an acid mine drainage (AMD) community. In parallel, we established and modeled the trend between synteny and functional relatedness in the 118 genomes available in the STRING database. By combining these models, we developed a gene functional annotation method that weights evolutionary distance to estimate the probability of functional associations of syntenous proteins between genome pairs. The method was applied to the hypothetical proteins and poorly annotated genes in newly assembled acid mine drainage Archaeal genomes to add or improve gene annotations. This is the first method to assign possible functions to poorly annotated genes through quantification of the probability of gene functional relationships based on synteny at a significant evolutionary distance, and has the potential for broad application.'),
(85198, 2011, 'plos', 'Near-native protein loop sampling using nonparametric density estimation accommodating sparcity', 'Joo, Hyun|Chavan, Archana G|Day, Ryan|Lennox, Kristin P|Sukhanov, Paul|Dahl, David B|Vannucci, Marina|Tsai, Jerry', 'Department of Chemistry, University of the Pacific, Stockton, California, United States of America.|Department of Chemistry, University of the Pacific, Stockton, California, United States of America.|Department of Chemistry, University of the Pacific, Stockton, California, United States of America.|Department of Chemistry, University of the Pacific, Stockton, California, United States of America.|Department of Chemistry, University of the Pacific, Stockton, California, United States of America.|Department of Chemistry, University of the Pacific, Stockton, California, United States of America.|Department of Chemistry, University of the Pacific, Stockton, California, United States of America.|Department of Chemistry, University of the Pacific, Stockton, California, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Algorithms|Humans|Markov Chains|Models, Statistical|Protein Structure, Secondary|Software|Statistics, Nonparametric', 'Journal Article', '10.1371/journal.pcbi.1002234', '22028638', 'Unlike the core structural elements of a protein like regular secondary structure, template based modeling (TBM) has difficulty with loop regions due to their variability in sequence and structure as well as the sparse sampling from a limited number of homologous templates. We present a novel, knowledge-based method for loop sampling that leverages homologous torsion angle information to estimate a continuous joint backbone dihedral angle density at each loop position. The xcfx86,xcfx88 distributions are estimated via a Dirichlet process mixture of hidden Markov models (DPM-HMM). Models are quickly generated based on samples from these distributions and were enriched using an end-to-end distance filter. The performance of the DPM-HMM method was evaluated against a diverse test set in a leave-one-out approach. Candidates as low as 0.45 xc3x85 RMSD and with a worst case of 3.66 xc3x85 were produced. For the canonical loops like the immunoglobulin complementarity-determining regions (mean RMSD <2.0 xc3x85), the DPM-HMM method performs as well or better than the best templates, demonstrating that our automated method recaptures these canonical loops without inclusion of any IgG specific terms or manual intervention. In cases with poor or few good templates (mean RMSD >7.0 xc3x85), this sampling method produces a population of loop structures to around 3.66 xc3x85 for loops up to 17 residues. In a direct test of sampling to the Loopy algorithm, our method demonstrates the ability to sample nearer native structures for both the canonical CDRH1 and non-canonical CDRH3 loops. Lastly, in the realistic test conditions of the CASP9 experiment, successful application of DPM-HMM for 90 loops from 45 TBM targets shows the general applicability of our sampling method in loop modeling problem. These results demonstrate that our DPM-HMM produces an advantage by consistently sampling near native loop structure. The software used in this analysis is available for download at http://www.stat.tamu.edu/~dahl/software/cortorgles/.'),
(85199, 2011, 'plos', 'Integrated information increases with fitness in the evolution of animats', 'Edlund, Jeffrey A|Chaumont, Nicolas|Hintze, Arend|Koch, Christof|Tononi, Giulio|Adami, Christoph', 'Computation & Neural Systems, California Institute of Technology, Pasadena, California, United States of America.|Computation & Neural Systems, California Institute of Technology, Pasadena, California, United States of America.|Computation & Neural Systems, California Institute of Technology, Pasadena, California, United States of America.|Computation & Neural Systems, California Institute of Technology, Pasadena, California, United States of America.|Computation & Neural Systems, California Institute of Technology, Pasadena, California, United States of America.|Computation & Neural Systems, California Institute of Technology, Pasadena, California, United States of America.', 'United States|United States|United States|United States|United States|United States', 0, 'Animals|Behavior, Animal|Biological Evolution|Genetic Fitness|Humans|Memory|Mental Processes', 'Journal Article', '10.1371/journal.pcbi.1002236', '22028639', 'One of the hallmarks of biological organisms is their ability to integrate disparate information sources to optimize their behavior in complex environments. How this capability can be quantified and related to the functional complexity of an organism remains a challenging problem, in particular since organismal functional complexity is not well-defined. We present here several candidate measures that quantify information and integration, and study their dependence on fitness as an artificial agent (animat) evolves over thousands of generations to solve a navigation task in a simple, simulated environment. We compare the ability of these measures to predict high fitness with more conventional information-theoretic processing measures. As the animat adapts by increasing its fit to the world, information integration and processing increase commensurately along the evolutionary line of descent. We suggest that the correlation of fitness with information integration and with processing measures implies that high fitness requires both information processing as well as integration, but that information integration may be a better measure when the task requires memory. A correlation of measures of information integration (but also information processing) and fitness strongly suggests that these measures reflect the functional complexity of the animat, and that such measures can be used to quantify functional complexity even in the absence of fitness data.'),
(85200, 2011, 'plos', 'Explaining observed infection and antibody age-profiles in populations with urogenital schistosomiasis', 'Mitchell, Kate M|Mutapi, Francisca|Savill, Nicholas J|Woolhouse, Mark E J', 'Centre for Immunology, Infection and Evolution, Institute of Immunology & Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom. Kate.Mitchell@lshtm.ac.uk|Centre for Immunology, Infection and Evolution, Institute of Immunology & Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom. Kate.Mitchell@lshtm.ac.uk|Centre for Immunology, Infection and Evolution, Institute of Immunology & Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom. Kate.Mitchell@lshtm.ac.uk|Centre for Immunology, Infection and Evolution, Institute of Immunology & Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom. Kate.Mitchell@lshtm.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Adolescent|Adult|Age Factors|Antibodies, Helminth|Antigens, Helminth|Child|Humans|Models, Immunological|Schistosomiasis haematobia|Young Adult', 'Journal Article', '10.1371/journal.pcbi.1002237', '22028640', 'Urogenital schistosomiasis is a tropical disease infecting more than 100 million people in sub-Saharan Africa. Individuals in endemic areas endure repeated infections with long-lived schistosome worms, and also encounter larval and egg stages of the life cycle. Protective immunity against infection develops slowly with age. Distinctive age-related patterns of infection and specific antibody responses are seen in endemic areas, including an infection peak shift and a switch in the antibody types produced. Deterministic models describing changing levels of infection and antibody with age in homogeneously exposed populations were developed to identify the key mechanisms underlying the antibody switch, and to test two theories for the slow development of protective immunity: that (i) exposure to dying (long-lived) worms, or (ii) experience of a threshold level of antigen, is necessary to stimulate protective antibody. Different model structures were explored, including alternative stages of the life cycle as the main antigenic source and the principal target of protective antibody, different worm survival distributions, antigen thresholds and immune cross-regulation. Models were identified which could reproduce patterns of infection and antibody consistent with field data. Models with dying worms as the main source of protective antigen could reproduce all of these patterns, but so could some models with other continually-encountered life stages acting as the principal antigen source. An antigen threshold enhanced the ability of the model to replicate these patterns, but was not essential for it to do so. Models including either non-exponential worm survival or cross-regulation were more likely to be able to reproduce field patterns, but neither of these was absolutely required. The combination of life cycle stage stimulating, and targeted by, antibody was found to be critical in determining whether models could successfully reproduce patterns in the data, and a number of combinations were excluded as being inconsistent with field data.'),
(85201, 2011, 'plos', 'Ensemble-based computational approach discriminates functional activity of p53 cancer and rescue mutants', 'Demir, xc3x96zlem|Baronio, Roberta|Salehi, Faezeh|Wassman, Christopher D|Hall, Linda|Hatfield, G Wesley|Chamberlin, Richard|Kaiser, Peter|Lathrop, Richard H|Amaro, Rommie E', 'Department of Pharmaceutical Sciences, University of California, Irvine, California, United States of America.|Department of Pharmaceutical Sciences, University of California, Irvine, California, United States of America.|Department of Pharmaceutical Sciences, University of California, Irvine, California, United States of America.|Department of Pharmaceutical Sciences, University of California, Irvine, California, United States of America.|Department of Pharmaceutical Sciences, University of California, Irvine, California, United States of America.|Department of Pharmaceutical Sciences, University of California, Irvine, California, United States of America.|Department of Pharmaceutical Sciences, University of California, Irvine, California, United States of America.|Department of Pharmaceutical Sciences, University of California, Irvine, California, United States of America.|Department of Pharmaceutical Sciences, University of California, Irvine, California, United States of America.|Department of Pharmaceutical Sciences, University of California, Irvine, California, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 27, 'Humans|Models, Molecular|Molecular Dynamics Simulation|Mutation|Neoplasms|Protein Binding|Protein Conformation|Tumor Suppressor Protein p53', 'Journal Article', '10.1371/journal.pcbi.1002238', '22028641', 'The tumor suppressor protein p53 can lose its function upon single-point missense mutations in the core DNA-binding domain (cancer mutants). Activity can be restored by second-site suppressor mutations (rescue mutants). This paper relates the functional activity of p53 cancer and rescue mutants to their overall molecular dynamics (MD), without focusing on local structural details. A novel global measure of protein flexibility for the p53 core DNA-binding domain, the number of clusters at a certain RMSD cutoff, was computed by clustering over 0.7 xc2xb5s of explicitly solvated all-atom MD simulations. For wild-type p53 and a sample of p53 cancer or rescue mutants, the number of clusters was a good predictor of in vivo p53 functional activity in cell-based assays. This number-of-clusters (NOC) metric was strongly correlated (r(2)xe2x80x8a=xe2x80x8a0.77) with reported values of experimentally measured xcex94xcex94G protein thermodynamic stability. Interpreting the number of clusters as a measure of protein flexibility: (i) p53 cancer mutants were more flexible than wild-type protein, (ii) second-site rescue mutations decreased the flexibility of cancer mutants, and (iii) negative controls of non-rescue second-site mutants did not. This new method reflects the overall stability of the p53 core domain and can discriminate which second-site mutations restore activity to p53 cancer mutants.'),
(85202, 2011, 'plos', 'Representation of dynamical stimuli in populations of threshold neurons', 'Tchumatchenko, Tatjana|Wolf, Fred', 'Department of Nonlinear Dynamics, Max Planck Institute for Dynamics and Self-Organization, Goettingen, Germany. tatjana@nld.ds.mpg.de|Department of Nonlinear Dynamics, Max Planck Institute for Dynamics and Self-Organization, Goettingen, Germany. tatjana@nld.ds.mpg.de', 'Germany|Germany', 0, 'Animals|Membrane Potentials|Models, Neurological|Neurons|Synapses', 'Journal Article', '10.1371/journal.pcbi.1002239', '22028642', 'Many sensory or cognitive events are associated with dynamic current modulations in cortical neurons. This raises an urgent demand for tractable model approaches addressing the merits and limits of potential encoding strategies. Yet, current theoretical approaches addressing the response to mean- and variance-encoded stimuli rarely provide complete response functions for both modes of encoding in the presence of correlated noise. Here, we investigate the neuronal population response to dynamical modifications of the mean or variance of the synaptic bombardment using an alternative threshold model framework. In the variance and mean channel, we provide explicit expressions for the linear and non-linear frequency response functions in the presence of correlated noise and use them to derive population rate response to step-like stimuli. For mean-encoded signals, we find that the complete response function depends only on the temporal width of the input correlation function, but not on other functional specifics. Furthermore, we show that both mean- and variance-encoded signals can relay high-frequency inputs, and in both schemes step-like changes can be detected instantaneously. Finally, we obtain the pairwise spike correlation function and the spike triggered average from the linear mean-evoked response function. These results provide a maximally tractable limiting case that complements and extends previous results obtained in the integrate and fire framework.'),
(85203, 2011, 'plos', 'Most random gene expression signatures are significantly associated with breast cancer outcome', 'Venet, David|Dumont, Jacques E|Detours, Vincent', 'IRIDIA-CoDE, Universitxc3xa9 Libre de Bruxelles, Brussels, Belgium.|IRIDIA-CoDE, Universitxc3xa9 Libre de Bruxelles, Brussels, Belgium.|IRIDIA-CoDE, Universitxc3xa9 Libre de Bruxelles, Brussels, Belgium.', 'Belgium|Belgium|Belgium', 0, 'Animals|Biomarkers, Tumor|Breast Neoplasms|Carcinoma|Confounding Factors (Epidemiology)|Female|Gene Expression Profiling|Humans|Mice|Prognosis', 'Journal Article', '10.1371/journal.pcbi.1002240', '22028643', 'Bridging the gap between animal or in vitro models and human disease is essential in medical research. Researchers often suggest that a biological mechanism is relevant to human cancer from the statistical association of a gene expression marker (a signature) of this mechanism, that was discovered in an experimental system, with disease outcome in humans. We examined this argument for breast cancer. Surprisingly, we found that gene expression signatures-unrelated to cancer-of the effect of postprandial laughter, of mice social defeat and of skin fibroblast localization were all significantly associated with breast cancer outcome. We next compared 47 published breast cancer outcome signatures to signatures made of random genes. Twenty-eight of them (60%) were not significantly better outcome predictors than random signatures of identical size and 11 (23%) were worst predictors than the median random signature. More than 90% of random signatures >100 genes were significant outcome predictors. We next derived a metagene, called meta-PCNA, by selecting the 1% genes most positively correlated with proliferation marker PCNA in a compendium of normal tissues expression. Adjusting breast cancer expression data for meta-PCNA abrogated almost entirely the outcome association of published and random signatures. We also found that, in the absence of adjustment, the hazard ratio of outcome association of a signature strongly correlated with meta-PCNA (R(2)xe2x80x8a=xe2x80x8a0.9). This relation also applied to single-gene expression markers. Moreover, >50% of the breast cancer transcriptome was correlated with meta-PCNA. A corollary was that purging cell cycle genes out of a signature failed to rule out the confounding effect of proliferation. Hence, it is questionable to suggest that a mechanism is relevant to human breast cancer from the finding that a gene expression marker for this mechanism predicts human breast cancer outcome, because most markers do. The methods we present help to overcome this problem.'),
(85204, 2011, 'plos', 'NHE inhibition does not improve Na(+) or Ca(2+) overload during reperfusion: using modeling to illuminate the mechanisms underlying a therapeutic failure', 'Roberts, Byron N|Christini, David J', 'Greenberg Division of Cardiology and Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medical College, New York, New York, United States of America.|Greenberg Division of Cardiology and Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medical College, New York, New York, United States of America.', 'United States|United States', 0, 'Animals|Computer Simulation|Humans|Hydrogen-Ion Concentration|Models, Cardiovascular|Myocardial Reperfusion Injury|Rats|Sodium|Sodium-Hydrogen Exchangers|Sodium-Potassium-Exchanging ATPase|Treatment Failure', 'Journal Article', '10.1371/journal.pcbi.1002241', '22028644', 'Reperfusion injury results from pathologies of cardiac myocyte physiology that develop when previously ischemic myocardium experiences a restoration of normal perfusion. Events in the development of reperfusion injury begin with the restoration of a proton gradient upon reperfusion, which then allows the sodium-proton exchanger (NHE) to increase flux, removing protons from the intracellular space while importing sodium. The resulting sodium overload drives increased reverse-mode sodium-calcium exchanger (NCX) activity, creating a secondary calcium overload that has pathologic consequences. One of the attempts to reduce reperfusion-related damage, NHE inhibition, has shown little clinical benefit, and only when NHE inhibitors are given prior to reperfusion. In an effort to further understand why NHE inhibitors have been largely unsuccessful, we employed a new mathematical cardiomyocyte model that we developed for the study of ischemia and reperfusion. Using this model, we simulated 20 minutes of ischemia and 10 minutes of reperfusion, while also simulating NHE inhibition by reducing NHE flux in our model by varying amounts and at different time points. In our simulations, when NHE inhibition is applied at the onset of reperfusion, increasing the degree of inhibition increases the peak sodium and calcium concentrations, as well as reducing intracellular pH recovery. When inhibition was instituted at earlier time points, some modest improvements were seen, largely due to reduced sodium concentrations prior to reperfusion. Analysis of all sodium flux pathways suggests that the sodium-potassium pump (NaK) plays the largest role in exacerbated sodium overload during reperfusion, and that reduced NaK flux is largely the result of impaired pH recovery. While NHE inhibition does indeed reduce sodium influx through that exchanger, the resulting prolongation of intracellular acidosis paradoxically increases sodium overload, largely mediated by impaired NaK function.'),
(85205, 2011, 'plos', 'The effects of dominance on leadership and energetic gain: a dynamic game between pairs of social foragers', 'Rands, Sean A', 'Centre for Behavioural Biology, School of Veterinary Science, University of Bristol, Bristol, United Kingdom. sean.rands@bristol.ac.uk', 'United Kingdom', 11, 'Animals|Behavior, Animal|Energy Metabolism|Female|Game Theory|Leadership|Male|Models, Biological|Social Dominance', 'Journal Article', '10.1371/journal.pcbi.1002252', '22028645', 'Although social behaviour can bring many benefits to an individual, there are also costs that may be incurred whenever the members of a social group interact. The formation of dominance hierarchies could offer a means of reducing some of the costs of social interaction, but individuals within the hierarchy may end up paying differing costs dependent upon their position within the hierarchy. These differing interaction costs may therefore influence the behaviour of the group, as subordinate individuals may experience very different benefits and costs to dominants when the group is conducting a given behaviour. Here, a state-dependent dynamic game is described which considers a pair of social foragers where there is a set dominance relationship within the pair. The model considers the case where the subordinate member of the pair pays an interference cost when it and the dominant individual conduct specific pairs of behaviours together. The model demonstrates that if the subordinate individual pays these energetic costs when it interacts with the dominant individual, this has effects upon the behaviour of both subordinate and the dominant individuals. Including interaction costs increases the amount of foraging behaviour both individuals conduct, with the behaviour of the pair being driven by the subordinate individual. The subordinate will tend to be the lighter individual for longer periods of time when interaction costs are imposed. This supports earlier suggestions that lighter individuals should act as the decision-maker within the pair, giving leadership-like behaviours that are based upon energetic state. Pre-existing properties of individuals such as their dominance will be less important for determining which individual makes the decisions for the pair. This suggests that, even with strict behavioural hierarchies, identifying which individual is the dominant one is not sufficient for identifying which one is the leader.'),
(85206, 2011, 'plos', 'Accelerated Profile HMM Searches', 'Eddy, Sean R', 'HHMI Janelia Farm Research Campus, Ashburn, Virginia, United States of America. eddys@janelia.hhmi.org', 'United States', 0, 'Algorithms|Computational Biology|Databases, Protein|Information Storage and Retrieval|Markov Chains|Sequence Alignment|Software', 'Journal Article', '10.1371/journal.pcbi.1002195', '22039361', 'Profile hidden Markov models (profile HMMs) and probabilistic inference methods have made important contributions to the theory of sequence database homology search. However, practical use of profile HMM methods has been hindered by the computational expense of existing software implementations. Here I describe an acceleration heuristic for profile HMMs, the multiple segment Viterbi (MSV) algorithm. The MSV algorithm computes an optimal sum of multiple ungapped local alignment segments using a striped vector-parallel approach previously described for fast Smith/Waterman alignment. MSV scores follow the same statistical distribution as gapped optimal local alignment scores, allowing rapid evaluation of significance of an MSV score and thus facilitating its use as a heuristic filter. I also describe a 20-fold acceleration of the standard profile HMM Forward/Backward algorithms using a method I call sparse rescaling. These methods are assembled in a pipeline in which high-scoring MSV hits are passed on for reanalysis with the full HMM Forward/Backward algorithm. This accelerated pipeline is implemented in the freely available HMMER3 software package. Performance benchmarks show that the use of the heuristic MSV filter sacrifices negligible sensitivity compared to unaccelerated profile HMM searches. HMMER3 is substantially more sensitive and 100- to 1000-fold faster than HMMER2. HMMER3 is now about as fast as BLAST for protein searches.'),
(85207, 2011, 'plos', 'BioStar: an online question & answer resource for the bioinformatics community', 'Parnell, Laurence D|Lindenbaum, Pierre|Shameer, Khader|DallOlio, Giovanni Marco|Swan, Daniel C|Jensen, Lars Juhl|Cockell, Simon J|Pedersen, Brent S|Mangan, Mary E|Miller, Christopher A|Albert, Istvan', 'Nutrition and Genomics Laboratory, Jean Mayer-United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, United States of America.|Nutrition and Genomics Laboratory, Jean Mayer-United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, United States of America.|Nutrition and Genomics Laboratory, Jean Mayer-United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, United States of America.|Nutrition and Genomics Laboratory, Jean Mayer-United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, United States of America.|Nutrition and Genomics Laboratory, Jean Mayer-United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, United States of America.|Nutrition and Genomics Laboratory, Jean Mayer-United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, United States of America.|Nutrition and Genomics Laboratory, Jean Mayer-United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, United States of America.|Nutrition and Genomics Laboratory, Jean Mayer-United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, United States of America.|Nutrition and Genomics Laboratory, Jean Mayer-United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, United States of America.|Nutrition and Genomics Laboratory, Jean Mayer-United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, United States of America.|Nutrition and Genomics Laboratory, Jean Mayer-United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Computational Biology|Cooperative Behavior|Humans|Information Dissemination|Information Seeking Behavior|Internet|Research', 'Journal Article', '10.1371/journal.pcbi.1002216', '22046109', '-'),
(85208, 2011, 'plos', 'Receptive field inference with localized priors', 'Park, Mijung|Pillow, Jonathan W', 'Department of Electrical and Computer Engineering, The University of Texas at Austin, Austin, Texas, United States of America. mjpark@mail.utexas.edu|Department of Electrical and Computer Engineering, The University of Texas at Austin, Austin, Texas, United States of America. mjpark@mail.utexas.edu', 'United States|United States', 41, 'Action Potentials|Algorithms|Animals|Bayes Theorem|Computational Biology|Computer Simulation|Markov Chains|Models, Neurological|Monte Carlo Method|Photic Stimulation|Primates|Regression Analysis|Reproducibility of Results|Retinal Ganglion Cells', 'Journal Article', '10.1371/journal.pcbi.1002219', '22046110', 'The linear receptive field describes a mapping from sensory stimuli to a one-dimensional variable governing a neurons spike response. However, traditional receptive field estimators such as the spike-triggered average converge slowly and often require large amounts of data. Bayesian methods seek to overcome this problem by biasing estimates towards solutions that are more likely a priori, typically those with small, smooth, or sparse coefficients. Here we introduce a novel Bayesian receptive field estimator designed to incorporate locality, a powerful form of prior information about receptive field structure. The key to our approach is a hierarchical receptive field model that flexibly adapts to localized structure in both spacetime and spatiotemporal frequency, using an inference method known as empirical Bayes. We refer to our method as automatic locality determination (ALD), and show that it can accurately recover various types of smooth, sparse, and localized receptive fields. We apply ALD to neural data from retinal ganglion cells and V1 simple cells, and find it achieves error rates several times lower than standard estimators. Thus, estimates of comparable accuracy can be achieved with substantially less data. Finally, we introduce a computationally efficient Markov Chain Monte Carlo (MCMC) algorithm for fully Bayesian inference under the ALD prior, yielding accurate Bayesian confidence intervals for small or noisy datasets.'),
(85209, 2011, 'plos', 'Decoding complex chemical mixtures with a physical model of a sensor array', 'Tsitron, Julia|Ault, Addison D|Broach, James R|Morozov, Alexandre V', 'Department of Physics & Astronomy and BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, New Jersey, United States of America.|Department of Physics & Astronomy and BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, New Jersey, United States of America.|Department of Physics & Astronomy and BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, New Jersey, United States of America.|Department of Physics & Astronomy and BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, New Jersey, United States of America.', 'Jersey|Jersey|Jersey|Jersey', 10, 'Algorithms|Bayes Theorem|Biosensing Techniques|Complex Mixtures|Computational Biology|Computer Simulation|Humans|Models, Biological|Protein Binding|Receptors, G-Protein-Coupled|Smell|Thermodynamics|Uridine Diphosphate Sugars', 'Journal Article', '10.1371/journal.pcbi.1002224', '22046111', 'Combinatorial sensor arrays, such as the olfactory system, can detect a large number of analytes using a relatively small number of receptors. However, the complex pattern of receptor responses to even a single analyte, coupled with the non-linearity of responses to mixtures of analytes, makes quantitative prediction of compound concentrations in a mixture a challenging task. Here we develop a physical model that explicitly takes receptor-ligand interactions into account, and apply it to infer concentrations of highly related sugar nucleotides from the output of four engineered G-protein-coupled receptors. We also derive design principles that enable accurate mixture discrimination with cross-specific sensor arrays. The optimal sensor parameters exhibit relatively weak dependence on component concentrations, making a single designed array useful for analyzing a sizable range of mixtures. The maximum number of mixture components that can be successfully discriminated is twice the number of sensors in the array. Finally, antagonistic receptor responses, well-known to play an important role in natural olfactory systems, prove to be essential for the accurate prediction of component concentrations.'),
(85210, 2011, 'plos', 'Conformation regulation of the X chromosome inactivation center: a model', 'Scialdone, Antonio|Cataudella, Ilaria|Barbieri, Mariano|Prisco, Antonella|Nicodemi, Mario', 'Department of Computational and Systems Biology, John Innes Centre, Norwich, United Kingdom.|Department of Computational and Systems Biology, John Innes Centre, Norwich, United Kingdom.|Department of Computational and Systems Biology, John Innes Centre, Norwich, United Kingdom.|Department of Computational and Systems Biology, John Innes Centre, Norwich, United Kingdom.|Department of Computational and Systems Biology, John Innes Centre, Norwich, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 23, 'Animals|Cell Nucleus|Chromatin|Chromatin Assembly and Disassembly|Computational Biology|Computer Simulation|Female|Male|Mice|Models, Genetic|Thermodynamics|X Chromosome Inactivation', 'Journal Article', '10.1371/journal.pcbi.1002229', '22046112', 'X-Chromosome Inactivation (XCI) is the process whereby one, randomly chosen X becomes transcriptionally silenced in female cells. XCI is governed by the Xic, a locus on the X encompassing an array of genes which interact with each other and with key molecular factors. The mechanism, though, establishing the fate of the Xs, and the corresponding alternative modifications of the Xic architecture, is still mysterious. In this study, by use of computer simulations, we explore the scenario where chromatin conformations emerge from its interaction with diffusing molecular factors. Our aim is to understand the physical mechanisms whereby stable, non-random conformations are established on the Xics, how complex architectural changes are reliably regulated, and how they lead to opposite structures on the two alleles. In particular, comparison against current experimental data indicates that a few key cis-regulatory regions orchestrate the organization of the Xic, and that two major molecular regulators are involved.'),
(85211, 2011, 'plos', 'STDP allows fast rate-modulated coding with Poisson-like spike trains', 'Gilson, Matthieu|Masquelier, Timothée|Hugues, Etienne', 'Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Australia. gilsonm@unimelb.edu.au|Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Australia. gilsonm@unimelb.edu.au|Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Australia. gilsonm@unimelb.edu.au', 'Australia|Australia|Australia', 19, 'Computational Biology|Computer Simulation|Models, Neurological|Neuronal Plasticity|Neurons|Poisson Distribution', 'Journal Article', '10.1371/journal.pcbi.1002231', '22046113', 'Spike timing-dependent plasticity (STDP) has been shown to enable single neurons to detect repeatedly presented spatiotemporal spike patterns. This holds even when such patterns are embedded in equally dense random spiking activity, that is, in the absence of external reference times such as a stimulus onset. Here we demonstrate, both analytically and numerically, that STDP can also learn repeating rate-modulated patterns, which have received more experimental evidence, for example, through post-stimulus time histograms (PSTHs). Each input spike train is generated from a rate function using a stochastic sampling mechanism, chosen to be an inhomogeneous Poisson process here. Learning is feasible provided significant covarying rate modulations occur within the typical timescale of STDP (~10-20 ms) for sufficiently many inputs (~100 among 1000 in our simulations), a condition that is met by many experimental PSTHs. Repeated pattern presentations induce spike-time correlations that are captured by STDP. Despite imprecise input spike times and even variable spike counts, a single trained neuron robustly detects the pattern just a few milliseconds after its presentation. Therefore, temporal imprecision and Poisson-like firing variability are not an obstacle to fast temporal coding. STDP provides an appealing mechanism to learn such rate patterns, which, beyond sensory processing, may also be involved in many cognitive tasks.'),
(85212, 2011, 'plos', 'Ten simple rules for getting involved in your scientific community', 'Michaut, Magali', 'Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Australia. gilsonm@unimelb.edu.au', 'Australia', 10, 'Humans|Information Dissemination|Research|Science|Social Networking|Societies', 'Editorial', '10.1371/journal.pcbi.1002232', '22046114', '-');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85213, 2011, 'plos', 'Grid cells, place cells, and geodesic generalization for spatial reinforcement learning', 'Gustafson, Nicholas J|Daw, Nathaniel D', 'Center for Neural Science, New York University, New York, New York, United States of America. njg245@nyu.edu|Center for Neural Science, New York University, New York, New York, United States of America. njg245@nyu.edu', 'United States|United States', 15, 'Animals|Computer Simulation|Entorhinal Cortex|Hippocampus|Maze Learning|Models, Neurological|Neurons|Rats|Reinforcement (Psychology)|Spatial Behavior', 'Journal Article', '10.1371/journal.pcbi.1002235', '22046115', 'Reinforcement learning (RL) provides an influential characterization of the brains mechanisms for learning to make advantageous choices. An important problem, though, is how complex tasks can be represented in a way that enables efficient learning. We consider this problem through the lens of spatial navigation, examining how two of the brains location representations--hippocampal place cells and entorhinal grid cells--are adapted to serve as basis functions for approximating value over space for RL. Although much previous work has focused on these systems roles in combining upstream sensory cues to track location, revisiting these representations with a focus on how they support this downstream decision function offers complementary insights into their characteristics. Rather than localization, the key problem in learning is generalization between past and present situations, which may not match perfectly. Accordingly, although neural populations collectively offer a precise representation of position, our simulations of navigational tasks verify the suggestion that RL gains efficiency from the more diffuse tuning of individual neurons, which allows learning about rewards to generalize over longer distances given fewer training experiences. However, work on generalization in RL suggests the underlying representation should respect the environments layout. In particular, although it is often assumed that neurons track location in Euclidean coordinates (that a place cells activity declines as the crow flies away from its peak), the relevant metric for value is geodesic: the distance along a path, around any obstacles. We formalize this intuition and present simulations showing how Euclidean, but not geodesic, representations can interfere with RL by generalizing inappropriately across barriers. Our proposal that place and grid responses should be modulated by geodesic distances suggests novel predictions about how obstacles should affect spatial firing fields, which provides a new viewpoint on data concerning both spatial codes.'),
(85214, 2011, 'plos', 'Teaching bioinformatics at the secondary school level', 'Lewitter, Fran|Bourne, Philip E', 'Center for Neural Science, New York University, New York, New York, United States of America. njg245@nyu.edu|Center for Neural Science, New York University, New York, New York, United States of America. njg245@nyu.edu', 'United States|United States', 11, 'Adolescent|Computational Biology|Curriculum|Humans|Internet|Schools|Students|Teaching', 'Editorial', '10.1371/journal.pcbi.1002242', '22046116', '-'),
(85215, 2011, 'plos', 'Ten simple rules for teaching bioinformatics at the high school level', 'Form, David|Lewitter, Fran', 'Center for Neural Science, New York University, New York, New York, United States of America. njg245@nyu.edu|Center for Neural Science, New York University, New York, New York, United States of America. njg245@nyu.edu', 'United States|United States', 12, 'Computational Biology|Curriculum|Humans|Schools|Teaching', 'Editorial', '10.1371/journal.pcbi.1002243', '22046117', '-'),
(85216, 2011, 'plos', 'A first attempt to bring computational biology into advanced high school biology classrooms', 'Gallagher, Suzanne Renick|Coon, William|Donley, Kristin|Scott, Abby|Goldberg, Debra S', 'Department of Computer Science, University of Colorado, Boulder, Colorado, United States of America.|Department of Computer Science, University of Colorado, Boulder, Colorado, United States of America.|Department of Computer Science, University of Colorado, Boulder, Colorado, United States of America.|Department of Computer Science, University of Colorado, Boulder, Colorado, United States of America.|Department of Computer Science, University of Colorado, Boulder, Colorado, United States of America.', 'United States|United States|United States|United States|United States', 13, 'Adolescent|Algorithms|Computational Biology|Curriculum|Data Mining|Humans|Phylogeny|Schools|Sequence Analysis, DNA|Students', 'Journal Article', '10.1371/journal.pcbi.1002244', '22046118', 'Computer science has become ubiquitous in many areas of biological research, yet most high school and even college students are unaware of this. As a result, many college biology majors graduate without adequate computational skills for contemporary fields of biology. The absence of a computational element in secondary school biology classrooms is of growing concern to the computational biology community and biology teachers who would like to acquaint their students with updated approaches in the discipline. We present a first attempt to correct this absence by introducing a computational biology element to teach genetic evolution into advanced biology classes in two local high schools. Our primary goal was to show students how computation is used in biology and why a basic understanding of computation is necessary for research in many fields of biology. This curriculum is intended to be taught by a computational biologist who has worked with a high school advanced biology teacher to adapt the unit for his/her classroom, but a motivated high school teacher comfortable with mathematics and computing may be able to teach this alone. In this paper, we present our curriculum, which takes into consideration the constraints of the required curriculum, and discuss our experiences teaching it. We describe the successes and challenges we encountered while bringing this unit to high school students, discuss how we addressed these challenges, and make suggestions for future versions of this curriculum.We believe that our curriculum can be a valuable seed for further development of computational activities aimed at high school biology students. Further, our experiences may be of value to others teaching computational biology at this level. Our curriculum can be obtained at http://ecsite.cs.colorado.edu/?page_id=149#biology or by contacting the authors.'),
(85217, 2011, 'plos', 'Ten simple rules for developing a short bioinformatics training course', 'Via, Allegra|De Las Rivas, Javier|Attwood, Teresa K|Landsman, David|Brazas, Michelle D|Leunissen, Jack A M|Tramontano, Anna|Schneider, Maria Victoria', 'Department of Computer Science, University of Colorado, Boulder, Colorado, United States of America.|Department of Computer Science, University of Colorado, Boulder, Colorado, United States of America.|Department of Computer Science, University of Colorado, Boulder, Colorado, United States of America.|Department of Computer Science, University of Colorado, Boulder, Colorado, United States of America.|Department of Computer Science, University of Colorado, Boulder, Colorado, United States of America.|Department of Computer Science, University of Colorado, Boulder, Colorado, United States of America.|Department of Computer Science, University of Colorado, Boulder, Colorado, United States of America.|Department of Computer Science, University of Colorado, Boulder, Colorado, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 24, 'Computational Biology|Curriculum|Humans|Teaching', 'Editorial', '10.1371/journal.pcbi.1002245', '22046119', '-'),
(85218, 2011, 'plos', 'Unbiased simulations reveal the inward-facing conformation of the human serotonin transporter and Na(+) ion release', 'Koldsø, Heidi|Noer, Pernille|Grouleff, Julie|Autzen, Henriette Elisabeth|Sinning, Steffen|Schiøtt, Birgit', 'Center for Insoluble Protein Structures and Interdisciplinary Nanoscience Center, Department of Chemistry, Aarhus University, Aarhus, Denmark.|Center for Insoluble Protein Structures and Interdisciplinary Nanoscience Center, Department of Chemistry, Aarhus University, Aarhus, Denmark.|Center for Insoluble Protein Structures and Interdisciplinary Nanoscience Center, Department of Chemistry, Aarhus University, Aarhus, Denmark.|Center for Insoluble Protein Structures and Interdisciplinary Nanoscience Center, Department of Chemistry, Aarhus University, Aarhus, Denmark.|Center for Insoluble Protein Structures and Interdisciplinary Nanoscience Center, Department of Chemistry, Aarhus University, Aarhus, Denmark.|Center for Insoluble Protein Structures and Interdisciplinary Nanoscience Center, Department of Chemistry, Aarhus University, Aarhus, Denmark.', 'Denmark|Denmark|Denmark|Denmark|Denmark|Denmark', 42, 'Binding Sites|Cytoplasm|Humans|Models, Biological|Molecular Dynamics Simulation|Mutagenesis, Site-Directed|Mutation|Protein Binding|Protein Conformation|Serotonin Plasma Membrane Transport Proteins|Sodium|Water', 'Journal Article', '10.1371/journal.pcbi.1002246', '22046120', 'Monoamine transporters are responsible for termination of synaptic signaling and are involved in depression, control of appetite, and anxiety amongst other neurological processes. Despite extensive efforts, the structures of the monoamine transporters and the transport mechanism of ions and substrates are still largely unknown. Structural knowledge of the human serotonin transporter (hSERT) is much awaited for understanding the mechanistic details of substrate translocation and binding of antidepressants and drugs of abuse. The publication of the crystal structure of the homologous leucine transporter has resulted in homology models of the monoamine transporters. Here we present extended molecular dynamics simulations of an experimentally supported homology model of hSERT with and without the natural substrate yielding a total of more than 1.5 µs of simulation of the protein dimer. The simulations reveal a transition of hSERT from an outward-facing occluded conformation to an inward-facing conformation in a one-substrate-bound state. Simulations with a second substrate in the proposed symport effector site did not lead to conformational changes associated with translocation. The central substrate binding site becomes fully exposed to the cytoplasm leaving both the Na(+)-ion in the Na2-site and the substrate in direct contact with the cytoplasm through water interactions. The simulations reveal how sodium is released and show indications of early events of substrate transport. The notion that ion dissociation from the Na2-site drives translocation is supported by experimental studies of a Na2-site mutant. Transmembrane helices (TMs) 1 and 6 are identified as the helices involved in the largest movements during transport.'),
(85219, 2011, 'plos', 'LTS and FS inhibitory interneurons, short-term synaptic plasticity, and cortical circuit dynamics', 'Hayut, Itai|Fanselow, Erika E|Connors, Barry W|Golomb, David', 'Department of Physiology and Neurobiology and Zlotowski Center for Neuroscience, Ben Gurion University, Beer-Sheva, Israel.|Department of Physiology and Neurobiology and Zlotowski Center for Neuroscience, Ben Gurion University, Beer-Sheva, Israel.|Department of Physiology and Neurobiology and Zlotowski Center for Neuroscience, Ben Gurion University, Beer-Sheva, Israel.|Department of Physiology and Neurobiology and Zlotowski Center for Neuroscience, Ben Gurion University, Beer-Sheva, Israel.', 'Israel|Israel|Israel|Israel', 17, 'Action Potentials|Animals|Cerebral Cortex|Computational Biology|Electric Stimulation|Epilepsy, Absence|Humans|Interneurons|Models, Neurological|Neuronal Plasticity|Neurotransmitter Agents|Rats|Thalamus', 'Journal Article', '10.1371/journal.pcbi.1002248', '22046121', 'Somatostatin-expressing, low threshold-spiking (LTS) cells and fast-spiking (FS) cells are two common subtypes of inhibitory neocortical interneuron. Excitatory synapses from regular-spiking (RS) pyramidal neurons to LTS cells strongly facilitate when activated repetitively, whereas RS-to-FS synapses depress. This suggests that LTS neurons may be especially relevant at high rate regimes and protect cortical circuits against over-excitation and seizures. However, the inhibitory synapses from LTS cells usually depress, which may reduce their effectiveness at high rates. We ask: by which mechanisms and at what firing rates do LTS neurons control the activity of cortical circuits responding to thalamic input, and how is control by LTS neurons different from that of FS neurons? We study rate models of circuits that include RS cells and LTS and FS inhibitory cells with short-term synaptic plasticity. LTS neurons shift the RS firing-rate vs. current curve to the right at high rates and reduce its slope at low rates, the LTS effect is delayed and prolonged. FS neurons always shift the curve to the right and affect RS firing transiently. In an RS-LTS-FS network, FS neurons reach a quiescent state if they receive weak input, LTS neurons are quiescent if RS neurons receive weak input, and both FS and RS populations are active if they both receive large inputs. In general, FS neurons tend to follow the spiking of RS neurons much more closely than LTS neurons. A novel type of facilitation-induced slow oscillations is observed above the LTS firing threshold with a frequency determined by the time scale of recovery from facilitation. To conclude, contrary to earlier proposals, LTS neurons affect the transient and steady state responses of cortical circuits over a range of firing rates, not only during the high rate regime, LTS neurons protect against over-activation about as well as FS neurons.'),
(85220, 2011, 'plos', 'Second order dimensionality reduction using minimum and maximum mutual information models', 'Fitzgerald, Jeffrey D|Rowekamp, Ryan J|Sincich, Lawrence C|Sharpee, Tatyana O', 'Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America.|Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America.|Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America.|Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America.', 'United States|United States|United States|United States', 39, 'Action Potentials|Algorithms|Animals|Computer Simulation|Geniculate Bodies|Macaca|Models, Neurological|Retinal Ganglion Cells', 'Journal Article', '10.1371/journal.pcbi.1002249', '22046122', 'Conventional methods used to characterize multidimensional neural feature selectivity, such as spike-triggered covariance (STC) or maximally informative dimensions (MID), are limited to Gaussian stimuli or are only able to identify a small number of features due to the curse of dimensionality. To overcome these issues, we propose two new dimensionality reduction methods that use minimum and maximum information models. These methods are information theoretic extensions of STC that can be used with non-Gaussian stimulus distributions to find relevant linear subspaces of arbitrary dimensionality. We compare these new methods to the conventional methods in two ways: with biologically-inspired simulated neurons responding to natural images and with recordings from macaque retinal and thalamic cells responding to naturalistic time-varying stimuli. With non-Gaussian stimuli, the minimum and maximum information methods significantly outperform STC in all cases, whereas MID performs best in the regime of low dimensional feature spaces.'),
(85221, 2011, 'plos', 'A sparse coding model with synaptically local plasticity and spiking neurons can account for the diverse shapes of V1 simple cell receptive fields', 'Zylberberg, Joel|Murphy, Jason Timothy|DeWeese, Michael Robert', 'Department of Physics, University of California, Berkeley, California, United States of America. joelz@berkeley.edu|Department of Physics, University of California, Berkeley, California, United States of America. joelz@berkeley.edu|Department of Physics, University of California, Berkeley, California, United States of America. joelz@berkeley.edu', 'United States|United States|United States', 92, 'Action Potentials|Animals|Macaca|Models, Neurological|Neuronal Plasticity|Neurons|Rats|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1002250', '22046123', 'Sparse coding algorithms trained on natural images can accurately predict the features that excite visual cortical neurons, but it is not known whether such codes can be learned using biologically realistic plasticity rules. We have developed a biophysically motivated spiking network, relying solely on synaptically local information, that can predict the full diversity of V1 simple cell receptive field shapes when trained on natural images. This represents the first demonstration that sparse coding principles, operating within the constraints imposed by cortical architecture, can successfully reproduce these receptive fields. We further prove, mathematically, that sparseness and decorrelation are the key ingredients that allow for synaptically local plasticity rules to optimize a cooperative, linear generative image model formed by the neural representation. Finally, we discuss several interesting emergent properties of our network, with the intent of bridging the gap between theoretical and experimental studies of visual cortex.'),
(85222, 2011, 'plos', 'Metabolic regulation in progression to autoimmune diabetes', 'Sysi-Aho, Marko|Ermolov, Andrey|Gopalacharyulu, Peddinti V|Tripathi, Abhishek|Seppxc3xa4nen-Laakso, Tuulikki|Maukonen, Johanna|Mattila, Ismo|Ruohonen, Suvi T|Vxc3xa4hxc3xa4talo, Laura|Yetukuri, Laxman|Hxc3xa4rkxc3xb6nen, Taina|Lindfors, Erno|Nikkilxc3xa4, Janne|Ilonen, Jorma|Simell, Olli|Saarela, Maria|Knip, Mikael|Kaski, Samuel|Savontaus, Eriika|Orexc5xa1ixc4x8d, Matej', 'VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.|VTT Technical Research Centre of Finland, Espoo, Finland.', 'Finland|Finland|Finland|Finland|Finland|Finland|Finland|Finland|Finland|Finland|Finland|Finland|Finl', 80, 'Adiponectin|Animals|Cluster Analysis|Computational Biology|Diabetes Mellitus, Type 1|Disease Progression|Female|Humans|Insulin|Insulin Resistance|Insulin-Secreting Cells|Leptin|Liver|Lysophosphatidylcholines|Male|Metabolic Networks and Pathways|Metabolome|Mice|Mice, Inbred NOD|Models, Biological|Risk Factors', 'Journal Article', '10.1371/journal.pcbi.1002257', '22046124', 'Recent evidence from serum metabolomics indicates that specific metabolic disturbances precede xcexb2-cell autoimmunity in humans and can be used to identify those children who subsequently progress to type 1 diabetes. The mechanisms behind these disturbances are unknown. Here we show the specificity of the pre-autoimmune metabolic changes, as indicated by their conservation in a murine model of type 1 diabetes. We performed a study in non-obese prediabetic (NOD) mice which recapitulated the design of the human study and derived the metabolic states from longitudinal lipidomics data. We show that female NOD mice who later progress to autoimmune diabetes exhibit the same lipidomic pattern as prediabetic children. These metabolic changes are accompanied by enhanced glucose-stimulated insulin secretion, normoglycemia, upregulation of insulinotropic amino acids in islets, elevated plasma leptin and adiponectin, and diminished gut microbial diversity of the Clostridium leptum group. Together, the findings indicate that autoimmune diabetes is preceded by a state of increased metabolic demands on the islets resulting in elevated insulin secretion and suggest alternative metabolic related pathways as therapeutic targets to prevent diabetes.'),
(85223, 2011, 'plos', 'Transcriptomic coordination in the human metabolic network reveals links between n-3 fat intake, adipose tissue gene expression and metabolic health', 'Morine, Melissa J|Tierney, Audrey C|van Ommen, Ben|Daniel, Hannelore|Toomey, Sinead|Gjelstad, Ingrid M F|Gormley, Isobel C|Pxc3xa9rez-Martinez, Pablo|Drevon, Christian A|Lxc3xb3pez-Miranda, Jose|Roche, Helen M', 'Nutrigenomics Research Group, UCD Conway Institute, University College Dublin, Ireland.|Nutrigenomics Research Group, UCD Conway Institute, University College Dublin, Ireland.|Nutrigenomics Research Group, UCD Conway Institute, University College Dublin, Ireland.|Nutrigenomics Research Group, UCD Conway Institute, University College Dublin, Ireland.|Nutrigenomics Research Group, UCD Conway Institute, University College Dublin, Ireland.|Nutrigenomics Research Group, UCD Conway Institute, University College Dublin, Ireland.|Nutrigenomics Research Group, UCD Conway Institute, University College Dublin, Ireland.|Nutrigenomics Research Group, UCD Conway Institute, University College Dublin, Ireland.|Nutrigenomics Research Group, UCD Conway Institute, University College Dublin, Ireland.|Nutrigenomics Research Group, UCD Conway Institute, University College Dublin, Ireland.|Nutrigenomics Research Group, UCD Conway Institute, University College Dublin, Ireland.', 'Ireland|Ireland|Ireland|Ireland|Ireland|Ireland|Ireland|Ireland|Ireland|Ireland|Ireland', 33, 'Adipogenesis|Adipose Tissue|Computational Biology|Fatty Acids, Omega-3|Gene Expression|Gene Expression Profiling|Health Status|Humans|Metabolic Networks and Pathways|Models, Biological|Multivariate Analysis|Oxidative Stress|Promoter Regions, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002223', '22072950', 'Understanding the molecular link between diet and health is a key goal in nutritional systems biology. As an alternative to pathway analysis, we have developed a joint multivariate and network-based approach to analysis of a dataset of habitual dietary records, adipose tissue transcriptomics and comprehensive plasma marker profiles from human volunteers with the Metabolic Syndrome. With this approach we identified prominent co-expressed sub-networks in the global metabolic network, which showed correlated expression with habitual n-3 PUFA intake and urinary levels of the oxidative stress marker 8-iso-PGF(2xcexb1). These sub-networks illustrated inherent cross-talk between distinct metabolic pathways, such as between triglyceride metabolism and production of lipid signalling molecules. In a parallel promoter analysis, we identified several adipogenic transcription factors as potential transcriptional regulators associated with habitual n-3 PUFA intake. Our results illustrate advantages of network-based analysis, and generate novel hypotheses on the transcriptomic link between habitual n-3 PUFA intake, adipose tissue function and oxidative stress.'),
(85224, 2011, 'plos', 'How landscape heterogeneity frames optimal diffusivity in searching processes', 'Raposo, E P|Bartumeus, F|da Luz, M G E|Ribeiro-Neto, P J|Souza, T A|Viswanathan, G M', 'Laboratório de Física Teórica e Computacional, Departamento de Física, Universidade Federal de Pernambuco, Recife, Brazil. ernesto@df.ufpe.br|Laboratório de Física Teórica e Computacional, Departamento de Física, Universidade Federal de Pernambuco, Recife, Brazil. ernesto@df.ufpe.br|Laboratório de Física Teórica e Computacional, Departamento de Física, Universidade Federal de Pernambuco, Recife, Brazil. ernesto@df.ufpe.br|Laboratório de Física Teórica e Computacional, Departamento de Física, Universidade Federal de Pernambuco, Recife, Brazil. ernesto@df.ufpe.br|Laboratório de Física Teórica e Computacional, Departamento de Física, Universidade Federal de Pernambuco, Recife, Brazil. ernesto@df.ufpe.br|Laboratório de Física Teórica e Computacional, Departamento de Física, Universidade Federal de Pernambuco, Recife, Brazil. ernesto@df.ufpe.br', 'Brazil|Brazil|Brazil|Brazil|Brazil|Brazil', 37, 'Animals|Behavior, Animal|Computational Biology|Conservation of Natural Resources|Ecosystem|Feeding Behavior|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002233', '22072951', 'Theoretical and empirical investigations of search strategies typically have failed to distinguish the distinct roles played by density versus patchiness of resources. It is well known that motility and diffusivity of organisms often increase in environments with low density of resources, but thus far there has been little progress in understanding the specific role of landscape heterogeneity and disorder on random, non-oriented motility. Here we address the general question of how the landscape heterogeneity affects the efficiency of encounter interactions under global constant density of scarce resources. We unveil the key mechanism coupling the landscape structure with optimal search diffusivity. In particular, our main result leads to an empirically testable prediction: enhanced diffusivity (including superdiffusive searches), with shift in the diffusion exponent, favors the success of target encounters in heterogeneous landscapes.'),
(85225, 2011, 'plos', 'High degree of heterogeneity in Alzheimers disease progression patterns', 'Komarova, Natalia L|Thalhauser, Craig J', 'Department of Mathematics, University of California Irvine, United States of America. komarova@uci.edu|Department of Mathematics, University of California Irvine, United States of America. komarova@uci.edu', 'United States|United States', 31, 'Aged|Aged, 80 and over|Aging|Alzheimer Disease|Cohort Studies|Computational Biology|Disease Progression|Humans|Longitudinal Studies|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1002251', '22072952', 'There have been several reports on the varying rates of progression among Alzheimers Disease (AD) patients, however, there has been no quantitative study of the amount of heterogeneity in AD. Obtaining a reliable quantitative measure of AD progression rates and their variances among the patients for each stage of AD is essential for evaluating results of any clinical study. The Global Deterioration Scale (GDS) and Functional Assessment Staging procedure (FAST) characterize seven stages in the course of AD from normal aging to severe dementia. Each GDS/FAST stage has a published mean duration, but the variance is unknown. We use statistical analysis to reconstruct GDS/FAST stage durations in a cohort of 648 AD patients with an average follow-up time of 4.78 years. Calculations for GDS/FAST stages 4-6 reveal that the standard deviations for stage durations are comparable with their mean values, indicating the presence of large variations in the AD progression among patients. Such amount of heterogeneity in the course of progression of AD is consistent with the existence of several sub-groups of AD patients, which differ by their patterns of decline.'),
(85226, 2011, 'plos', 'Learning the optimal control of coordinated eye and head movements', 'Saeb, Sohrab|Weber, Cornelius|Triesch, Jochen', 'Frankfurt Institute for Advanced Studies (FIAS), Goethe University Frankfurt, Germany. saeb@fias.uni-frankfurt.de|Frankfurt Institute for Advanced Studies (FIAS), Goethe University Frankfurt, Germany. saeb@fias.uni-frankfurt.de|Frankfurt Institute for Advanced Studies (FIAS), Goethe University Frankfurt, Germany. saeb@fias.uni-frankfurt.de', 'Germany|Germany|Germany', 17, 'Adaptation, Physiological|Computational Biology|Eye Movements|Head Movements|Humans|Learning|Models, Neurological|Restraint, Physical|Saccades|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1002253', '22072953', 'Various optimality principles have been proposed to explain the characteristics of coordinated eye and head movements during visual orienting behavior. At the same time, researchers have suggested several neural models to underly the generation of saccades, but these do not include online learning as a mechanism of optimization. Here, we suggest an open-loop neural controller with a local adaptation mechanism that minimizes a proposed cost function. Simulations show that the characteristics of coordinated eye and head movements generated by this model match the experimental data in many aspects, including the relationship between amplitude, duration and peak velocity in head-restrained and the relative contribution of eye and head to the total gaze shift in head-free conditions. Our model is a first step towards bringing together an optimality principle and an incremental local learning mechanism into a unified control scheme for coordinated eye and head movements.'),
(85227, 2011, 'plos', 'The statistics of bulk segregant analysis using next generation sequencing', 'Magwene, Paul M|Willis, John H|Kelly, John K', 'Department of Biology and IGSP Center for Systems Biology, Duke University, Durham, North Carolina, United States of America. paul.magwene@duke.edu|Department of Biology and IGSP Center for Systems Biology, Duke University, Durham, North Carolina, United States of America. paul.magwene@duke.edu|Department of Biology and IGSP Center for Systems Biology, Duke University, Durham, North Carolina, United States of America. paul.magwene@duke.edu', 'United States|United States|United States', 100, 'Chromosome Mapping|Computational Biology|DNA, Fungal|Gene Frequency|High-Throughput Nucleotide Sequencing|Models, Genetic|Models, Statistical|Quantitative Trait Loci|Saccharomyces cerevisiae|Statistics, Nonparametric', 'Journal Article', '10.1371/journal.pcbi.1002255', '22072954', 'We describe a statistical framework for QTL mapping using bulk segregant analysis (BSA) based on high throughput, short-read sequencing. Our proposed approach is based on a smoothed version of the standard G statistic, and takes into account variation in allele frequency estimates due to sampling of segregants to form bulks as well as variation introduced during the sequencing of bulks. Using simulation, we explore the impact of key experimental variables such as bulk size and sequencing coverage on the ability to detect QTLs. Counterintuitively, we find that relatively large bulks maximize the power to detect QTLs even though this implies weaker selection and less extreme allele frequency differences. Our simulation studies suggest that with large bulks and sufficient sequencing depth, the methods we propose can be used to detect even weak effect QTLs and we demonstrate the utility of this framework by application to a BSA experiment in the budding yeast Saccharomyces cerevisiae.'),
(85228, 2011, 'plos', 'Interspecies translation of disease networks increases robustness and predictive accuracy', 'Anvar, Seyed Yahya|Tucker, Allan|Vinciotti, Veronica|Venema, Andrea|van Ommen, Gert-Jan B|van der Maarel, Silvere M|Raz, Vered|t Hoen, Peter A C', 'Center for Human and Clinical Genetics, Leiden University Medical Center, The Netherlands. s.y.anvar@lumc.nl|Center for Human and Clinical Genetics, Leiden University Medical Center, The Netherlands. s.y.anvar@lumc.nl|Center for Human and Clinical Genetics, Leiden University Medical Center, The Netherlands. s.y.anvar@lumc.nl|Center for Human and Clinical Genetics, Leiden University Medical Center, The Netherlands. s.y.anvar@lumc.nl|Center for Human and Clinical Genetics, Leiden University Medical Center, The Netherlands. s.y.anvar@lumc.nl|Center for Human and Clinical Genetics, Leiden University Medical Center, The Netherlands. s.y.anvar@lumc.nl|Center for Human and Clinical Genetics, Leiden University Medical Center, The Netherlands. s.y.anvar@lumc.nl|Center for Human and Clinical Genetics, Leiden University Medical Center, The Netherlands. s.y.anvar@lumc.nl', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 0, 'Algorithms|Animals|Artificial Intelligence|Bayes Theorem|Computational Biology|Databases, Genetic|Disease|Disease Models, Animal|Drosophila|Gene Expression|Gene Regulatory Networks|Humans|Mice|Models, Genetic|Muscular Dystrophy, Animal|Muscular Dystrophy, Oculopharyngeal|Phenotype|Species Specificity|Transcriptome', 'Journal Article', '10.1371/journal.pcbi.1002258', '22072955', 'Gene regulatory networks give important insights into the mechanisms underlying physiology and pathophysiology. The derivation of gene regulatory networks from high-throughput expression data via machine learning strategies is problematic as the reliability of these models is often compromised by limited and highly variable samples, heterogeneity in transcript isoforms, noise, and other artifacts. Here, we develop a novel algorithm, dubbed Dandelion, in which we construct and train intraspecies Bayesian networks that are translated and assessed on independent test sets from other species in a reiterative procedure. The interspecies disease networks are subjected to multi-layers of analysis and evaluation, leading to the identification of the most consistent relationships within the network structure. In this study, we demonstrate the performance of our algorithms on datasets from animal models of oculopharyngeal muscular dystrophy (OPMD) and patient materials. We show that the interspecies network of genes coding for the proteasome provide highly accurate predictions on gene expression levels and disease phenotype. Moreover, the cross-species translation increases the stability and robustness of these networks. Unlike existing modeling approaches, our algorithms do not require assumptions on notoriously difficult one-to-one mapping of protein orthologues or alternative transcripts and can deal with missing data. We show that the identified key components of the OPMD disease network can be confirmed in an unseen and independent disease model. This study presents a state-of-the-art strategy in constructing interspecies disease networks that provide crucial information on regulatory relationships among genes, leading to better understanding of the disease molecular mechanisms.'),
(85229, 2011, 'plos', 'Stability properties of underdominance in finite subdivided populations', 'Altrock, Philipp M|Traulsen, Arne|Reed, Floyd A', 'Evolutionary Theory Group, Max-Planck-Institute for Evolutionary Biology, Plön, Germany. altrock@evolbio.mpg.de|Evolutionary Theory Group, Max-Planck-Institute for Evolutionary Biology, Plön, Germany. altrock@evolbio.mpg.de|Evolutionary Theory Group, Max-Planck-Institute for Evolutionary Biology, Plön, Germany. altrock@evolbio.mpg.de', 'Germany|Germany|Germany', 35, 'Animals|Biological Evolution|Computational Biology|Extinction, Biological|Gene Flow|Gene Frequency|Genes, Dominant|Genetics, Population|Genomic Instability|Humans|Models, Genetic|Mutation|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002260', '22072956', 'IN ISOLATED populations underdominance leads to bistable evolutionary dynamics: below a certain mutant allele frequency the wildtype succeeds. Above this point, the potentially underdominant mutant allele fixes. In subdivided populations with gene flow there can be stable states with coexistence of wildtypes and mutants: polymorphism can be maintained because of a migration-selection equilibrium, i.e., selection against rare recent immigrant alleles that tend to be heterozygous. We focus on the stochastic evolutionary dynamics of systems where demographic fluctuations in the coupled populations are the main source of internal noise. We discuss the influence of fitness, migration rate, and the relative sizes of two interacting populations on the mean extinction times of a group of potentially underdominant mutant alleles. We classify realistic initial conditions according to their impact on the stochastic extinction process. Even in small populations, where demographic fluctuations are large, stability properties predicted from deterministic dynamics show remarkable robustness. Fixation of the mutant allele becomes unlikely but the time to its extinction can be long.'),
(85230, 2011, 'plos', 'Neural dynamics as sampling: a model for stochastic computation in recurrent networks of spiking neurons', 'Buesing, Lars|Bill, Johannes|Nessler, Bernhard|Maass, Wolfgang', 'Institute for Theoretical Computer Science, Graz University of Technology, Graz, Austria. lars@gatsby.ucl.ac.uk|Institute for Theoretical Computer Science, Graz University of Technology, Graz, Austria. lars@gatsby.ucl.ac.uk|Institute for Theoretical Computer Science, Graz University of Technology, Graz, Austria. lars@gatsby.ucl.ac.uk|Institute for Theoretical Computer Science, Graz University of Technology, Graz, Austria. lars@gatsby.ucl.ac.uk', 'Austria|Austria|Austria|Austria', 169, 'Action Potentials|Algorithms|Animals|Computer Simulation|Humans|Markov Chains|Models, Neurological|Monte Carlo Method|Neurons|Primates|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002211', '22096452', 'The organization of computations in networks of spiking neurons in the brain is still largely unknown, in particular in view of the inherently stochastic features of their firing activity and the experimentally observed trial-to-trial variability of neural systems in the brain. In principle there exists a powerful computational framework for stochastic computations, probabilistic inference by sampling, which can explain a large number of macroscopic experimental data in neuroscience and cognitive science. But it has turned out to be surprisingly difficult to create a link between these abstract models for stochastic computations and more detailed models of the dynamics of networks of spiking neurons. Here we create such a link and show that under some conditions the stochastic firing activity of networks of spiking neurons can be interpreted as probabilistic inference via Markov chain Monte Carlo (MCMC) sampling. Since common methods for MCMC sampling in distributed systems, such as Gibbs sampling, are inconsistent with the dynamics of spiking neurons, we introduce a different approach based on non-reversible Markov chains that is able to reflect inherent temporal processes of spiking neuronal activity through a suitable choice of random variables. We propose a neural network model and show by a rigorous theoretical analysis that its neural activity implements MCMC sampling of a given distribution, both for the case of discrete and continuous time. This provides a step towards closing the gap between abstract functional models of cortical computation and more detailed models of networks of spiking neurons.'),
(85231, 2011, 'plos', 'Trade-offs and constraints in allosteric sensing', 'Martins, Bruno M C|Swain, Peter S', 'Centre for Systems Biology at Edinburgh, The University of Edinburgh, Edinburgh UK. bruno.martins@ed.ac.uk|Centre for Systems Biology at Edinburgh, The University of Edinburgh, Edinburgh UK. bruno.martins@ed.ac.uk', 'United Kingdom|United Kingdom', 29, 'Allosteric Regulation|Bacterial Physiological Phenomena|Gene Expression Regulation|Models, Biological|Signal Transduction|Systems Biology|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002261', '22096453', 'Sensing extracellular changes initiates signal transduction and is the first stage of cellular decision-making. Yet relatively little is known about why one form of sensing biochemistry has been selected over another. To gain insight into this question, we studied the sensing characteristics of one of the biochemically simplest of sensors: the allosteric transcription factor. Such proteins, common in microbes, directly transduce the detection of a sensed molecule to changes in gene regulation. Using the Monod-Wyman-Changeux model, we determined six sensing characteristics--the dynamic range, the Hill number, the intrinsic noise, the information transfer capacity, the static gain, and the mean response time--as a function of the biochemical parameters of individual sensors and of the number of sensors. We found that specifying one characteristic strongly constrains others. For example, a high dynamic range implies a high Hill number and a high capacity, and vice versa. Perhaps surprisingly, these constraints are so strong that most of the space of characteristics is inaccessible given biophysically plausible ranges of parameter values. Within our approximations, we can calculate the probability distribution of the numbers of input molecules that maximizes information transfer and show that a population of one hundred allosteric transcription factors can in principle distinguish between more than four bands of input concentrations. Our results imply that allosteric sensors are unlikely to have been selected for high performance in one sensing characteristic but for a compromise in the performance of many.'),
(85232, 2011, 'plos', 'Identification of biochemical network modules based on shortest retroactive distances', 'Sridharan, Gautham Vivek|Hassoun, Soha|Lee, Kyongbum', 'Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts, United States of America.|Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts, United States of America.|Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts, United States of America.', 'United States|United States|United States', 0, 'Animals|Computer Simulation|ErbB Receptors|Humans|Liver|Metabolic Networks and Pathways|NADP|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002262', '22102800', 'Modularity analysis offers a route to better understand the organization of cellular biochemical networks as well as to derive practically useful, simplified models of these complex systems. While there is general agreement regarding the qualitative properties of a biochemical module, there is no clear consensus on the quantitative criteria that may be used to systematically derive these modules. In this work, we investigate cyclical interactions as the defining characteristic of a biochemical module. We utilize a round trip distance metric, termed Shortest Retroactive Distance (ShReD), to characterize the retroactive connectivity between any two reactions in a biochemical network and to group together network components that mutually influence each other. We evaluate the metric on two types of networks that feature feedback interactions: (i) epidermal growth factor receptor (EGFR) signaling and (ii) liver metabolism supporting drug transformation. For both networks, the ShReD partitions found hierarchically arranged modules that confirm biological intuition. In addition, the partitions also revealed modules that are less intuitive. In particular, ShReD-based partition of the metabolic network identified a redox module that couples reactions of glucose, pyruvate, lipid and drug metabolism through shared production and consumption of NADPH. Our results suggest that retroactive interactions arising from feedback loops and metabolic cycles significantly contribute to the modularity of biochemical networks. For metabolic networks, cofactors play an important role as allosteric effectors that mediate the retroactive interactions.'),
(85233, 2011, 'plos', 'Computational modeling and analysis of insulin induced eukaryotic translation initiation', 'Lequieu, Joshua|Chakrabarti, Anirikh|Nayak, Satyaprakash|Varner, Jeffrey D', 'School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, United States of America.|School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, United States of America.|School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, United States of America.|School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, United States of America.', 'United States|United States|United States|United States', 14, 'Animals|Computer Simulation|Eukaryota|Humans|Insulin|Insulin Receptor Substrate Proteins|PTEN Phosphohydrolase|Peptide Chain Initiation, Translational|Phosphatidylinositol 3-Kinases|Phosphorylation|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002263', '22102801', 'Insulin, the primary hormone regulating the level of glucose in the bloodstream, modulates a variety of cellular and enzymatic processes in normal and diseased cells. Insulin signals are processed by a complex network of biochemical interactions which ultimately induce gene expression programs or other processes such as translation initiation. Surprisingly, despite the wealth of literature on insulin signaling, the relative importance of the components linking insulin with translation initiation remains unclear. We addressed this question by developing and interrogating a family of mathematical models of insulin induced translation initiation. The insulin network was modeled using mass-action kinetics within an ordinary differential equation (ODE) framework. A family of model parameters was estimated, starting from an initial best fit parameter set, using 24 experimental data sets taken from literature. The residual between model simulations and each of the experimental constraints were simultaneously minimized using multiobjective optimization. Interrogation of the model population, using sensitivity and robustness analysis, identified an insulin-dependent switch that controlled translation initiation. Our analysis suggested that without insulin, a balance between the pro-initiation activity of the GTP-binding protein Rheb and anti-initiation activity of PTEN controlled basal initiation. On the other hand, in the presence of insulin a combination of PI3K and Rheb activity controlled inducible initiation, where PI3K was only critical in the presence of insulin. Other well known regulatory mechanisms governing insulin action, for example IRS-1 negative feedback, modulated the relative importance of PI3K and Rheb but did not fundamentally change the signal flow.'),
(85234, 2011, 'plos', 'Stochastic delay accelerates signaling in gene networks', 'Josixc4x87, Krexc5xa1imir|Lxc3xb3pez, Josxc3xa9 Manuel|Ott, William|Shiau, LieJune|Bennett, Matthew R', 'Department of Mathematics, University of Houston, Texas, United States of America.|Department of Mathematics, University of Houston, Texas, United States of America.|Department of Mathematics, University of Houston, Texas, United States of America.|Department of Mathematics, University of Houston, Texas, United States of America.|Department of Mathematics, University of Houston, Texas, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Animals|Computer Simulation|Gene Regulatory Networks|Humans|Protein Biosynthesis|Signal Transduction|Stochastic Processes|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002264', '22102802', 'The creation of protein from DNA is a dynamic process consisting of numerous reactions, such as transcription, translation and protein folding. Each of these reactions is further comprised of hundreds or thousands of sub-steps that must be completed before a protein is fully mature. Consequently, the time it takes to create a single protein depends on the number of steps in the reaction chain and the nature of each step. One way to account for these reactions in models of gene regulatory networks is to incorporate dynamical delay. However, the stochastic nature of the reactions necessary to produce protein leads to a waiting time that is randomly distributed. Here, we use queueing theory to examine the effects of such distributed delay on the propagation of information through transcriptionally regulated genetic networks. In an analytically tractable model we find that increasing the randomness in protein production delay can increase signaling speed in transcriptional networks. The effect is confirmed in stochastic simulations, and we demonstrate its impact in several common transcriptional motifs. In particular, we show that in feedforward loops signaling time and magnitude are significantly affected by distributed delay. In addition, delay has previously been shown to cause stable oscillations in circuits with negative feedback. We show that the period and the amplitude of the oscillations monotonically decrease as the variability of the delay time increases.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85235, 2011, 'plos', 'Representational switching by dynamical reorganization of attractor structure in a network model of the prefrontal cortex', 'Katori, Yuichi|Sakamoto, Kazuhiro|Saito, Naohiro|Tanji, Jun|Mushiake, Hajime|Aihara, Kazuyuki', 'FIRST, Aihara Innovative Mathematical Modelling Project, JST, Kawaguchi, Japan. katori@sat.t.u-tokyo.ac.jp|FIRST, Aihara Innovative Mathematical Modelling Project, JST, Kawaguchi, Japan. katori@sat.t.u-tokyo.ac.jp|FIRST, Aihara Innovative Mathematical Modelling Project, JST, Kawaguchi, Japan. katori@sat.t.u-tokyo.ac.jp|FIRST, Aihara Innovative Mathematical Modelling Project, JST, Kawaguchi, Japan. katori@sat.t.u-tokyo.ac.jp|FIRST, Aihara Innovative Mathematical Modelling Project, JST, Kawaguchi, Japan. katori@sat.t.u-tokyo.ac.jp|FIRST, Aihara Innovative Mathematical Modelling Project, JST, Kawaguchi, Japan. katori@sat.t.u-tokyo.ac.jp', 'Japan|Japan|Japan|Japan|Japan|Japan', 21, 'Animals|Haplorhini|Models, Neurological|Neural Networks (Computer)|Neurons|Prefrontal Cortex|Synapses', 'Journal Article', '10.1371/journal.pcbi.1002266', '22102803', 'The prefrontal cortex (PFC) plays a crucial role in flexible cognitive behavior by representing task relevant information with its working memory. The working memory with sustained neural activity is described as a neural dynamical system composed of multiple attractors, each attractor of which corresponds to an active state of a cell assembly, representing a fragment of information. Recent studies have revealed that the PFC not only represents multiple sets of information but also switches multiple representations and transforms a set of information to another set depending on a given task context. This representational switching between different sets of information is possibly generated endogenously by flexible network dynamics but details of underlying mechanisms are unclear. Here we propose a dynamically reorganizable attractor network model based on certain internal changes in synaptic connectivity, or short-term plasticity. We construct a network model based on a spiking neuron model with dynamical synapses, which can qualitatively reproduce experimentally demonstrated representational switching in the PFC when a monkey was performing a goal-oriented action-planning task. The model holds multiple sets of information that are required for action planning before and after representational switching by reconfiguration of functional cell assemblies. Furthermore, we analyzed population dynamics of this model with a mean field model and show that the changes in cell assemblies configuration correspond to those in attractor structure that can be viewed as a bifurcation process of the dynamical system. This dynamical reorganization of a neural network could be a key to uncovering the mechanism of flexible information processing in the PFC.'),
(85236, 2011, 'plos', 'Dynamical and structural analysis of a T cell survival network identifies novel candidate therapeutic targets for large granular lymphocyte leukemia', 'Saadatpour, Assieh|Wang, Rui-Sheng|Liao, Aijun|Liu, Xin|Loughran, Thomas P|Albert, István|Albert, Réka', 'Department of Mathematics, The Pennsylvania State University, University Park, United States of America.|Department of Mathematics, The Pennsylvania State University, University Park, United States of America.|Department of Mathematics, The Pennsylvania State University, University Park, United States of America.|Department of Mathematics, The Pennsylvania State University, University Park, United States of America.|Department of Mathematics, The Pennsylvania State University, University Park, United States of America.|Department of Mathematics, The Pennsylvania State University, University Park, United States of America.|Department of Mathematics, The Pennsylvania State University, University Park, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 0, 'Cell Survival|Humans|Leukemia, Large Granular Lymphocytic|Phosphorylation|Signal Transduction|Smad2 Protein|Smad3 Protein|T-Lymphocytes, Cytotoxic', 'Journal Article', '10.1371/journal.pcbi.1002267', '22102804', 'The blood cancer T cell large granular lymphocyte (T-LGL) leukemia is a chronic disease characterized by a clonal proliferation of cytotoxic T cells. As no curative therapy is yet known for this disease, identification of potential therapeutic targets is of immense importance. In this paper, we perform a comprehensive dynamical and structural analysis of a network model of this disease. By employing a network reduction technique, we identify the stationary states (fixed points) of the system, representing normal and diseased (T-LGL) behavior, and analyze their precursor states (basins of attraction) using an asynchronous Boolean dynamic framework. This analysis identifies the T-LGL states of 54 components of the network, out of which 36 (67%) are corroborated by previous experimental evidence and the rest are novel predictions. We further test and validate one of these newly identified states experimentally. Specifically, we verify the prediction that the node SMAD is over-active in leukemic T-LGL by demonstrating the predominant phosphorylation of the SMAD family members Smad2 and Smad3. Our systematic perturbation analysis using dynamical and structural methods leads to the identification of 19 potential therapeutic targets, 68% of which are corroborated by experimental evidence. The novel therapeutic targets provide valuable guidance for wet-bench experiments. In addition, we successfully identify two new candidates for engineering long-lived T cells necessary for the delivery of virus and cancer vaccines. Overall, this study provides a birds-eye-view of the avenues available for identification of therapeutic targets for similar diseases through perturbation of the underlying signal transduction network.'),
(85237, 2011, 'plos', 'A density-dependent switch drives stochastic clustering and polarization of signaling molecules', 'Jilkine, Alexandra|Angenent, Sigurd B|Wu, Lani F|Altschuler, Steven J', 'Molecular and Cellular Biology, University of Arizona, Tucson, United States of America.|Molecular and Cellular Biology, University of Arizona, Tucson, United States of America.|Molecular and Cellular Biology, University of Arizona, Tucson, United States of America.|Molecular and Cellular Biology, University of Arizona, Tucson, United States of America.', 'United States|United States|United States|United States', 0, 'Cell Communication|Cluster Analysis|Computer Simulation|Feedback, Physiological|Signal Transduction|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002271', '22102805', 'Positive feedback plays a key role in the ability of signaling molecules to form highly localized clusters in the membrane or cytosol of cells. Such clustering can occur in the absence of localizing mechanisms such as pre-existing spatial cues, diffusional barriers, or molecular cross-linking. What prevents positive feedback from amplifying inevitable biological noise when an un-clustered off state is desired? And, what limits the spread of clusters when an on state is desired? Here, we show that a minimal positive feedback circuit provides the general principle for both suppressing and amplifying noise: below a critical density of signaling molecules, clustering switches off, above this threshold, highly localized clusters are recurrently generated. Clustering occurs only in the stochastic regime, suggesting that finite sizes of molecular populations cannot be ignored in signal transduction networks. The emergence of a dominant cluster for finite numbers of molecules is partly a phenomenon of random sampling, analogous to the fixation or loss of neutral mutations in finite populations. We refer to our model as the neutral drift polarity model. Regulating the density of signaling molecules provides a simple mechanism for a positive feedback circuit to robustly switch between clustered and un-clustered states. The intrinsic ability of positive feedback both to create and suppress clustering is a general mechanism that could operate within diverse biological networks to create dynamic spatial organization.'),
(85238, 2011, 'plos', 'Reversible and noisy progression towards a commitment point enables adaptable and reliable cellular decision-making', 'Kuchina, Anna|Espinar, Lorena|Garcia-Ojalvo, Jordi|Süel, Gürol M', 'Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, United States of America.|Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, United States of America.|Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, United States of America.|Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, United States of America.', 'United States|United States|United States|United States', 0, 'Bacillus subtilis|Models, Theoretical|Spores, Bacterial', 'Journal Article', '10.1371/journal.pcbi.1002273', '22102806', 'Cells must make reliable decisions under fluctuating extracellular conditions, but also be flexible enough to adapt to such changes. How cells reconcile these seemingly contradictory requirements through the dynamics of cellular decision-making is poorly understood. To study this issue we quantitatively measured gene expression and protein localization in single cells of the model organism Bacillus subtilis during the progression to spore formation. We found that sporulation proceeded through noisy and reversible steps towards an irreversible, all-or-none commitment point. Specifically, we observed cell-autonomous and spontaneous bursts of gene expression and transient protein localization events during sporulation. Based on these measurements we developed mathematical population models to investigate how the degree of reversibility affects cellular decision-making. In particular, we evaluated the effect of reversibility on the 1) reliability in the progression to sporulation, and 2) adaptability under changing extracellular stress conditions. Results show that reversible progression allows cells to remain responsive to long-term environmental fluctuations. In contrast, the irreversible commitment point supports reliable execution of cell fate choice that is robust against short-term reductions in stress. This combination of opposite dynamic behaviors (reversible and irreversible) thus maximizes both adaptable and reliable decision-making over a broad range of changes in environmental conditions. These results suggest that decision-making systems might employ a general hybrid strategy to cope with unpredictably fluctuating environmental conditions.'),
(85239, 2011, 'plos', 'Construction and analysis of an integrated regulatory network derived from high-throughput sequencing data', 'Cheng, Chao|Yan, Koon-Kiu|Hwang, Woochang|Qian, Jiang|Bhardwaj, Nitin|Rozowsky, Joel|Lu, Zhi John|Niu, Wei|Alves, Pedro|Kato, Masaomi|Snyder, Michael|Gerstein, Mark', 'Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, 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', 67, 'Animals|Caenorhabditis elegans|Cluster Analysis|Databases, Genetic|Gene Expression Profiling|Gene Expression Regulation|Gene Regulatory Networks|MicroRNAs|Models, Genetic|Oligonucleotide Array Sequence Analysis|Sequence Analysis, DNA|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002190', '22125477', 'We present a network framework for analyzing multi-level regulation in higher eukaryotes based on systematic integration of various high-throughput datasets. The network, namely the integrated regulatory network, consists of three major types of regulation: TFxe2x86x92gene, TFxe2x86x92miRNA and miRNAxe2x86x92gene. We identified the target genes and target miRNAs for a set of TFs based on the ChIP-Seq binding profiles, the predicted targets of miRNAs using annotated 3UTR sequences and conservation information. Making use of the system-wide RNA-Seq profiles, we classified transcription factors into positive and negative regulators and assigned a sign for each regulatory interaction. Other types of edges such as protein-protein interactions and potential intra-regulations between miRNAs based on the embedding of miRNAs in their host genes were further incorporated. We examined the topological structures of the network, including its hierarchical organization and motif enrichment. We found that transcription factors downstream of the hierarchy distinguish themselves by expressing more uniformly at various tissues, have more interacting partners, and are more likely to be essential. We found an over-representation of notable network motifs, including a FFL in which a miRNA cost-effectively shuts down a transcription factor and its target. We used data of C. elegans from the modENCODE project as a primary model to illustrate our framework, but further verified the results using other two data sets. As more and more genome-wide ChIP-Seq and RNA-Seq data becomes available in the near future, our methods of data integration have various potential applications.'),
(85240, 2011, 'plos', 'Phosphorylation of the Arp2 subunit relieves auto-inhibitory interactions for Arp2/3 complex activation', 'Narayanan, Arjun|LeClaire, Lawrence L|Barber, Diane L|Jacobson, Matthew P', 'Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California, USA. arjun.nufc@gmail.com|Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California, USA. arjun.nufc@gmail.com|Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California, USA. arjun.nufc@gmail.com|Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California, USA. arjun.nufc@gmail.com', 'United States|United States|United States|United States', 0, 'Actin Cytoskeleton|Actin-Related Protein 2|Actin-Related Protein 2-3 Complex|Humans|Molecular Dynamics Simulation|Mutation|Phosphorylation|Polymerization|Protein Conformation|Protein Processing, Post-Translational', 'Journal Article', '10.1371/journal.pcbi.1002226', '22125478', 'Actin filament assembly by the actin-related protein (Arp) 2/3 complex is necessary to build many cellular structures, including lamellipodia at the leading edge of motile cells and phagocytic cups, and to move endosomes and intracellular pathogens. The crucial role of the Arp2/3 complex in cellular processes requires precise spatiotemporal regulation of its activity. While binding of nucleation-promoting factors (NPFs) has long been considered essential to Arp2/3 complex activity, we recently showed that phosphorylation of the Arp2 subunit is also necessary for Arp2/3 complex activation. Using molecular dynamics simulations and biochemical assays with recombinant Arp2/3 complex, we now show how phosphorylation of Arp2 induces conformational changes permitting activation. The simulations suggest that phosphorylation causes reorientation of Arp2 relative to Arp3 by destabilizing a network of salt-bridge interactions at the interface of the Arp2, Arp3, and ARPC4 subunits. Simulations also suggest a gain-of-function ARPC4 mutant that we show experimentally to have substantial activity in the absence of NPFs. We propose a model in which a network of auto-inhibitory salt-bridge interactions holds the Arp2 subunit in an inactive orientation. These auto-inhibitory interactions are destabilized upon phosphorylation of Arp2, allowing Arp2 to reorient to an activation-competent state.'),
(85241, 2011, 'plos', 'The what and where of adding channel noise to the Hodgkin-Huxley equations', 'Goldwyn, Joshua H|Shea-Brown, Eric', 'Department of Applied Mathematics, University of Washington, Seattle, Washington, USA. jgoldwyn@uw.edu|Department of Applied Mathematics, University of Washington, Seattle, Washington, USA. jgoldwyn@uw.edu', 'United States|United States', 86, 'Action Potentials|Animals|Axons|Decapodiformes|Electric Conductivity|Markov Chains|Models, Neurological|Potassium Channels|Sodium Channels|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002247', '22125479', 'Conductance-based equations for electrically active cells form one of the most widely studied mathematical frameworks in computational biology. This framework, as expressed through a set of differential equations by Hodgkin and Huxley, synthesizes the impact of ionic currents on a cells voltage--and the highly nonlinear impact of that voltage back on the currents themselves--into the rapid push and pull of the action potential. Later studies confirmed that these cellular dynamics are orchestrated by individual ion channels, whose conformational changes regulate the conductance of each ionic current. Thus, kinetic equations familiar from physical chemistry are the natural setting for describing conductances, for small-to-moderate numbers of channels, these will predict fluctuations in conductances and stochasticity in the resulting action potentials. At first glance, the kinetic equations provide a far more complex (and higher-dimensional) description than the original Hodgkin-Huxley equations or their counterparts. This has prompted more than a decade of efforts to capture channel fluctuations with noise terms added to the equations of Hodgkin-Huxley type. Many of these approaches, while intuitively appealing, produce quantitative errors when compared to kinetic equations, others, as only very recently demonstrated, are both accurate and relatively simple. We review what works, what doesnt, and why, seeking to build a bridge to well-established results for the deterministic equations of Hodgkin-Huxley type as well as to more modern models of ion channel dynamics. As such, we hope that this review will speed emerging studies of how channel noise modulates electrophysiological dynamics and function. We supply user-friendly MATLAB simulation code of these stochastic versions of the Hodgkin-Huxley equations on the ModelDB website (accession number 138950) and http://www.amath.washington.edu/~etsb/tutorials.html.'),
(85242, 2011, 'plos', 'Significance of input correlations in striatal function', 'Yim, Man Yi|Aertsen, Ad|Kumar, Arvind', 'Bernstein Center Freiburg and Neurobiology & Biophysics, Faculty of Biology, University of Freiburg, Freiburg, Germany. yim@bcf.uni-freiburg.de|Bernstein Center Freiburg and Neurobiology & Biophysics, Faculty of Biology, University of Freiburg, Freiburg, Germany. yim@bcf.uni-freiburg.de|Bernstein Center Freiburg and Neurobiology & Biophysics, Faculty of Biology, University of Freiburg, Freiburg, Germany. yim@bcf.uni-freiburg.de', 'Germany|Germany|Germany', 0, 'Animals|Basal Ganglia|Computer Simulation|Corpus Striatum|Electric Stimulation|Feedback, Physiological|Humans|Models, Neurological|Neocortex|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1002254', '22125480', 'The striatum is the main input station of the basal ganglia and is strongly associated with motor and cognitive functions. Anatomical evidence suggests that individual striatal neurons are unlikely to share their inputs from the cortex. Using a biologically realistic large-scale network model of striatum and cortico-striatal projections, we provide a functional interpretation of the special anatomical structure of these projections. Specifically, we show that weak pairwise correlation within the pool of inputs to individual striatal neurons enhances the saliency of signal representation in the striatum. By contrast, correlations among the input pools of different striatal neurons render the signal representation less distinct from background activity. We suggest that for the network architecture of the striatum, there is a preferred cortico-striatal input configuration for optimal signal representation. It is further enhanced by the low-rate asynchronous background activity in striatum, supported by the balance between feedforward and feedback inhibitions in the striatal network. Thus, an appropriate combination of rates and correlations in the striatal input sets the stage for action selection presumably implemented in the basal ganglia.'),
(85243, 2011, 'plos', 'PLoS Computational Biology Conference Postcards from ISMB/ECCB 2011', 'Madrigal, Pedro|Sela, Noa|Lin, Simon M', 'Institute of Plant Genetics, Polish Academy of Science, Poznaxc5x84, Poland. pmad@igr.poznan.pl|Institute of Plant Genetics, Polish Academy of Science, Poznaxc5x84, Poland. pmad@igr.poznan.pl|Institute of Plant Genetics, Polish Academy of Science, Poznaxc5x84, Poland. pmad@igr.poznan.pl', 'Poland|Poland|Poland', 0, 'Animals|Computational Biology|Humans|Precision Medicine', 'Congress', '10.1371/journal.pcbi.1002259', '22125481', '-'),
(85244, 2011, 'plos', 'Speed, sensitivity, and bistability in auto-activating signaling circuits', 'Hermsen, Rutger|Erickson, David W|Hwa, Terence', 'Center for Theoretical Biological Physics and Department of Physics, University of California at San Diego, La Jolla, California, USA. hermsen@ctbp.ucsd.edu|Center for Theoretical Biological Physics and Department of Physics, University of California at San Diego, La Jolla, California, USA. hermsen@ctbp.ucsd.edu|Center for Theoretical Biological Physics and Department of Physics, University of California at San Diego, La Jolla, California, USA. hermsen@ctbp.ucsd.edu', 'United States|United States|United States', 27, 'Computational Biology|Escherichia coli|Escherichia coli Proteins|Gene Expression Regulation|Homeostasis|Models, Biological|Signal Transduction|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002265', '22125482', 'Cells employ a myriad of signaling circuits to detect environmental signals and drive specific gene expression responses. A common motif in these circuits is inducible auto-activation: a transcription factor that activates its own transcription upon activation by a ligand or by post-transcriptional modification. Examples range from the two-component signaling systems in bacteria and plants to the genetic circuits of animal viruses such as HIV. We here present a theoretical study of such circuits, based on analytical calculations, numerical computations, and simulation. Our results reveal several surprising characteristics. They show that auto-activation can drastically enhance the sensitivity of the circuits response to input signals: even without molecular cooperativity, an ultra-sensitive threshold response can be obtained. However, the increased sensitivity comes at a cost: auto-activation tends to severely slow down the speed of induction, a stochastic effect that was strongly underestimated by earlier deterministic models. This slow-induction effect again requires no molecular cooperativity and is intimately related to the bimodality recently observed in non-cooperative auto-activation circuits. These phenomena pose strong constraints on the use of auto-activation in signaling networks. To achieve both a high sensitivity and a rapid induction, an inducible auto-activation circuit is predicted to acquire low cooperativity and low fold-induction. Examples from Escherichia colis two-component signaling systems support these predictions.'),
(85245, 2011, 'plos', 'Virus replication strategies and the critical CTL numbers required for the control of infection', 'Yates, Andrew J|Van Baalen, Minus|Antia, Rustom', 'Department of Systems and Computational Biology, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA. andrew.yates@einstein.yu.edu|Department of Systems and Computational Biology, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA. andrew.yates@einstein.yu.edu|Department of Systems and Computational Biology, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA. andrew.yates@einstein.yu.edu', 'United States|United States|United States', 9, 'Animals|Cell Count|Computational Biology|Host-Pathogen Interactions|Macaca mulatta|Models, Immunological|Simian Acquired Immunodeficiency Syndrome|Simian Immunodeficiency Virus|T-Lymphocytes, Cytotoxic|Virion|Virus Diseases|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.1002274', '22125483', 'Vaccines that elicit protective cytotoxic T lymphocytes (CTL) may improve on or augment those designed primarily to elicit antibody responses. However, we have little basis for estimating the numbers of CTL required for sterilising immunity at an infection site. To address this we begin with a theoretical estimate obtained from measurements of CTL surveillance rates and the growth rate of a virus. We show how this estimate needs to be modified to account for (i) the dynamics of CTL-infected cell conjugates, and (ii) features of the virus lifecycle in infected cells. We show that provided the inoculum size of the virus is low, the dynamics of CTL-infected cell conjugates can be ignored, but knowledge of virus life-histories is required for estimating critical thresholds of CTL densities. We show that accounting for virus replication strategies increases estimates of the minimum density of CTL required for immunity over those obtained with the canonical model of virus dynamics, and demonstrate that this modeling framework allows us to predict and compare the ability of CTL to control viruses with different life history strategies. As an example we predict that lytic viruses are more difficult to control than budding viruses when net reproduction rates and infected cell lifetimes are controlled for. Further, we use data from acute SIV infection in rhesus macaques to calculate a lower bound on the density of CTL that a vaccine must generate to control infection at the entry site. We propose that critical CTL densities can be better estimated either using quantitative models incorporating virus life histories or with in vivo assays using virus-infected cells rather than peptide-pulsed targets.'),
(85246, 2011, 'plos', 'Gene expression divergence is coupled to evolution of DNA structure in coding regions', 'Dai, Zhiming|Dai, Xianhua', 'School of Information Science and Technology, Sun Yat-Sen University, Guangzhou, China. zhimdai@gmail.com|School of Information Science and Technology, Sun Yat-Sen University, Guangzhou, China. zhimdai@gmail.com', 'China|China', 0, 'Animals|Base Sequence|Cluster Analysis|Computational Biology|DNA|Drosophila|Evolution, Molecular|Gene Expression Regulation|Models, Genetic|Nucleic Acid Conformation|Open Reading Frames|Regulatory Sequences, Nucleic Acid|Saccharomyces|Sequence Analysis, DNA|Structure-Activity Relationship|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002275', '22125484', 'Sequence changes in coding region and regulatory region of the gene itself (cis) determine most of gene expression divergence between closely related species. But gene expression divergence between yeast species is not correlated with evolution of primary nucleotide sequence. This indicates that other factors in cis direct gene expression divergence. Here, we studied the contribution of DNA three-dimensional structural evolution as cis to gene expression divergence. We found that the evolution of DNA structure in coding regions and gene expression divergence are correlated in yeast. Similar result was also observed between Drosophila species. DNA structure is associated with the binding of chromatin remodelers and histone modifiers to DNA sequences in coding regions, which influence RNA polymerase II occupancy that controls gene expression level. We also found that genes with similar DNA structures are involved in the same biological process and function. These results reveal the previously unappreciated roles of DNA structure as cis-effects in gene expression.'),
(85247, 2011, 'plos', 'Optimizing experimental design for comparing models of brain function', 'Daunizeau, Jean|Preuschoff, Kerstin|Friston, Karl|Stephan, Klaas', 'Wellcome Trust Centre for Neuroimaging, University College of London, London, UK. jean.daunizeau@gmail.com|Wellcome Trust Centre for Neuroimaging, University College of London, London, UK. jean.daunizeau@gmail.com|Wellcome Trust Centre for Neuroimaging, University College of London, London, UK. jean.daunizeau@gmail.com|Wellcome Trust Centre for Neuroimaging, University College of London, London, UK. jean.daunizeau@gmail.com', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 34, 'Bayes Theorem|Brain|Brain Mapping|Computational Biology|Computer Simulation|Feedback, Physiological|Humans|Magnetic Resonance Imaging|Models, Neurological|Monte Carlo Method|Psychomotor Performance|Reproducibility of Results|Research Design', 'Journal Article', '10.1371/journal.pcbi.1002280', '22125485', 'This article presents the first attempt to formalize the optimization of experimental design with the aim of comparing models of brain function based on neuroimaging data. We demonstrate our approach in the context of Dynamic Causal Modelling (DCM), which relates experimental manipulations to observed network dynamics (via hidden neuronal states) and provides an inference framework for selecting among candidate models. Here, we show how to optimize the sensitivity of model selection by choosing among experimental designs according to their respective model selection accuracy. Using Bayesian decision theory, we (i) derive the Laplace-Chernoff risk for model selection, (ii) disclose its relationship with classical design optimality criteria and (iii) assess its sensitivity to basic modelling assumptions. We then evaluate the approach when identifying brain networks using DCM. Monte-Carlo simulations and empirical analyses of fMRI data from a simple bimanual motor task in humans serve to demonstrate the relationship between network identification and the optimal experimental design. For example, we show that deciding whether there is a feedback connection requires shorter epoch durations, relative to asking whether there is experimentally induced change in a connection that is known to be present. Finally, we discuss limitations and potential extensions of this work.'),
(85248, 2011, 'plos', 'Sparse gamma rhythms arising through clustering in adapting neuronal networks', 'Kilpatrick, Zachary P|Ermentrout, Bard', 'Department of Mathematics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. zpkilpat@pitt.edu|Department of Mathematics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. zpkilpat@pitt.edu', 'United States|United States', 0, 'Action Potentials|Brain Waves|Cluster Analysis|Computer Simulation|Cortical Synchronization|Fourier Analysis|Humans|Interneurons|Least-Squares Analysis|Models, Neurological|Nerve Net|Pyramidal Cells', 'Journal Article', '10.1371/journal.pcbi.1002281', '22125486', 'Gamma rhythms (30-100 Hz) are an extensively studied synchronous brain state responsible for a number of sensory, memory, and motor processes. Experimental evidence suggests that fast-spiking interneurons are responsible for carrying the high frequency components of the rhythm, while regular-spiking pyramidal neurons fire sparsely. We propose that a combination of spike frequency adaptation and global inhibition may be responsible for this behavior. Excitatory neurons form several clusters that fire every few cycles of the fast oscillation. This is first shown in a detailed biophysical network model and then analyzed thoroughly in an idealized model. We exploit the fact that the timescale of adaptation is much slower than that of the other variables. Singular perturbation theory is used to derive an approximate periodic solution for a single spiking unit. This is then used to predict the relationship between the number of clusters arising spontaneously in the network as it relates to the adaptation time constant. We compare this to a complementary analysis that employs a weak coupling assumption to predict the first Fourier mode to destabilize from the incoherent state of an associated phase model as the external noise is reduced. Both approaches predict the same scaling of cluster number with respect to the adaptation time constant, which is corroborated in numerical simulations of the full system. Thus, we develop several testable predictions regarding the formation and characteristics of gamma rhythms with sparsely firing excitatory neurons.'),
(85249, 2011, 'plos', 'Collective animal behavior from Bayesian estimation and probability matching', 'Pérez-Escudero, Alfonso|de Polavieja, Gonzalo G', 'Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain. alfonso.perez.escudero@cajal.csic.es|Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain. alfonso.perez.escudero@cajal.csic.es', 'Spain|Spain', 0, 'Animals|Bayes Theorem|Behavior, Animal|Choice Behavior|Computational Biology|Environment|Models, Biological|Models, Statistical|Smegmamorpha', 'Journal Article', '10.1371/journal.pcbi.1002282', '22125487', 'Animals living in groups make movement decisions that depend, among other factors, on social interactions with other group members. Our present understanding of social rules in animal collectives is mainly based on empirical fits to observations, with less emphasis in obtaining first-principles approaches that allow their derivation. Here we show that patterns of collective decisions can be derived from the basic ability of animals to make probabilistic estimations in the presence of uncertainty. We build a decision-making model with two stages: Bayesian estimation and probabilistic matching. In the first stage, each animal makes a Bayesian estimation of which behavior is best to perform taking into account personal information about the environment and social information collected by observing the behaviors of other animals. In the probability matching stage, each animal chooses a behavior with a probability equal to the Bayesian-estimated probability that this behavior is the most appropriate one. This model derives very simple rules of interaction in animal collectives that depend only on two types of reliability parameters, one that each animal assigns to the other animals and another given by the quality of the non-social information. We test our model by obtaining theoretically a rich set of observed collective patterns of decisions in three-spined sticklebacks, Gasterosteus aculeatus, a shoaling fish species. The quantitative link shown between probabilistic estimation and collective rules of behavior allows a better contact with other fields such as foraging, mate selection, neurobiology and psychology, and gives predictions for experiments directly testing the relationship between estimation and collective behavior.'),
(85250, 2011, 'plos', 'Replication pauses of the wild-type and mutant mitochondrial DNA polymerase gamma: a simulation study', 'Song, Zhuo|Cao, Yang|Samuels, David C', 'Center for Human Genetic Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Center for Human Genetic Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Center for Human Genetic Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.', 'United States|United States|United States', 3, 'Animals|Computational Biology|Computer Simulation|DNA Polymerase gamma|DNA Replication|DNA, Mitochondrial|DNA-Directed DNA Polymerase|Mice|Mice, Transgenic|Models, Genetic|Mutation|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002287', '22125488', 'The activity of polymerase xcexb3 is complicated, involving both correct and incorrect DNA polymerization events, exonuclease activity, and the disassociation of the polymerase:DNA complex. Pausing of pol-xcexb3 might increase the chance of deletion and depletion of mitochondrial DNA. We have developed a stochastic simulation of pol-xcexb3 that models its activities on the level of individual nucleotides for the replication of mtDNA. This method gives us insights into the pausing of two pol-xcexb3 variants: the A467T substitution that causes PEO and Alpers syndrome, and the exonuclease deficient pol-xcexb3 (exo(-)) in premature aging mouse models. To measure the pausing, we analyzed simulation results for the longest time for the polymerase to move forward one nucleotide along the DNA strand. Our model of the exo(-) polymerase had extremely long pauses, with a 30 to 300-fold increase in the time required for the longest single forward step compared to the wild-type, while the naturally occurring A467T variant showed at most a doubling in the length of the pauses compared to the wild-type. We identified the cause of these differences in the polymerase pausing time to be the number of disassociations occurring in each forward step of the polymerase.'),
(85251, 2011, 'plos', 'Deciphering the Arginine-binding preferences at the substrate-binding groove of Ser/Thr kinases by computational surface mapping', 'Ben-Shimon, Avraham|Niv, Masha Y', 'Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment and The Fritz Haber Center for Molecular Dynamics, The Hebrew University, Israel.|Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment and The Fritz Haber Center for Molecular Dynamics, The Hebrew University, Israel.', 'Israel|Israel', 10, 'Algorithms|Amino Acid Sequence|Arginine|Binding Sites|Computational Biology|Computer Simulation|Models, Molecular|Molecular Sequence Data|Protein Binding|Protein Conformation|Protein Interaction Mapping|Protein-Serine-Threonine Kinases|Proteins|Reproducibility of Results|Substrate Specificity|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002288', '22125489', 'Protein kinases are key signaling enzymes that catalyze the transfer of xcexb3-phosphate from an ATP molecule to a phospho-accepting residue in the substrate. Unraveling the molecular features that govern the preference of kinases for particular residues flanking the phosphoacceptor is important for understanding kinase specificities toward their substrates and for designing substrate-like peptidic inhibitors. We applied ANCHORSmap, a new fragment-based computational approach for mapping amino acid side chains on protein surfaces, to predict and characterize the preference of kinases toward Arginine binding. We focus on positions P-2 and P-5, commonly occupied by Arginine (Arg) in substrates of basophilic Ser/Thr kinases. The method accurately identified all the P-2/P-5 Arg binding sites previously determined by X-ray crystallography and produced Arg preferences that corresponded to those experimentally found by peptide arrays. The predicted Arg-binding positions and their associated pockets were analyzed in terms of shape, physicochemical properties, amino acid composition, and in-silico mutagenesis, providing structural rationalization for previously unexplained trends in kinase preferences toward Arg moieties. This methodology sheds light on several kinases that were described in the literature as having non-trivial preferences for Arg, and provides some surprising departures from the prevailing views regarding residues that determine kinase specificity toward Arg. In particular, we found that the preference for a P-5 Arg is not necessarily governed by the 170/230 acidic pair, as was previously assumed, but by several different pairs of acidic residues, selected from positions 133, 169, and 230 (PKA numbering). The acidic residue at position 230 serves as a pivotal element in recognizing Arg from both the P-2 and P-5 positions.'),
(85252, 2011, 'plos', 'Genome majority vote improves gene predictions', 'Wall, Michael E|Raghavan, Sindhu|Cohn, Judith D|Dunbar, John', 'Computer, Computational, and Statistical Sciences Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA. mewall@lanl.gov|Computer, Computational, and Statistical Sciences Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA. mewall@lanl.gov|Computer, Computational, and Statistical Sciences Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA. mewall@lanl.gov|Computer, Computational, and Statistical Sciences Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA. mewall@lanl.gov', 'Mexico|Mexico|Mexico|Mexico', 0, 'Algorithms|Base Sequence|Chromosome Mapping|Computational Biology|Computer Simulation|Escherichia coli|Genes, Bacterial|Genome, Bacterial|Models, Genetic|Models, Statistical|Molecular Sequence Data|Sequence Alignment|Transcription Initiation Site', 'Journal Article', '10.1371/journal.pcbi.1002284', '22131910', 'Recent studies have noted extensive inconsistencies in gene start sites among orthologous genes in related microbial genomes. Here we provide the first documented evidence that imposing gene start consistency improves the accuracy of gene start-site prediction. We applied an algorithm using a genome majority vote (GMV) scheme to increase the consistency of gene starts among orthologs. We used a set of validated Escherichia coli genes as a standard to quantify accuracy. Results showed that the GMV algorithm can correct hundreds of gene prediction errors in sets of five or ten genomes while introducing few errors. Using a conservative calculation, we project that GMV would resolve many inconsistencies and errors in publicly available microbial gene maps. Our simple and logical solution provides a notable advance toward accurate gene maps.'),
(85253, 2011, 'plos', 'Comparative microbial modules resource: generation and visualization of multi-species biclusters', 'Kacmarczyk, Thadeous|Waltman, Peter|Bate, Ashley|Eichenberger, Patrick|Bonneau, Richard', '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.|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|United States|United States', 0, 'Algorithms|Cluster Analysis|Computational Biology|Databases, Factual|Escherichia coli|Genome, Bacterial|Nitrogen|Salmonella typhimurium|Software|Systems Biology|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1002228', '22144874', 'The increasing abundance of large-scale, high-throughput datasets for many closely related organisms provides opportunities for comparative analysis via the simultaneous biclustering of datasets from multiple species. These analyses require a reformulation of how to organize multi-species datasets and visualize comparative genomics data analyses results. Recently, we developed a method, multi-species cMonkey, which integrates heterogeneous high-throughput datatypes from multiple species to identify conserved regulatory modules. Here we present an integrated data visualization system, built upon the Gaggle, enabling exploration of our methods results (available at http://meatwad.bio.nyu.edu/cmmr.html). The system can also be used to explore other comparative genomics datasets and outputs from other data analysis procedures - results from other multiple-species clustering programs or from independent clustering of different single-species datasets. We provide an example use of our system for two bacteria, Escherichia coli and Salmonella Typhimurium. We illustrate the use of our system by exploring conserved biclusters involved in nitrogen metabolism, uncovering a putative function for yjjI, a currently uncharacterized gene that we predict to be involved in nitrogen assimilation.'),
(85254, 2011, 'plos', 'Validation of skeletal muscle cis-regulatory module predictions reveals nucleotide composition bias in functional enhancers', 'Kwon, Andrew T|Chou, Alice Yi|Arenillas, David J|Wasserman, Wyeth W', 'Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Genetics Graduate Program, and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.|Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Genetics Graduate Program, and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.|Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Genetics Graduate Program, and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.|Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Genetics Graduate Program, and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.', 'Canada|Canada|Canada|Canada', 0, 'Animals|Base Composition|Chromatin Immunoprecipitation|Computational Biology|Computer Simulation|Conserved Sequence|Genome|Histones|Humans|Mice|Models, Genetic|Models, Statistical|Muscle Fibers, Skeletal|Muscle, Skeletal|MyoD Protein|NIH 3T3 Cells|Phylogeny|Regulatory Sequences, Nucleic Acid|Reproducibility of Results|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1002256', '22144875', 'We performed a genome-wide scan for muscle-specific cis-regulatory modules (CRMs) using three computational prediction programs. Based on the predictions, 339 candidate CRMs were tested in cell culture with NIH3T3 fibroblasts and C2C12 myoblasts for capacity to direct selective reporter gene expression to differentiated C2C12 myotubes. A subset of 19 CRMs validated as functional in the assay. The rate of predictive success reveals striking limitations of computational regulatory sequence analysis methods for CRM discovery. Motif-based methods performed no better than predictions based only on sequence conservation. Analysis of the properties of the functional sequences relative to inactive sequences identifies nucleotide sequence composition can be an important characteristic to incorporate in future methods for improved predictive specificity. Muscle-related TFBSs predicted within the functional sequences display greater sequence conservation than non-TFBS flanking regions. Comparison with recent MyoD and histone modification ChIP-Seq data supports the validity of the functional regions.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85255, 2011, 'plos', 'Dominant glint based prey localization in horseshoe bats: a possible strategy for noise rejection', 'Vanderelst, Dieter|Reijniers, Jonas|Firzlaff, Uwe|Peremans, Herbert', 'Active Perception Lab, University Antwerp, Antwerp, Belgium. dieter.vanderelst@ua.ac.be|Active Perception Lab, University Antwerp, Antwerp, Belgium. dieter.vanderelst@ua.ac.be|Active Perception Lab, University Antwerp, Antwerp, Belgium. dieter.vanderelst@ua.ac.be|Active Perception Lab, University Antwerp, Antwerp, Belgium. dieter.vanderelst@ua.ac.be', 'Belgium|Belgium|Belgium|Belgium', 0, 'Animals|Chiroptera|Computational Biology|Computer Simulation|Ear, External|Echolocation|Entropy|Models, Biological|Noise', 'Journal Article', '10.1371/journal.pcbi.1002268', '22144876', 'Rhinolophidae or Horseshoe bats emit long and narrowband calls. Fluttering insect prey generates echoes in which amplitude and frequency shifts are present, i.e. glints. These glints are reliable cues about the presence of prey and also encode certain properties of the prey. In this paper, we propose that these glints, i.e. the dominant glints, are also reliable signals upon which to base prey localization. In contrast to the spectral cues used by many other bats, the localization cues in Rhinolophidae are most likely provided by self-induced amplitude modulations generated by pinnae movement. Amplitude variations in the echo not introduced by the moving pinnae can be considered as noise interfering with the localization process. The amplitude of the dominant glints is very stable. Therefore, these parts of the echoes contain very little noise. However, using only the dominant glints potentially comes at a cost. Depending on the flutter rate of the insect, a limited number of dominant glints will be present in each echo giving the bat a limited number of sample points on which to base localization. We evaluate the feasibility of a strategy under which Rhinolophidae use only dominant glints. We use a computational model of the echolocation task faced by Rhinolophidae. Our model includes the spatial filtering of the echoes by the morphology of the sonar apparatus of Rhinolophus rouxii as well as the amplitude modulations introduced by pinnae movements. Using this model, we evaluate whether the dominant glints provide Rhinolophidae with enough information to perform localization. Our simulations show that Rhinolophidae can use dominant glints in the echoes as carriers for self-induced amplitude modulations serving as localization cues. In particular, it is shown that the reduction in noise achieved by using only the dominant glints outweighs the information loss that occurs by sampling the echo.'),
(85256, 2011, 'plos', 'Identifying single copy orthologs in Metazoa', 'Creevey, Christopher J|Muller, Jean|Doerks, Tobias|Thompson, Julie D|Arendt, Detlev|Bork, Peer', 'Teagasc, Animal & Grassland Research and Innovation Centre, Grange, Dunsany, County Meath, Ireland.|Teagasc, Animal & Grassland Research and Innovation Centre, Grange, Dunsany, County Meath, Ireland.|Teagasc, Animal & Grassland Research and Innovation Centre, Grange, Dunsany, County Meath, Ireland.|Teagasc, Animal & Grassland Research and Innovation Centre, Grange, Dunsany, County Meath, Ireland.|Teagasc, Animal & Grassland Research and Innovation Centre, Grange, Dunsany, County Meath, Ireland.|Teagasc, Animal & Grassland Research and Innovation Centre, Grange, Dunsany, County Meath, Ireland.', 'Ireland|Ireland|Ireland|Ireland|Ireland|Ireland', 0, 'Animals|Databases, Genetic|Evolution, Molecular|Expressed Sequence Tags|Gene Dosage|Genome|Genomics|Humans|Multigene Family|Phylogeny', 'Journal Article', '10.1371/journal.pcbi.1002269', '22144877', 'The identification of single copy (1-to-1) orthologs in any group of organisms is important for functional classification and phylogenetic studies. The Metazoa are no exception, but only recently has there been a wide-enough distribution of taxa with sufficiently high quality sequenced genomes to gain confidence in the wide-spread single copy status of a gene.Here, we present a phylogenetic approach for identifying overlooked single copy orthologs from multigene families and apply it to the Metazoa. Using 18 sequenced metazoan genomes of high quality we identified a robust set of 1,126 orthologous groups that have been retained in single copy since the last common ancestor of Metazoa. We found that the use of the phylogenetic procedure increased the number of single copy orthologs found by over a third more than standard taxon-count approaches. The orthologs represented a wide range of functional categories, expression profiles and levels of divergence.To demonstrate the value of our set of single copy orthologs, we used them to assess the completeness of 24 currently published metazoan genomes and 62 EST datasets. We found that the annotated genes in published genomes vary in coverage from 79% (Ciona intestinalis) to 99.8% (human) with an average of 92%, suggesting a value for the underlying error rate in genome annotation, and a strategy for identifying single copy orthologs in larger datasets. In contrast, the vast majority of EST datasets with no corresponding genome sequence available are largely under-sampled and probably do not accurately represent the actual genomic complement of the organisms from which they are derived.'),
(85257, 2011, 'plos', 'Multiscale modeling of red blood cell mechanics and blood flow in malaria', 'Fedosov, Dmitry A|Lei, Huan|Caswell, Bruce|Suresh, Subra|Karniadakis, George E', 'Division of Applied Mathematics, Brown University, Providence, Rhode Island, USA.|Division of Applied Mathematics, Brown University, Providence, Rhode Island, USA.|Division of Applied Mathematics, Brown University, Providence, Rhode Island, USA.|Division of Applied Mathematics, Brown University, Providence, Rhode Island, USA.|Division of Applied Mathematics, Brown University, Providence, Rhode Island, USA.', 'United States|United States|United States|United States|United States', 71, 'Cell Adhesion|Computer Simulation|Elastic Modulus|Erythrocyte Deformability|Erythrocyte Membrane|Erythrocytes|Flow Cytometry|Hemorheology|Humans|Malaria, Falciparum|Models, Biological|Plasmodium falciparum|Viscosity', 'Journal Article', '10.1371/journal.pcbi.1002270', '22144878', 'Red blood cells (RBCs) infected by a Plasmodium parasite in malaria may lose their membrane deformability with a relative membrane stiffening more than ten-fold in comparison with healthy RBCs leading to potential capillary occlusions. Moreover, infected RBCs are able to adhere to other healthy and parasitized cells and to the vascular endothelium resulting in a substantial disruption of normal blood circulation. In the present work, we simulate infected RBCs in malaria using a multiscale RBC model based on the dissipative particle dynamics method, coupling scales at the sub-cellular level with scales at the vessel size. Our objective is to conduct a full validation of the RBC model with a diverse set of experimental data, including temperature dependence, and to identify the limitations of this purely mechanistic model. The simulated elastic deformations of parasitized RBCs match those obtained in optical-tweezers experiments for different stages of intra-erythrocytic parasite development. The rheological properties of RBCs in malaria are compared with those obtained by optical magnetic twisting cytometry and by monitoring membrane fluctuations at room, physiological, and febrile temperatures. We also study the dynamics of infected RBCs in Poiseuille flow in comparison with healthy cells and present validated bulk viscosity predictions of malaria-infected blood for a wide range of parasitemia levels (percentage of infected RBCs with respect to the total number of cells in a unit volume).'),
(85258, 2011, 'plos', 'BeadArray expression analysis using bioconductor', 'Ritchie, Matthew E|Dunning, Mark J|Smith, Mike L|Shi, Wei|Lynch, Andy G', 'Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. mritchie@wehi.edu.au|Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. mritchie@wehi.edu.au|Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. mritchie@wehi.edu.au|Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. mritchie@wehi.edu.au|Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. mritchie@wehi.edu.au', 'Australia|Australia|Australia|Australia|Australia', 0, 'Computational Biology|Gene Expression Profiling|Oligonucleotide Array Sequence Analysis|Research Design|Software', 'Journal Article', '10.1371/journal.pcbi.1002276', '22144879', 'Illumina whole-genome expression BeadArrays are a popular choice in gene profiling studies. Aside from the vendor-provided software tools for analyzing BeadArray expression data (GenomeStudio/BeadStudio), there exists a comprehensive set of open-source analysis tools in the Bioconductor project, many of which have been tailored to exploit the unique properties of this platform. In this article, we explore a number of these software packages and demonstrate how to perform a complete analysis of BeadArray data in various formats. The key steps of importing data, performing quality assessments, preprocessing, and annotation in the common setting of assessing differential expression in designed experiments will be covered.'),
(85259, 2011, 'plos', 'Computational mass spectrometry-based proteomics', 'Käll, Lukas|Vitek, Olga', 'Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden.|Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden.', 'Sweden|Sweden', 40, 'Biomedical Research|Chromatography, Liquid|Humans|Mass Spectrometry|Proteomics|Signal Processing, Computer-Assisted', 'Journal Article', '10.1371/journal.pcbi.1002277', '22144880', '-'),
(85260, 2011, 'plos', 'Genomics and privacy: implications of the new reality of closed data for the field', 'Greenbaum, Dov|Sboner, Andrea|Mu, Xinmeng Jasmine|Gerstein, Mark', 'Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, USA.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, USA.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, USA.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, USA.', 'United States|United States|United States|United States', 0, 'Computer Security|Genetic Privacy|Genomics|Humans', 'Journal Article', '10.1371/journal.pcbi.1002278', '22144881', 'Open source and open data have been driving forces in bioinformatics in the past. However, privacy concerns may soon change the landscape, limiting future access to important data sets, including personal genomics data. Here we survey this situation in some detail, describing, in particular, how the large scale of the data from personal genomic sequencing makes it especially hard to share data, exacerbating the privacy problem. We also go over various aspects of genomic privacy: first, there is basic identifiability of subjects having their genome sequenced. However, even for individuals who have consented to be identified, there is the prospect of very detailed future characterization of their genotype, which, unanticipated at the time of their consent, may be more personal and invasive than the release of their medical records. We go over various computational strategies for dealing with the issue of genomic privacy. One can slice and reformat datasets to allow them to be partially shared while securing the most private variants. This is particularly applicable to functional genomics information, which can be largely processed without variant information. For handling the most private data there are a number of legal and technological approaches-for example, modifying the informed consent procedure to acknowledge that privacy cannot be guaranteed, and/or employing a secure cloud computing environment. Cloud computing in particular may allow access to the data in a more controlled fashion than the current practice of downloading and computing on large datasets. Furthermore, it may be particularly advantageous for small labs, given that the burden of many privacy issues falls disproportionately on them in comparison to large corporations and genome centers. Finally, we discuss how education of future genetics researchers will be important, with curriculums emphasizing privacy and data security. However, teaching personal genomics with identifiable subjects in the university setting will, in turn, create additional privacy issues and social conundrums.'),
(85261, 2011, 'plos', 'Chemotaxis when bacteria remember: drift versus diffusion', 'Chatterjee, Sakuntala|da Silveira, Rava Azeredo|Kafri, Yariv', 'Department of Physics, Technion, Haifa, Israel. sakuntala@physics.technion.ac.il|Department of Physics, Technion, Haifa, Israel. sakuntala@physics.technion.ac.il|Department of Physics, Technion, Haifa, Israel. sakuntala@physics.technion.ac.il', 'Israel|Israel|Israel', 10, 'Algorithms|Bacterial Physiological Phenomena|Chemotaxis|Computational Biology|Computer Simulation|Diffusion|Escherichia coli|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002283', '22144882', 'Escherichia coli (E. coli) bacteria govern their trajectories by switching between running and tumbling modes as a function of the nutrient concentration they experienced in the past. At short time one observes a drift of the bacterial population, while at long time one observes accumulation in high-nutrient regions. Recent work has viewed chemotaxis as a compromise between drift toward favorable regions and accumulation in favorable regions. A number of earlier studies assume that a bacterium resets its memory at tumbles - a fact not borne out by experiment - and make use of approximate coarse-grained descriptions. Here, we revisit the problem of chemotaxis without resorting to any memory resets. We find that when bacteria respond to the environment in a non-adaptive manner, chemotaxis is generally dominated by diffusion, whereas when bacteria respond in an adaptive manner, chemotaxis is dominated by a bias in the motion. In the adaptive case, favorable drift occurs together with favorable accumulation. We derive our results from detailed simulations and a variety of analytical arguments. In particular, we introduce a new coarse-grained description of chemotaxis as biased diffusion, and we discuss the way it departs from older coarse-grained descriptions.'),
(85262, 2011, 'plos', 'Modelling the spread of HIV immune escape mutants in a vaccinated population', 'Fryer, Helen R|McLean, Angela R', 'The Institute for Emerging Infections, The Oxford Martin School, Department of Zoology, Oxford University, Oxford, United Kingdom. helen.fryer@zoo.ox.ac.uk|The Institute for Emerging Infections, The Oxford Martin School, Department of Zoology, Oxford University, Oxford, United Kingdom. helen.fryer@zoo.ox.ac.uk', 'United Kingdom|United Kingdom', 5, 'AIDS Vaccines|Computational Biology|Epidemics|Epitopes, T-Lymphocyte|HIV|HIV Infections|HLA Antigens|Host-Pathogen Interactions|Humans|Models, Immunological|Mutation|T-Lymphocytes, Cytotoxic', 'Journal Article', '10.1371/journal.pcbi.1002289', '22144883', 'Because cytotoxic T-lymphocytes (CTLs) have been shown to play a role in controlling human immunodeficiency virus (HIV) infection and because CTL-based simian immunodeficiency virus (SIV) vaccines have proved effective in non-human primates, one goal of HIV vaccine design is to elicit effective CTL responses in humans. Such a vaccine could improve viral control in patients who later become infected, thereby reducing onwards transmission and enhancing life expectancy in the absence of treatment. The ability of HIV to evolve mutations that evade CTLs and the ability of these escape mutants to spread amongst the population poses a challenge to the development of an effective and robust vaccine. We present a mathematical model of within-host evolution and between-host transmission of CTL escape mutants amongst a population receiving a vaccine that elicits CTL responses to multiple epitopes. Within-host evolution at each epitope is represented by the outgrowth of escape mutants in hosts who restrict the epitope and their reversion in hosts who do not restrict the epitope. We use this model to investigate how the evolution and spread of escape mutants could affect the impact of a vaccine. We show that in the absence of escape, such a vaccine could markedly reduce the prevalence of both infection and disease in the population. However the impact of such a vaccine could be significantly abated by CTL escape mutants, especially if their selection in hosts who restrict the epitope is rapid and their reversion in hosts who do not restrict the epitope is slow. We also use the model to address whether a vaccine should span a broad or narrow range of CTL epitopes and target epitopes restricted by rare or common HLA types. We discuss the implications and limitations of our findings.'),
(85263, 2011, 'plos', 'Dynamics of mutant cells in hierarchical organized tissues', 'Werner, Benjamin|Dingli, David|Lenaerts, Tom|Pacheco, Jorge M|Traulsen, Arne', 'Evolutionary Theory Group, Max-Planck-Institute for Evolutionary Biology, Plön, Germany. werner@evolbio.mpg.de|Evolutionary Theory Group, Max-Planck-Institute for Evolutionary Biology, Plön, Germany. werner@evolbio.mpg.de|Evolutionary Theory Group, Max-Planck-Institute for Evolutionary Biology, Plön, Germany. werner@evolbio.mpg.de|Evolutionary Theory Group, Max-Planck-Institute for Evolutionary Biology, Plön, Germany. werner@evolbio.mpg.de|Evolutionary Theory Group, Max-Planck-Institute for Evolutionary Biology, Plön, Germany. werner@evolbio.mpg.de', 'Germany|Germany|Germany|Germany|Germany', 40, 'Cell Differentiation|Cell Growth Processes|Colon|Computer Simulation|Epidermal Cells|Hematopoiesis|Humans|Models, Biological|Mutation|Stem Cells|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002290', '22144884', 'Most tissues in multicellular organisms are maintained by continuous cell renewal processes. However, high turnover of many cells implies a large number of error-prone cell divisions. Hierarchical organized tissue structures with stem cell driven cell differentiation provide one way to prevent the accumulation of mutations, because only few stem cells are long lived. We investigate the deterministic dynamics of cells in such a hierarchical multi compartment model, where each compartment represents a certain stage of cell differentiation. The dynamics of the interacting system is described by ordinary differential equations coupled across compartments. We present analytical solutions for these equations, calculate the corresponding extinction times and compare our results to individual based stochastic simulations. Our general compartment structure can be applied to different tissues, as for example hematopoiesis, the epidermis, or colonic crypts. The solutions provide a description of the average time development of stem cell and non stem cell driven mutants and can be used to illustrate general and specific features of the dynamics of mutant cells in such hierarchically structured populations. We illustrate one possible application of this approach by discussing the origin and dynamics of PIG-A mutant clones that are found in the bloodstream of virtually every healthy adult human. From this it is apparent, that not only the occurrence of a mutant but also the compartment of origin is of importance.'),
(85264, 2011, 'plos', 'Estimated comparative integration hotspots identify different behaviors of retroviral gene transfer vectors', 'Ambrosi, Alessandro|Glad, Ingrid K|Pellin, Danilo|Cattoglio, Claudia|Mavilio, Fulvio|Di Serio, Clelia|Frigessi, Arnoldo', 'University Center of Statistics for the Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy.|University Center of Statistics for the Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy.|University Center of Statistics for the Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy.|University Center of Statistics for the Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy.|University Center of Statistics for the Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy.|University Center of Statistics for the Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy.|University Center of Statistics for the Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy|Italy', 15, 'Antigens, CD34|Chromosomes, Human, Pair 6|Genetic Loci|Genetic Vectors|Genome, Human|HIV|HLA Antigens|Hematopoietic Stem Cells|Histones|Humans|Models, Genetic|Moloney murine leukemia virus|Reproducibility of Results|Virus Integration', 'Journal Article', '10.1371/journal.pcbi.1002292', '22144885', 'Integration of retroviral vectors in the human genome follows non random patterns that favor insertional deregulation of gene expression and may cause risks of insertional mutagenesis when used in clinical gene therapy. Understanding how viral vectors integrate into the human genome is a key issue in predicting these risks. We provide a new statistical method to compare retroviral integration patterns. We identified the positions where vectors derived from the Human Immunodeficiency Virus (HIV) and the Moloney Murine Leukemia Virus (MLV) show different integration behaviors in human hematopoietic progenitor cells. Non-parametric density estimation was used to identify candidate comparative hotspots, which were then tested and ranked. We found 100 significative comparative hotspots, distributed throughout the chromosomes. HIV hotspots were wider and contained more genes than MLV ones. A Gene Ontology analysis of HIV targets showed enrichment of genes involved in antigen processing and presentation, reflecting the high HIV integration frequency observed at the MHC locus on chromosome 6. Four histone modifications/variants had a different mean density in comparative hotspots (H2AZ, H3K4me1, H3K4me3, H3K9me1), while gene expression within the comparative hotspots did not differ from background. These findings suggest the existence of epigenetic or nuclear three-dimensional topology contexts guiding retroviral integration to specific chromosome areas.'),
(85265, 2011, 'plos', 'A tale of two stories: astrocyte regulation of synaptic depression and facilitation', 'De Pittà, Maurizio|Volman, Vladislav|Berry, Hugues|Ben-Jacob, Eshel', 'School of Physics and Astronomy, Tel Aviv University, Ramat Aviv, Israel.|School of Physics and Astronomy, Tel Aviv University, Ramat Aviv, Israel.|School of Physics and Astronomy, Tel Aviv University, Ramat Aviv, Israel.|School of Physics and Astronomy, Tel Aviv University, Ramat Aviv, Israel.', 'Israel|Israel|Israel|Israel', 56, 'Astrocytes|Calcium|Computer Simulation|Hippocampus|Models, Neurological|Neuronal Plasticity|Neurotransmitter Agents|Synapses|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002293', '22162957', 'Short-term presynaptic plasticity designates variations of the amplitude of synaptic information transfer whereby the amount of neurotransmitter released upon presynaptic stimulation changes over seconds as a function of the neuronal firing activity. While a consensus has emerged that the resulting decrease (depression) and/or increase (facilitation) of the synapse strength are crucial to neuronal computations, their modes of expression in vivo remain unclear. Recent experimental studies have reported that glial cells, particularly astrocytes in the hippocampus, are able to modulate short-term plasticity but the mechanism of such a modulation is poorly understood. Here, we investigate the characteristics of short-term plasticity modulation by astrocytes using a biophysically realistic computational model. Mean-field analysis of the model, supported by intensive numerical simulations, unravels that astrocytes may mediate counterintuitive effects. Depending on the expressed presynaptic signaling pathways, astrocytes may globally inhibit or potentiate the synapse: the amount of released neurotransmitter in the presence of the astrocyte is transiently smaller or larger than in its absence. But this global effect usually coexists with the opposite local effect on paired pulses: with release-decreasing astrocytes most paired pulses become facilitated, namely the amount of neurotransmitter released upon spike i+1 is larger than that at spike i, while paired-pulse depression becomes prominent under release-increasing astrocytes. Moreover, we show that the frequency of astrocytic intracellular Ca(2+) oscillations controls the effects of the astrocyte on short-term synaptic plasticity. Our model explains several experimental observations yet unsolved, and uncovers astrocytic gliotransmission as a possible transient switch between short-term paired-pulse depression and facilitation. This possibility has deep implications on the processing of neuronal spikes and resulting information transfer at synapses.'),
(85266, 2011, 'plos', 'A whole-body model for glycogen regulation reveals a critical role for substrate cycling in maintaining blood glucose homeostasis', 'Xu, Ke|Morgan, Kevin T|Todd Gehris, Abby|Elston, Timothy C|Gomez, Shawn M', 'Department of Biomedical Engineering, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.|Department of Biomedical Engineering, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.|Department of Biomedical Engineering, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.|Department of Biomedical Engineering, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.|Department of Biomedical Engineering, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.', 'United States|United States|United States|United States|United States', 20, 'Blood Glucose|Computer Simulation|Glycogen Phosphorylase|Glycogen Synthase|Homeostasis|Liver Glycogen|Substrate Cycling', 'Journal Article', '10.1371/journal.pcbi.1002272', '22163177', 'Timely, and sometimes rapid, metabolic adaptation to changes in food supply is critical for survival as an organism moves from the fasted to the fed state, and vice versa. These transitions necessitate major metabolic changes to maintain energy homeostasis as the source of blood glucose moves away from ingested carbohydrates, through hepatic glycogen stores, towards gluconeogenesis. The integration of hepatic glycogen regulation with extra-hepatic energetics is a key aspect of these adaptive mechanisms. Here we use computational modeling to explore hepatic glycogen regulation under fed and fasting conditions in the context of a whole-body model. The model was validated against previous experimental results concerning glycogen phosphorylase a (active) and glycogen synthase a dynamics. The model qualitatively reproduced physiological changes that occur during transition from the fed to the fasted state. Analysis of the model reveals a critical role for the inhibition of glycogen synthase phosphatase by glycogen phosphorylase a. This negative regulation leads to high levels of glycogen synthase activity during fasting conditions, which in turn increases substrate (futile) cycling, priming the system for a rapid response once an external source of glucose is restored. This work demonstrates that a mechanistic understanding of the design principles used by metabolic control circuits to maintain homeostasis can benefit from the incorporation of mathematical descriptions of these networks into whole-body contextual models that mimic in vivo conditions.'),
(85267, 2011, 'plos', 'Structural insights into the inhibition of cytosolic 5-nucleotidase II (cN-II) by ribonucleoside 5-monophosphate analogues', 'Gallier, Franck|Lallemand, Perrine|Meurillon, Maïa|Jordheim, Lars P|Dumontet, Charles|Périgaud, Christian|Lionne, Corinne|Peyrottes, Suzanne|Chaloin, Laurent', 'Institut des Biomolécules Max Mousseron, UMR 5247, CNRS - Universités Montpellier 1 et 2, Université Montpellier 2, Montpellier, France.|Institut des Biomolécules Max Mousseron, UMR 5247, CNRS - Universités Montpellier 1 et 2, Université Montpellier 2, Montpellier, France.|Institut des Biomolécules Max Mousseron, UMR 5247, CNRS - Universités Montpellier 1 et 2, Université Montpellier 2, Montpellier, France.|Institut des Biomolécules Max Mousseron, UMR 5247, CNRS - Universités Montpellier 1 et 2, Université Montpellier 2, Montpellier, France.|Institut des Biomolécules Max Mousseron, UMR 5247, CNRS - Universités Montpellier 1 et 2, Université Montpellier 2, Montpellier, France.|Institut des Biomolécules Max Mousseron, UMR 5247, CNRS - Universités Montpellier 1 et 2, Université Montpellier 2, Montpellier, France.|Institut des Biomolécules Max Mousseron, UMR 5247, CNRS - Universités Montpellier 1 et 2, Université Montpellier 2, Montpellier, France.|Institut des Biomolécules Max Mousseron, UMR 5247, CNRS - Universités Montpellier 1 et 2, Université Montpellier 2, Montpellier, France.|Institut des Biomolécules Max Mousseron, UMR 5247, CNRS - Universités Montpellier 1 et 2, Université Montpellier 2, Montpellier, France.', 'France|France|France|France|France|France|France|France|France', 22, '5-Nucleotidase|Binding Sites|Hydrolysis|Inosine Monophosphate|Models, Molecular|Ribonucleotides|Structure-Activity Relationship|Substrate Specificity', 'Journal Article', '10.1371/journal.pcbi.1002295', '22174667', 'Cytosolic 5-nucleotidase II (cN-II) regulates the intracellular nucleotide pools within the cell by catalyzing the dephosphorylation of 6-hydroxypurine nucleoside 5-monophosphates. Beside this physiological function, high level of cN-II expression is correlated with abnormal patient outcome when treated with cytotoxic nucleoside analogues. To identify its specific role in the resistance phenomenon observed during cancer therapy, we screened a particular class of chemical compounds, namely ribonucleoside phosphonates to predict them as potential cN-II inhibitors. These compounds incorporate a chemically and enzymatically stable phosphorus-carbon linkage instead of a regular phosphoester bond. Amongst them, six compounds were predicted as better ligands than the natural substrate of cN-II, inosine 5-monophosphate (IMP). The study of purine and pyrimidine containing analogues and the introduction of chemical modifications within the phosphonate chain has allowed us to define general rules governing the theoretical affinity of such ligands. The binding strength of these compounds was scrutinized in silico and explained by an impressive number of van der Waals contacts, highlighting the decisive role of three cN-II residues that are Phe 157, His 209 and Tyr 210. Docking predictions were confirmed by experimental measurements of the nucleotidase activity in the presence of the three best available phosphonate analogues. These compounds were shown to induce a total inhibition of the cN-II activity at 2 mM. Altogether, this study emphasizes the importance of the non-hydrolysable phosphonate bond in the design of new competitive cN-II inhibitors and the crucial hydrophobic stacking promoted by three protein residues.'),
(85268, 2011, 'plos', 'Information routing driven by background chatter in a signaling network', 'Domedel-Puig, Núria|Rué, Pau|Pons, Antonio J|García-Ojalvo, Jordi', 'Departament de Física i Enginyeria Nuclear, Universitat Politècnica de Catalunya, Terrassa, Barcelona, Spain.|Departament de Física i Enginyeria Nuclear, Universitat Politècnica de Catalunya, Terrassa, Barcelona, Spain.|Departament de Física i Enginyeria Nuclear, Universitat Politècnica de Catalunya, Terrassa, Barcelona, Spain.|Departament de Física i Enginyeria Nuclear, Universitat Politècnica de Catalunya, Terrassa, Barcelona, Spain.', 'Spain|Spain|Spain|Spain', 6, 'Cell Communication|Humans|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002297', '22174668', 'Living systems are capable of processing multiple sources of information simultaneously. This is true even at the cellular level, where not only coexisting signals stimulate the cell, but also the presence of fluctuating conditions is significant. When information is received by a cell signaling network via one specific input, the existence of other stimuli can provide a background activity -or chatter- that may affect signal transmission through the network and, therefore, the response of the cell. Here we study the modulation of information processing by chatter in the signaling network of a human cell, specifically, in a Boolean model of the signal transduction network of a fibroblast. We observe that the level of external chatter shapes the response of the system to information carrying signals in a nontrivial manner, modulates the activity levels of the network outputs, and effectively determines the paths of information flow. Our results show that the interactions and node dynamics, far from being random, confer versatility to the signaling network and allow transitions between different information-processing scenarios.'),
(85269, 2011, 'plos', 'Coherent conformational degrees of freedom as a structural basis for allosteric communication', 'Mitternacht, Simon|Berezovsky, Igor N', 'Computational Biology Unit/Uni Research, University of Bergen, Bergen, Norway.|Computational Biology Unit/Uni Research, University of Bergen, Bergen, Norway.', 'Norway|Norway', 30, 'Allosteric Regulation|Allosteric Site|Binding Sites|Enzymes|Models, Molecular|Molecular Chaperones|Molecular Conformation|Protein Processing, Post-Translational|Proteins', 'Journal Article', '10.1371/journal.pcbi.1002301', '22174669', 'Conformational changes in allosteric regulation can to a large extent be described as motion along one or a few coherent degrees of freedom. The states involved are inherent to the protein, in the sense that they are visited by the protein also in the absence of effector ligands. Previously, we developed the measure binding leverage to find sites where ligand binding can shift the conformational equilibrium of a protein. Binding leverage is calculated for a set of motion vectors representing independent conformational degrees of freedom. In this paper, to analyze allosteric communication between binding sites, we introduce the concept of leverage coupling, based on the assumption that only pairs of sites that couple to the same conformational degrees of freedom can be allosterically connected. We demonstrate how leverage coupling can be used to analyze allosteric communication in a range of enzymes (regulated by both ligand binding and post-translational modifications) and huge molecular machines such as chaperones. Leverage coupling can be calculated for any protein structure to analyze both biological and latent catalytic and regulatory sites.'),
(85270, 2011, 'plos', 'Mathematical model of viral kinetics in vitro estimates the number of E2-CD81 complexes necessary for hepatitis C virus entry', 'Padmanabhan, Pranesh|Dixit, Narendra M', 'Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.|Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.', 'India|India', 12, 'Hepacivirus|Humans|Kinetics|Models, Biological|Tetraspanin 28|Viral Envelope Proteins|Virus Internalization', 'Journal Article', '10.1371/journal.pcbi.1002307', '22174670', 'Interaction between the hepatitis C virus (HCV) envelope protein E2 and the host receptor CD81 is essential for HCV entry into target cells. The number of E2-CD81 complexes necessary for HCV entry has remained difficult to estimate experimentally. Using the recently developed cell culture systems that allow persistent HCV infection in vitro, the dependence of HCV entry and kinetics on CD81 expression has been measured. We reasoned that analysis of the latter experiments using a mathematical model of viral kinetics may yield estimates of the number of E2-CD81 complexes necessary for HCV entry. Here, we constructed a mathematical model of HCV viral kinetics in vitro, in which we accounted explicitly for the dependence of HCV entry on CD81 expression. Model predictions of viral kinetics are in quantitative agreement with experimental observations. Specifically, our model predicts triphasic viral kinetics in vitro, where the first phase is characterized by cell proliferation, the second by the infection of susceptible cells and the third by the growth of cells refractory to infection. By fitting model predictions to the above data, we were able to estimate the threshold number of E2-CD81 complexes necessary for HCV entry into human hepatoma-derived cells. We found that depending on the E2-CD81 binding affinity, between 1 and 13 E2-CD81 complexes are necessary for HCV entry. With this estimate, our model captured data from independent experiments that employed different HCV clones and cells with distinct CD81 expression levels, indicating that the estimate is robust. Our study thus quantifies the molecular requirements of HCV entry and suggests guidelines for intervention strategies that target the E2-CD81 interaction. Further, our model presents a framework for quantitative analyses of cell culture studies now extensively employed to investigate HCV infection.'),
(85271, 2011, 'plos', 'Predictability of evolutionary trajectories in fitness landscapes', 'Lobkovsky, Alexander E|Wolf, Yuri I|Koonin, Eugene V', 'National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.|National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.|National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.', 'United States|United States|United States', 0, 'Amino Acids|Animals|Evolution, Molecular|Humans|Models, Genetic|Mutation|Protein Folding|Proteins', 'Journal Article', '10.1371/journal.pcbi.1002302', '22194675', 'Experimental studies on enzyme evolution show that only a small fraction of all possible mutation trajectories are accessible to evolution. However, these experiments deal with individual enzymes and explore a tiny part of the fitness landscape. We report an exhaustive analysis of fitness landscapes constructed with an off-lattice model of protein folding where fitness is equated with robustness to misfolding. This model mimics the essential features of the interactions between amino acids, is consistent with the key paradigms of protein folding and reproduces the universal distribution of evolutionary rates among orthologous proteins. We introduce mean path divergence as a quantitative measure of the degree to which the starting and ending points determine the path of evolution in fitness landscapes. Global measures of landscape roughness are good predictors of path divergence in all studied landscapes: the mean path divergence is greater in smooth landscapes than in rough ones. The model-derived and experimental landscapes are significantly smoother than random landscapes and resemble additive landscapes perturbed with moderate amounts of noise, thus, these landscapes are substantially robust to mutation. The model landscapes show a deficit of suboptimal peaks even compared with noisy additive landscapes with similar overall roughness. We suggest that smoothness and the substantial deficit of peaks in the fitness landscapes of protein evolution are fundamental consequences of the physics of protein folding.'),
(85272, 2011, 'plos', 'A hierarchical neuronal model for generation and online recognition of birdsongs', 'Yildiz, Izzet B|Kiebel, Stefan J', 'Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany. yildiz@cbs.mpg.de|Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany. yildiz@cbs.mpg.de', 'Germany|Germany', 0, 'Animals|Association Learning|Bayes Theorem|Computer Simulation|Models, Neurological|Neural Pathways|Neurons|Songbirds|Vocalization, Animal', 'Journal Article', '10.1371/journal.pcbi.1002303', '22194676', 'The neuronal system underlying learning, generation and recognition of song in birds is one of the best-studied systems in the neurosciences. Here, we use these experimental findings to derive a neurobiologically plausible, dynamic, hierarchical model of birdsong generation and transform it into a functional model of birdsong recognition. The generation model consists of neuronal rate models and includes critical anatomical components like the premotor song-control nucleus HVC (proper name), the premotor nucleus RA (robust nucleus of the arcopallium), and a model of the syringeal and respiratory organs. We use Bayesian inference of this dynamical system to derive a possible mechanism for how birds can efficiently and robustly recognize the songs of their conspecifics in an online fashion. Our results indicate that the specific way birdsong is generated enables a listening bird to robustly and rapidly perceive embedded information at multiple time scales of a song. The resulting mechanism can be useful for investigating the functional roles of auditory recognition areas and providing predictions for future birdsong experiments.'),
(85273, 2011, 'plos', 'Tuning the mammalian circadian clock: robust synergy of two loops', 'Relógio, Angela|Westermark, Pal O|Wallach, Thomas|Schellenberg, Katja|Kramer, Achim|Herzel, Hanspeter', 'Institute for Theoretical Biology, Humboldt University, Berlin, Germany. angela.relogio@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt University, Berlin, Germany. angela.relogio@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt University, Berlin, Germany. angela.relogio@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt University, Berlin, Germany. angela.relogio@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt University, Berlin, Germany. angela.relogio@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt University, Berlin, Germany. angela.relogio@biologie.hu-berlin.de', 'Germany|Germany|Germany|Germany|Germany|Germany', 0, 'Animals|CLOCK Proteins|Circadian Clocks|Gene Products, rev|Humans|Mammals|Mice|Models, Biological|Nuclear Receptor Subfamily 1, Group D, Member 1|Period Circadian Proteins|Suprachiasmatic Nucleus', 'Journal Article', '10.1371/journal.pcbi.1002309', '22194677', 'The circadian clock is accountable for the regulation of internal rhythms in most living organisms. It allows the anticipation of environmental changes during the day and a better adaptation of physiological processes. In mammals the main clock is located in the suprachiasmatic nucleus (SCN) and synchronizes secondary clocks throughout the body. Its molecular constituents form an intracellular network which dictates circadian time and regulates clock-controlled genes. These clock-controlled genes are involved in crucial biological processes including metabolism and cell cycle regulation. Its malfunction can lead to disruption of biological rhythms and cause severe damage to the organism. The detailed mechanisms that govern the circadian system are not yet completely understood. Mathematical models can be of great help to exploit the mechanism of the circadian circuitry. We built a mathematical model for the core clock system using available data on phases and amplitudes of clock components obtained from an extensive literature search. This model was used to answer complex questions for example: how does the degradation rate of Per affect the period of the system and what is the role of the ROR/Bmal/REV-ERB (RBR) loop? Our findings indicate that an increase in the RNA degradation rate of the clock gene Period (Per) can contribute to increase or decrease of the period--a consequence of a non-monotonic effect of Per transcript stability on the circadian period identified by our model. Furthermore, we provide theoretical evidence for a potential role of the RBR loop as an independent oscillator. We carried out overexpression experiments on members of the RBR loop which lead to loss of oscillations consistent with our predictions. These findings challenge the role of the RBR loop as a merely auxiliary loop and might change our view of the clock molecular circuitry and of the function of the nuclear receptors (REV-ERB and ROR) as a putative driving force of molecular oscillations.'),
(85274, 2011, 'plos', 'Translating clinical findings into knowledge in drug safety evaluation--drug induced liver injury prediction system (DILIps)', 'Liu, Zhichao|Shi, Qiang|Ding, Don|Kelly, Reagan|Fang, Hong|Tong, Weida', 'Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, Jefferson, Arizona, USA.|Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, Jefferson, Arizona, USA.|Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, Jefferson, Arizona, USA.|Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, Jefferson, Arizona, USA.|Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, Jefferson, Arizona, USA.|Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, Jefferson, Arizona, USA.', 'United States|United States|United States|United States|United States|United States', 0, 'Animals|Anti-Infective Agents|Anti-Inflammatory Agents|Chemical and Drug Induced Liver Injury|Databases, Factual|Drug-Related Side Effects and Adverse Reactions|Humans|Liver|Models, Biological|Predictive Value of Tests', 'Journal Article', '10.1371/journal.pcbi.1002310', '22194678', 'Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the Rule of Three was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85275, 2011, 'plos', 'Increased vulnerability of human ventricle to re-entrant excitation in hERG-linked variant 1 short QT syndrome', 'Adeniran, Ismail|McPate, Mark J|Witchel, Harry J|Hancox, Jules C|Zhang, Henggui', 'Biological Physics Group, School of Physics & Astronomy, The University of Manchester, Manchester, UK.|Biological Physics Group, School of Physics & Astronomy, The University of Manchester, Manchester, UK.|Biological Physics Group, School of Physics & Astronomy, The University of Manchester, Manchester, UK.|Biological Physics Group, School of Physics & Astronomy, The University of Manchester, Manchester, UK.|Biological Physics Group, School of Physics & Astronomy, The University of Manchester, Manchester, UK.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 46, 'Action Potentials|ERG1 Potassium Channel|Electrocardiography|Ether-A-Go-Go Potassium Channels|Heart|Heart Ventricles|Humans|Markov Chains|Models, Cardiovascular|Mutation|Ventricular Function', 'Journal Article', '10.1371/journal.pcbi.1002313', '22194679', 'The short QT syndrome (SQTS) is a genetically heterogeneous condition characterized by abbreviated QT intervals and an increased susceptibility to arrhythmia and sudden death. This simulation study identifies arrhythmogenic mechanisms in the rapid-delayed rectifier K(+) current (I(Kr))-linked SQT1 variant of the SQTS. Markov chain (MC) models were found to be superior to Hodgkin-Huxley (HH) models in reproducing experimental data regarding effects of the N588K mutation on KCNH2-encoded hERG. These ionic channel models were then incorporated into human ventricular action potential (AP) models and into 1D and 2D idealised and realistic transmural ventricular tissue simulations and into a 3D anatomical model. In single cell models, the N588K mutation abbreviated ventricular cell AP duration at 90% repolarization (APD(90)) and decreased the maximal transmural voltage heterogeneity (xcexb4V) during APs. This resulted in decreased transmural heterogeneity of APD(90) and of the effective refractory period (ERP): effects that are anticipated to be anti-arrhythmic rather than pro-arrhythmic. However, with consideration of transmural heterogeneity of I(Kr) density in the intact tissue model based on the ten Tusscher-Noble-Noble-Panfilov ventricular model, not only did the N588K mutation lead to QT-shortening and increases in T-wave amplitude, but xcexb4V was found to be augmented in some local regions of ventricle tissue, resulting in increased tissue vulnerability for uni-directional conduction block and predisposing to formation of re-entrant excitation waves. In 2D and 3D tissue models, the N588K mutation facilitated and maintained re-entrant excitation waves due to the reduced substrate size necessary for sustaining re-entry. Thus, in SQT1 the N588K-hERG mutation facilitates initiation and maintenance of ventricular re-entry, increasing the lifespan of re-entrant spiral waves and the stability of scroll waves in 3D tissue.'),
(85276, 2011, 'plos', 'Switches, excitable responses and oscillations in the Ring1B/Bmi1 ubiquitination system', 'Nguyen, Lan K|Muñoz-García, Javier|Maccario, Helene|Ciechanover, Aaron|Kolch, Walter|Kholodenko, Boris N', 'Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.|Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.|Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.|Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.|Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.|Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.', 'Ireland|Ireland|Ireland|Ireland|Ireland|Ireland', 0, 'Computer Simulation|Gene Silencing|Nuclear Proteins|Polycomb-Group Proteins|Proteasome Endopeptidase Complex|Repressor Proteins|Ubiquitin|Ubiquitin-Protein Ligases|Ubiquitination', 'Journal Article', '10.1371/journal.pcbi.1002317', '22194680', 'In an active, self-ubiquitinated state, the Ring1B ligase monoubiquitinates histone H2A playing a critical role in Polycomb-mediated gene silencing. Following ubiquitination by external ligases, Ring1B is targeted for proteosomal degradation. Using biochemical data and computational modeling, we show that the Ring1B ligase can exhibit abrupt switches, overshoot transitions and self-perpetuating oscillations between its distinct ubiquitination and activity states. These different Ring1B states display canonical or multiply branched, atypical polyubiquitin chains and involve association with the Polycomb-group protein Bmi1. Bistable switches and oscillations may lead to all-or-none histone H2A monoubiquitination rates and result in discrete periods of gene (in)activity. Switches, overshoots and oscillations in Ring1B catalytic activity and proteosomal degradation are controlled by the abundances of Bmi1 and Ring1B, and the activities and abundances of external ligases and deubiquitinases, such as E6-AP and USP7.'),
(85277, 2011, 'plos', 'Role of histone tails in structural stability of the nucleosome', 'Biswas, Mithun|Voltz, Karine|Smith, Jeremy C|Langowski, Jxc3xb6rg', 'Computational Molecular Biophysics, Interdisciplinary Center for Scientific Computing (IWR), University of Heidelberg, Heidelberg, Germany.|Computational Molecular Biophysics, Interdisciplinary Center for Scientific Computing (IWR), University of Heidelberg, Heidelberg, Germany.|Computational Molecular Biophysics, Interdisciplinary Center for Scientific Computing (IWR), University of Heidelberg, Heidelberg, Germany.|Computational Molecular Biophysics, Interdisciplinary Center for Scientific Computing (IWR), University of Heidelberg, Heidelberg, Germany.', 'Germany|Germany|Germany|Germany', 0, 'Histones|Models, Molecular|Molecular Dynamics Simulation|Nucleosomes|Protein Conformation|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1002279', '22207822', 'Histone tails play an important role in nucleosome structure and dynamics. Here we investigate the effect of truncation of histone tails H3, H4, H2A and H2B on nucleosome structure with 100 ns all-atom molecular dynamics simulations. Tail domains of H3 and H2B show propensity of xcexb1-helics formation during the intact nucleosome simulation. On truncation of H4 or H2B tails no structural change occurs in histones. However, H3 or H2A tail truncation results in structural alterations in the histone core domain, and in both the cases the structural change occurs in the H2Axcexb13 domain. We also find that the contacts between the histone H2A C terminal docking domain and surrounding residues are destabilized upon H3 tail truncation. The relation between the present observations and corresponding experiments is discussed.'),
(85278, 2011, 'plos', 'Robust signal processing in living cells', 'Steuer, Ralf|Waldherr, Steffen|Sourjik, Victor|Kollmann, Markus', 'Institute for Theoretical Biology, Humboldt University of Berlin, Berlin, Germany. ralf.steuer@hu-berlin.de|Institute for Theoretical Biology, Humboldt University of Berlin, Berlin, Germany. ralf.steuer@hu-berlin.de|Institute for Theoretical Biology, Humboldt University of Berlin, Berlin, Germany. ralf.steuer@hu-berlin.de|Institute for Theoretical Biology, Humboldt University of Berlin, Berlin, Germany. ralf.steuer@hu-berlin.de', 'Germany|Germany|Germany|Germany', 35, 'Bacterial Proteins|Cell Communication|Chemotaxis|Escherichia coli|Membrane Proteins|Methyl-Accepting Chemotaxis Proteins|Models, Biological|Signal Transduction|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002218', '22215991', 'Cellular signaling networks have evolved an astonishing ability to function reliably and with high fidelity in uncertain environments. A crucial prerequisite for the high precision exhibited by many signaling circuits is their ability to keep the concentrations of active signaling compounds within tightly defined bounds, despite strong stochastic fluctuations in copy numbers and other detrimental influences. Based on a simple mathematical formalism, we identify topological organizing principles that facilitate such robust control of intracellular concentrations in the face of multifarious perturbations. Our framework allows us to judge whether a multiple-input-multiple-output reaction network is robust against large perturbations of network parameters and enables the predictive design of perfectly robust synthetic network architectures. Utilizing the Escherichia coli chemotaxis pathway as a hallmark example, we provide experimental evidence that our framework indeed allows us to unravel the topological organization of robust signaling. We demonstrate that the specific organization of the pathway allows the system to maintain global concentration robustness of the diffusible response regulator CheY with respect to several dominant perturbations. Our framework provides a counterpoint to the hypothesis that cellular function relies on an extensive machinery to fine-tune or control intracellular parameters. Rather, we suggest that for a large class of perturbations, there exists an appropriate topology that renders the network output invariant to the respective perturbations.'),
(85279, 2011, 'plos', 'Modeling brain resonance phenomena using a neural mass model', 'Spiegler, Andreas|Knösche, Thomas R|Schwab, Karin|Haueisen, Jens|Atay, Fatihcan M', 'Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany. spiegler@cbs.mpg.de|Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany. spiegler@cbs.mpg.de|Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany. spiegler@cbs.mpg.de|Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany. spiegler@cbs.mpg.de|Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany. spiegler@cbs.mpg.de', 'Germany|Germany|Germany|Germany|Germany', 48, 'Brain|Electroencephalography|Epilepsy|Humans|Models, Neurological|Nerve Net|Schizophrenia', 'Journal Article', '10.1371/journal.pcbi.1002298', '22215992', 'Stimulation with rhythmic light flicker (photic driving) plays an important role in the diagnosis of schizophrenia, mood disorder, migraine, and epilepsy. In particular, the adjustment of spontaneous brain rhythms to the stimulus frequency (entrainment) is used to assess the functional flexibility of the brain. We aim to gain deeper understanding of the mechanisms underlying this technique and to predict the effects of stimulus frequency and intensity. For this purpose, a modified Jansen and Rit neural mass model (NMM) of a cortical circuit is used. This mean field model has been designed to strike a balance between mathematical simplicity and biological plausibility. We reproduced the entrainment phenomenon observed in EEG during a photic driving experiment. More generally, we demonstrate that such a single area model can already yield very complex dynamics, including chaos, for biologically plausible parameter ranges. We chart the entire parameter space by means of characteristic Lyapunov spectra and Kaplan-Yorke dimension as well as time series and power spectra. Rhythmic and chaotic brain states were found virtually next to each other, such that small parameter changes can give rise to switching from one to another. Strikingly, this characteristic pattern of unpredictability generated by the model was matched to the experimental data with reasonable accuracy. These findings confirm that the NMM is a useful model of brain dynamics during photic driving. In this context, it can be used to study the mechanisms of, for example, perception and epileptic seizure generation. In particular, it enabled us to make predictions regarding the stimulus amplitude in further experiments for improving the entrainment effect.'),
(85280, 2011, 'plos', 'Systematic search for recipes to generate induced pluripotent stem cells', 'Chang, Rui|Shoemaker, Robert|Wang, Wei', 'Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, United States of America.|Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, United States of America.|Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, United States of America.', 'United States|United States|United States', 0, 'Cell Differentiation|Embryonic Stem Cells|Humans|Induced Pluripotent Stem Cells|Phenotype|Regenerative Medicine|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002300', '22215993', 'Generation of induced pluripotent stem cells (iPSCs) opens a new avenue in regenerative medicine. One of the major hurdles for therapeutic applications is to improve the efficiency of generating iPSCs and also to avoid the tumorigenicity, which requires searching for new reprogramming recipes. We present a systems biology approach to efficiently evaluate a large number of possible recipes and find those that are most effective at generating iPSCs. We not only recovered several experimentally confirmed recipes but we also suggested new ones that may improve reprogramming efficiency and quality. In addition, our approach allows one to estimate the cell-state landscape, monitor the progress of reprogramming, identify important regulatory transition states, and ultimately understand the mechanisms of iPSC generation.'),
(85281, 2011, 'plos', 'Combinatorial binding in human and mouse embryonic stem cells identifies conserved enhancers active in early embryonic development', 'Göke, Jonathan|Jung, Marc|Behrens, Sarah|Chavez, Lukas|OKeeffe, Sean|Timmermann, Bernd|Lehrach, Hans|Adjaye, James|Vingron, Martin', 'Department of Computational Molecular Biology, Max-Planck Institute for Molecular Genetics, Berlin, Germany. goeke@molgen.mpg.de|Department of Computational Molecular Biology, Max-Planck Institute for Molecular Genetics, Berlin, Germany. goeke@molgen.mpg.de|Department of Computational Molecular Biology, Max-Planck Institute for Molecular Genetics, Berlin, Germany. goeke@molgen.mpg.de|Department of Computational Molecular Biology, Max-Planck Institute for Molecular Genetics, Berlin, Germany. goeke@molgen.mpg.de|Department of Computational Molecular Biology, Max-Planck Institute for Molecular Genetics, Berlin, Germany. goeke@molgen.mpg.de|Department of Computational Molecular Biology, Max-Planck Institute for Molecular Genetics, Berlin, Germany. goeke@molgen.mpg.de|Department of Computational Molecular Biology, Max-Planck Institute for Molecular Genetics, Berlin, Germany. goeke@molgen.mpg.de|Department of Computational Molecular Biology, Max-Planck Institute for Molecular Genetics, Berlin, Germany. goeke@molgen.mpg.de|Department of Computational Molecular Biology, Max-Planck Institute for Molecular Genetics, Berlin, Germany. goeke@molgen.mpg.de', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany', 0, 'Animals|Binding Sites|Embryo, Mammalian|Embryonic Development|Embryonic Stem Cells|Gene Expression Regulation, Developmental|Homeodomain Proteins|Humans|Mice|Octamer Transcription Factor-3|SOXB1 Transcription Factors|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002304', '22215994', 'Transcription factors are proteins that regulate gene expression by binding to cis-regulatory sequences such as promoters and enhancers. In embryonic stem (ES) cells, binding of the transcription factors OCT4, SOX2 and NANOG is essential to maintain the capacity of the cells to differentiate into any cell type of the developing embryo. It is known that transcription factors interact to regulate gene expression. In this study we show that combinatorial binding is strongly associated with co-localization of the transcriptional co-activator Mediator, H3K27ac and increased expression of nearby genes in embryonic stem cells. We observe that the same loci bound by Oct4, Nanog and Sox2 in ES cells frequently drive expression in early embryonic development. Comparison of mouse and human ES cells shows that less than 5% of individual binding events for OCT4, SOX2 and NANOG are shared between species. In contrast, about 15% of combinatorial binding events and even between 53% and 63% of combinatorial binding events at enhancers active in early development are conserved. Our analysis suggests that the combination of OCT4, SOX2 and NANOG binding is critical for transcription in ES cells and likely plays an important role for embryogenesis by binding at conserved early developmental enhancers. Our data suggests that the fast evolutionary rewiring of regulatory networks mainly affects individual binding events, whereas gene regulatory hotspots which are bound by multiple factors and active in multiple tissues throughout early development are under stronger evolutionary constraints.'),
(85282, 2011, 'plos', 'Balanced synaptic input shapes the correlation between neural spike trains', 'Litwin-Kumar, Ashok|Oswald, Anne-Marie M|Urban, Nathaniel N|Doiron, Brent', 'Program for Neural Computation, Carnegie Mellon University and University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. alk@cmu.edu|Program for Neural Computation, Carnegie Mellon University and University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. alk@cmu.edu|Program for Neural Computation, Carnegie Mellon University and University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. alk@cmu.edu|Program for Neural Computation, Carnegie Mellon University and University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. alk@cmu.edu', 'United States|United States|United States|United States', 0, 'Action Potentials|Animals|Brain|Mice|Mice, Inbred Strains|Models, Neurological|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002305', '22215995', 'Stimulus properties, attention, and behavioral context influence correlations between the spike times produced by a pair of neurons. However, the biophysical mechanisms that modulate these correlations are poorly understood. With a combined theoretical and experimental approach, we show that the rate of balanced excitatory and inhibitory synaptic input modulates the magnitude and timescale of pairwise spike train correlation. High rate synaptic inputs promote spike time synchrony rather than long timescale spike rate correlations, while low rate synaptic inputs produce opposite results. This correlation shaping is due to a combination of enhanced high frequency input transfer and reduced firing rate gain in the high input rate state compared to the low state. Our study extends neural modulation from single neuron responses to population activity, a necessary step in understanding how the dynamics and processing of neural activity change across distinct brain states.'),
(85283, 2011, 'plos', 'Emergent behaviors from a cellular automaton model for invasive tumor growth in heterogeneous microenvironments', 'Jiao, Yang|Torquato, Salvatore', 'Physical Science in Oncology Center, Princeton Institute for the Science and Technology of Materials, Princeton University, Princeton, New Jersey, United States of America.|Physical Science in Oncology Center, Princeton Institute for the Science and Technology of Materials, Princeton University, Princeton, New Jersey, United States of America.', 'Jersey|Jersey', 57, 'Algorithms|Cell Transformation, Neoplastic|Humans|Neoplasm Invasiveness|Neoplasms', 'Journal Article', '10.1371/journal.pcbi.1002314', '22215996', 'Understanding tumor invasion and metastasis is of crucial importance for both fundamental cancer research and clinical practice. In vitro experiments have established that the invasive growth of malignant tumors is characterized by the dendritic invasive branches composed of chains of tumor cells emanating from the primary tumor mass. The preponderance of previous tumor simulations focused on non-invasive (or proliferative) growth. The formation of the invasive cell chains and their interactions with the primary tumor mass and host microenvironment are not well understood. Here, we present a novel cellular automaton (CA) model that enables one to efficiently simulate invasive tumor growth in a heterogeneous host microenvironment. By taking into account a variety of microscopic-scale tumor-host interactions, including the short-range mechanical interactions between tumor cells and tumor stroma, degradation of the extracellular matrix by the invasive cells and oxygen/nutrient gradient driven cell motions, our CA model predicts a rich spectrum of growth dynamics and emergent behaviors of invasive tumors. Besides robustly reproducing the salient features of dendritic invasive growth, such as least-resistance paths of cells and intrabranch homotype attraction, we also predict nontrivial coupling between the growth dynamics of the primary tumor mass and the invasive cells. In addition, we show that the properties of the host microenvironment can significantly affect tumor morphology and growth dynamics, emphasizing the importance of understanding the tumor-host interaction. The capability of our CA model suggests that sophisticated in silico tools could eventually be utilized in clinical situations to predict neoplastic progression and propose individualized optimal treatment strategies.'),
(85284, 2011, 'plos', 'Two birds with one stone? Possible dual-targeting H1N1 inhibitors from traditional Chinese medicine', 'Chang, Su-Sen|Huang, Hung-Jin|Chen, Calvin Yu-Chian', 'Laboratory of Computational and Systems Biology, China Medical University, Taichung, Taiwan.|Laboratory of Computational and Systems Biology, China Medical University, Taichung, Taiwan.|Laboratory of Computational and Systems Biology, China Medical University, Taichung, Taiwan.', 'China|China|China', 74, 'Antiviral Agents|Aporphines|Artificial Intelligence|Databases, Factual|Diterpenes|Drug Resistance, Viral|Drugs, Chinese Herbal|Humans|Influenza A Virus, H1N1 Subtype|Influenza, Human|Medicine, Chinese Traditional|Molecular Dynamics Simulation|Mutation|Support Vector Machine', 'Journal Article', '10.1371/journal.pcbi.1002315', '22215997', 'The H1N1 influenza pandemic of 2009 has claimed over 18,000 lives. During this pandemic, development of drug resistance further complicated efforts to control and treat the widespread illness. This research utilizes traditional Chinese medicine Database@Taiwan (TCM Database@Taiwan) to screen for compounds that simultaneously target H1 and N1 to overcome current difficulties with virus mutations. The top three candidates were de novo derivatives of xylopine and rosmaricine. Bioactivity of the de novo derivatives against N1 were validated by multiple machine learning prediction models. Ability of the de novo compounds to maintain CoMFA/CoMSIA contour and form key interactions implied bioactivity within H1 as well. Addition of a pyridinium fragment was critical to form stable interactions in H1 and N1 as supported by molecular dynamics (MD) simulation. Results from MD, hydrophobic interactions, and torsion angles are consistent and support the findings of docking. Multiple anchors and lack of binding to residues prone to mutation suggest that the TCM de novo derivatives may be resistant to drug resistance and are advantageous over conventional H1N1 treatments such as oseltamivir. These results suggest that the TCM de novo derivatives may be suitable candidates of dual-targeting drugs for influenza.'),
(85285, 2011, 'plos', 'The FGGY carbohydrate kinase family: insights into the evolution of functional specificities', 'Zhang, Ying|Zagnitko, Olga|Rodionova, Irina|Osterman, Andrei|Godzik, Adam', 'Graduate School of Biomedical Sciences, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.|Graduate School of Biomedical Sciences, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.|Graduate School of Biomedical Sciences, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.|Graduate School of Biomedical Sciences, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.|Graduate School of Biomedical Sciences, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Evolution, Molecular|Genomics|Molecular Sequence Annotation|Pentoses|Phosphotransferases|Phosphotransferases (Alcohol Group Acceptor)|Phylogeny', 'Journal Article', '10.1371/journal.pcbi.1002318', '22215998', 'Function diversification in large protein families is a major mechanism driving expansion of cellular networks, providing organisms with new metabolic capabilities and thus adding to their evolutionary success. However, our understanding of the evolutionary mechanisms of functional diversity in such families is very limited, which, among many other reasons, is due to the lack of functionally well-characterized sets of proteins. Here, using the FGGY carbohydrate kinase family as an example, we built a confidently annotated reference set (CARS) of proteins by propagating experimentally verified functional assignments to a limited number of homologous proteins that are supported by their genomic and functional contexts. Then, we analyzed, on both the phylogenetic and the molecular levels, the evolution of different functional specificities in this family. The results show that the different functions (substrate specificities) encoded by FGGY kinases have emerged only once in the evolutionary history following an apparently simple divergent evolutionary model. At the same time, on the molecular level, one isofunctional group (L-ribulokinase, AraB) evolved at least two independent solutions that employed distinct specificity-determining residues for the recognition of a same substrate (L-ribulose). Our analysis provides a detailed model of the evolution of the FGGY kinase family. It also shows that only combined molecular and phylogenetic approaches can help reconstruct a full picture of functional diversifications in such diverse families.'),
(85286, 2011, 'plos', 'Genome comparison of human and non-human malaria parasites reveals species subset-specific genes potentially linked to human disease', 'Frech, Christian|Chen, Nansheng', 'Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.|Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.', 'Canada|Canada', 0, 'Animals|Genome, Protozoan|Humans|Malaria|Plasmodium|Plasmodium chabaudi|Plasmodium falciparum|Plasmodium knowlesi|Plasmodium vivax|Plasmodium yoelii|Species Specificity', 'Comparative Study', '10.1371/journal.pcbi.1002320', '22215999', 'Genes underlying important phenotypic differences between Plasmodium species, the causative agents of malaria, are frequently found in only a subset of species and cluster at dynamically evolving subtelomeric regions of chromosomes. We hypothesized that chromosome-internal regions of Plasmodium genomes harbour additional species subset-specific genes that underlie differences in human pathogenicity, human-to-human transmissibility, and human virulence. We combined sequence similarity searches with synteny block analyses to identify species subset-specific genes in chromosome-internal regions of six published Plasmodium genomes, including Plasmodium falciparum, Plasmodium vivax, Plasmodium knowlesi, Plasmodium yoelii, Plasmodium berghei, and Plasmodium chabaudi. To improve comparative analysis, we first revised incorrectly annotated gene models using homology-based gene finders and examined putative subset-specific genes within syntenic contexts. Confirmed subset-specific genes were then analyzed for their role in biological pathways and examined for molecular functions using publicly available databases. We identified 16 genes that are well conserved in the three primate parasites but not found in rodent parasites, including three key enzymes of the thiamine (vitamin B1) biosynthesis pathway. Thirteen genes were found to be present in both human parasites but absent in the monkey parasite P. knowlesi, including genes specifically upregulated in sporozoites or gametocytes that could be linked to parasite transmission success between humans. Furthermore, we propose 15 chromosome-internal P. falciparum-specific genes as new candidate genes underlying increased human virulence and detected a currently uncharacterized cluster of P. vivax-specific genes on chromosome 6 likely involved in erythrocyte invasion. In conclusion, Plasmodium species harbour many chromosome-internal differences in the form of protein-coding genes, some of which are potentially linked to human disease and thus promising leads for future laboratory research.'),
(85287, 2011, 'plos', 'Joint ancestry and association testing in admixed individuals', 'Shriner, Daniel|Adeyemo, Adebowale|Rotimi, Charles N', 'Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, Maryland, United States of America. shrinerda@mail.nih.gov|Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, Maryland, United States of America. shrinerda@mail.nih.gov|Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, Maryland, United States of America. shrinerda@mail.nih.gov', 'United States|United States|United States', 0, 'African Americans|Bayes Theorem|Chromosome Mapping|Diabetes Mellitus, Type 2|Genetic Linkage|Genetics, Population|Genotype|Humans|Linkage Disequilibrium|Phenotype|Polymorphism, Single Nucleotide', 'Journal Article', '10.1371/journal.pcbi.1002325', '22216000', 'For samples of admixed individuals, it is possible to test for both ancestry effects via admixture mapping and genotype effects via association mapping. Here, we describe a joint test called BMIX that combines admixture and association statistics at single markers. We first perform high-density admixture mapping using local ancestry. We then perform association mapping using stratified regression, wherein for each marker genotypes are stratified by local ancestry. In both stages, we use generalized linear models, providing the advantage that the joint test can be used with any phenotype distribution with an appropriate link function. To define the alternative densities for admixture mapping and association mapping, we describe a method based on autocorrelation to empirically estimate the testing burdens of admixture mapping and association mapping. We then describe a joint test that uses the posterior probabilities from admixture mapping as prior probabilities for association mapping, capitalizing on the reduced testing burden of admixture mapping relative to association mapping. By simulation, we show that BMIX is potentially orders-of-magnitude more powerful than the MIX score, which is currently the most powerful frequentist joint test. We illustrate the gain in power through analysis of fasting plasma glucose among 922 unrelated, non-diabetic, admixed African Americans from the Howard University Family Study. We detected loci at 1q24 and 6q26 as genome-wide significant via admixture mapping, both loci have been independently reported from linkage analysis. Using the association data, we resolved the 1q24 signal into two regions. One region, upstream of the gene FAM78B, contains three binding sites for the transcription factor PPARG and two binding sites for HNF1A, both previously implicated in the pathology of type 2 diabetes. The fact that both loci showed ancestry effects may provide novel insight into the genetic architecture of fasting plasma glucose in individuals of African ancestry.'),
(85288, 2011, 'plos', 'Integrating bioinformatics tools to handle glycosylation', 'Mazola, Yuliet|Chinea, Glay|Musacchio, Alexis', 'Department of Bioinformatics, Center for Genetic Engineering and Biotechnology, Havana, Cuba. yuliet.mazola@cigb.edu.cu|Department of Bioinformatics, Center for Genetic Engineering and Biotechnology, Havana, Cuba. yuliet.mazola@cigb.edu.cu|Department of Bioinformatics, Center for Genetic Engineering and Biotechnology, Havana, Cuba. yuliet.mazola@cigb.edu.cu', 'Cuba|Cuba|Cuba', 22, 'Animals|Carbohydrates|Computational Biology|Computer Simulation|Databases, Protein|Glycosylation|Humans|Models, Chemical|Polysaccharides|Protein Processing, Post-Translational|Proteins|Software', 'Journal Article', '10.1371/journal.pcbi.1002285', '22219715', '-'),
(85289, 2011, 'plos', 'Of toasters and molecular ticker tapes', 'Kording, Konrad P', 'Northwestern University, Departments of Physical Medicine and Rehabilitation, Physiology, and Applied Mathematics, Chicago, Illinois, United States of America. kk@northwestern.edu', 'United States', 0, 'Animals|Biomedical Research|Brain|Computational Biology|Humans|Models, Neurological|Molecular Biology|Neurosciences|Sequence Analysis, DNA|Software', 'Journal Article', '10.1371/journal.pcbi.1002291', '22219716', 'Experiments in systems neuroscience can be seen as consisting of three steps: (1) selecting the signals we are interested in, (2) probing the system with carefully chosen stimuli, and (3) getting data out of the brain. Here I discuss how emerging techniques in molecular biology are starting to improve these three steps. To estimate its future impact on experimental neuroscience, I will stress the analogy of ongoing progress with that of microprocessor production techniques. These techniques have allowed computers to simplify countless problems, because they are easier to use than mechanical timers, they are even built into toasters. Molecular biology may advance even faster than computer speeds and has made immense progress in understanding and designing molecules. These advancements may in turn produce impressive improvements to each of the three steps, ultimately shifting the bottleneck from obtaining data to interpreting it.'),
(85290, 2011, 'plos', 'Probabilistic inference in general graphical models through sampling in stochastic networks of spiking neurons', 'Pecevski, Dejan|Buesing, Lars|Maass, Wolfgang', 'Institute for Theoretical Computer Science, Graz University of Technology, Graz, Austria. dejan@igi.tugraz.at|Institute for Theoretical Computer Science, Graz University of Technology, Graz, Austria. dejan@igi.tugraz.at|Institute for Theoretical Computer Science, Graz University of Technology, Graz, Austria. dejan@igi.tugraz.at', 'Austria|Austria|Austria', 0, 'Action Potentials|Algorithms|Animals|Bayes Theorem|Brain|Computer Graphics|Computer Simulation|Humans|Markov Chains|Models, Neurological|Models, Statistical|Models, Theoretical|Neurons|Probability|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002294', '22219717', 'An important open problem of computational neuroscience is the generic organization of computations in networks of neurons in the brain. We show here through rigorous theoretical analysis that inherent stochastic features of spiking neurons, in combination with simple nonlinear computational operations in specific network motifs and dendritic arbors, enable networks of spiking neurons to carry out probabilistic inference through sampling in general graphical models. In particular, it enables them to carry out probabilistic inference in Bayesian networks with converging arrows (explaining away) and with undirected loops, that occur in many real-world tasks. Ubiquitous stochastic features of networks of spiking neurons, such as trial-to-trial variability and spontaneous activity, are necessary ingredients of the underlying computational organization. We demonstrate through computer simulations that this approach can be scaled up to neural emulations of probabilistic inference in fairly large graphical models, yielding some of the most complex computations that have been carried out so far in networks of spiking neurons.'),
(85291, 2011, 'plos', 'Recovering protein-protein and domain-domain interactions from aggregation of IP-MS proteomics of coregulator complexes', 'Mazloom, Amin R|Dannenfelser, Ruth|Clark, Neil R|Grigoryan, Arsen V|Linder, Kathryn M|Cardozo, Timothy J|Bond, Julia C|Boran, Aislyn D W|Iyengar, Ravi|Malovannaya, Anna|Lanz, Rainer B|Maayan, Avi', 'Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York (SBCNY), Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York (SBCNY), Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York (SBCNY), Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York (SBCNY), Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York (SBCNY), Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York (SBCNY), Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York (SBCNY), Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York (SBCNY), Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York (SBCNY), Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York (SBCNY), Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York (SBCNY), Mount Sinai School of Medicine, New York, New York, United States of America.|Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York (SBCNY), Mount Sinai School of Medicine, New York, New York, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 13, 'Algorithms|Animals|Computer Simulation|Humans|Immunoprecipitation|Intracellular Signaling Peptides and Proteins|Mass Spectrometry|Models, Statistical|Molecular Conformation|Protein Binding|Protein Interaction Mapping|Protein Kinases|Protein Phosphatase 2|Protein Structure, Tertiary|Protein-Serine-Threonine Kinases|Proteomics|Software', 'Journal Article', '10.1371/journal.pcbi.1002319', '22219718', 'Coregulator proteins (CoRegs) are part of multi-protein complexes that transiently assemble with transcription factors and chromatin modifiers to regulate gene expression. In this study we analyzed data from 3,290 immuno-precipitations (IP) followed by mass spectrometry (MS) applied to human cell lines aimed at identifying CoRegs complexes. Using the semi-quantitative spectral counts, we scored binary protein-protein and domain-domain associations with several equations. Unlike previous applications, our methods scored prey-prey protein-protein interactions regardless of the baits used. We also predicted domain-domain interactions underlying predicted protein-protein interactions. The quality of predicted protein-protein and domain-domain interactions was evaluated using known binary interactions from the literature, whereas one protein-protein interaction, between STRN and CTTNBP2NL, was validated experimentally, and one domain-domain interaction, between the HEAT domain of PPP2R1A and the Pkinase domain of STK25, was validated using molecular docking simulations. The scoring schemes presented here recovered known, and predicted many new, complexes, protein-protein, and domain-domain interactions. The networks that resulted from the predictions are provided as a web-based interactive application at http://maayanlab.net/HT-IP-MS-2-PPI-DDI/.'),
(85292, 2011, 'plos', 'Spatial guilds in the Serengeti food web revealed by a Bayesian group model', 'Baskerville, Edward B|Dobson, Andy P|Bedford, Trevor|Allesina, Stefano|Anderson, T Michael|Pascual, Mercedes', 'Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America. ebaskerv@umich.edu|Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America. ebaskerv@umich.edu|Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America. ebaskerv@umich.edu|Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America. ebaskerv@umich.edu|Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America. ebaskerv@umich.edu|Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America. ebaskerv@umich.edu', 'United States|United States|United States|United States|United States|United States', 38, 'Animals|Bayes Theorem|Ecosystem|Food Chain|Humans|Markov Chains|Models, Statistical|Models, Theoretical|Monte Carlo Method|Plants|Probability|Software|Tanzania', 'Journal Article', '10.1371/journal.pcbi.1002321', '22219719', 'Food webs, networks of feeding relationships in an ecosystem, provide fundamental insights into mechanisms that determine ecosystem stability and persistence. A standard approach in food-web analysis, and network analysis in general, has been to identify compartments, or modules, defined by many links within compartments and few links between them. This approach can identify large habitat boundaries in the network but may fail to identify other important structures. Empirical analyses of food webs have been further limited by low-resolution data for primary producers. In this paper, we present a Bayesian computational method for identifying group structure using a flexible definition that can describe both functional trophic roles and standard compartments. We apply this method to a newly compiled plant-mammal food web from the Serengeti ecosystem that includes high taxonomic resolution at the plant level, allowing a simultaneous examination of the signature of both habitat and trophic roles in network structure. We find that groups at the plant level reflect habitat structure, coupled at higher trophic levels by groups of herbivores, which are in turn coupled by carnivore groups. Thus the group structure of the Serengeti web represents a mixture of trophic guild structure and spatial pattern, in contrast to the standard compartments typically identified. The network topology supports recent ideas on spatial coupling and energy channels in ecosystems that have been proposed as important for persistence. Furthermore, our Bayesian approach provides a powerful, flexible framework for the study of network structure, and we believe it will prove instrumental in a variety of biological contexts.'),
(85293, 2011, 'plos', 'Evidence for sequential and increasing activation of replication origins along replication timing gradients in the human genome', 'Guilbaud, Guillaume|Rappailles, Aurélien|Baker, Antoine|Chen, Chun-Long|Arneodo, Alain|Goldar, Arach|dAubenton-Carafa, Yves|Thermes, Claude|Audit, Benjamin|Hyrien, Olivier', 'Institut de Biologie de lEcole Normale Supérieure (IBENS), CNRS UMR8197, Inserm U1024, Paris, France.|Institut de Biologie de lEcole Normale Supérieure (IBENS), CNRS UMR8197, Inserm U1024, Paris, France.|Institut de Biologie de lEcole Normale Supérieure (IBENS), CNRS UMR8197, Inserm U1024, Paris, France.|Institut de Biologie de lEcole Normale Supérieure (IBENS), CNRS UMR8197, Inserm U1024, Paris, France.|Institut de Biologie de lEcole Normale Supérieure (IBENS), CNRS UMR8197, Inserm U1024, Paris, France.|Institut de Biologie de lEcole Normale Supérieure (IBENS), CNRS UMR8197, Inserm U1024, Paris, France.|Institut de Biologie de lEcole Normale Supérieure (IBENS), CNRS UMR8197, Inserm U1024, Paris, France.|Institut de Biologie de lEcole Normale Supérieure (IBENS), CNRS UMR8197, Inserm U1024, Paris, France.|Institut de Biologie de lEcole Normale Supérieure (IBENS), CNRS UMR8197, Inserm U1024, Paris, France.|Institut de Biologie de lEcole Normale Supérieure (IBENS), CNRS UMR8197, Inserm U1024, Paris, France.', 'France|France|France|France|France|France|France|France|France|France', 93, 'Cell Separation|Computational Biology|DNA Replication|Flow Cytometry|Genetic Techniques|Genome, Human|HeLa Cells|Humans|Kinetics|Models, Genetic|Models, Statistical|Replication Origin|Saccharomyces cerevisiae|Sequence Analysis, DNA|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1002322', '22219720', 'Genome-wide replication timing studies have suggested that mammalian chromosomes consist of megabase-scale domains of coordinated origin firing separated by large originless transition regions. Here, we report a quantitative genome-wide analysis of DNA replication kinetics in several human cell types that contradicts this view. DNA combing in HeLa cells sorted into four temporal compartments of S phase shows that replication origins are spaced at 40 kb intervals and fire as small clusters whose synchrony increases during S phase and that replication fork velocity (mean 0.7 kb/min, maximum 2.0 kb/min) remains constant and narrowly distributed through S phase. However, multi-scale analysis of a genome-wide replication timing profile shows a broad distribution of replication timing gradients with practically no regions larger than 100 kb replicating at less than 2 kb/min. Therefore, HeLa cells lack large regions of unidirectional fork progression. Temporal transition regions are replicated by sequential activation of origins at a rate that increases during S phase and replication timing gradients are set by the delay and the spacing between successive origin firings rather than by the velocity of single forks. Activation of internal origins in a specific temporal transition region is directly demonstrated by DNA combing of the IGH locus in HeLa cells. Analysis of published origin maps in HeLa cells and published replication timing and DNA combing data in several other cell types corroborate these findings, with the interesting exception of embryonic stem cells where regions of unidirectional fork progression seem more abundant. These results can be explained if origins fire independently of each other but under the control of long-range chromatin structure, or if replication forks progressing from early origins stimulate initiation in nearby unreplicated DNA. These findings shed a new light on the replication timing program of mammalian genomes and provide a general model for their replication kinetics.'),
(85294, 2011, 'plos', 'Prediction of drug combinations by integrating molecular and pharmacological data', 'Zhao, Xing-Ming|Iskar, Murat|Zeller, Georg|Kuhn, Michael|van Noort, Vera|Bork, Peer', 'European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.|European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.|European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.|European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.|European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.|European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany', 119, 'Computational Biology|Computers|Drug Combinations|Drug Design|Drug Therapy|Humans|Models, Statistical|Models, Theoretical|Probability|Software|Technology, Pharmaceutical', 'Journal Article', '10.1371/journal.pcbi.1002323', '22219721', 'Combinatorial therapy is a promising strategy for combating complex disorders due to improved efficacy and reduced side effects. However, screening new drug combinations exhaustively is impractical considering all possible combinations between drugs. Here, we present a novel computational approach to predict drug combinations by integrating molecular and pharmacological data. Specifically, drugs are represented by a set of their properties, such as their targets or indications. By integrating several of these features, we show that feature patterns enriched in approved drug combinations are not only predictive for new drug combinations but also provide insights into mechanisms underlying combinatorial therapy. Further analysis confirmed that among our top ranked predictions of effective combinations, 69% are supported by literature, while the others represent novel potential drug combinations. We believe that our proposed approach can help to limit the search space of drug combinations and provide a new way to effectively utilize existing drugs for new purposes.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85295, 2011, 'plos', 'The rates of protein synthesis and degradation account for the differential response of neurons to spaced and massed training protocols', 'Naqib, Faisal|Farah, Carole A|Pack, Christopher C|Sossin, Wayne S', 'Department of Physiology, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.|Department of Physiology, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.|Department of Physiology, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.|Department of Physiology, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.', 'Canada|Canada|Canada|Canada', 0, 'Animals|Aplysia|Biochemistry|Cyclic AMP-Dependent Protein Kinases|Memory|Models, Biological|Models, Statistical|Models, Theoretical|Motor Neurons|Neuronal Plasticity|Neurons|Plasmids|Sensory Receptor Cells|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002324', '22219722', 'The sensory-motor neuron synapse of Aplysia is an excellent model system for investigating the biochemical changes underlying memory formation. In this system, training that is separated by rest periods (spaced training) leads to persistent changes in synaptic strength that depend on biochemical pathways that are different from those that occur when the training lacks rest periods (massed training). Recently, we have shown that in isolated sensory neurons, applications of serotonin, the neurotransmitter implicated in inducing these synaptic changes during memory formation, lead to desensitization of the PKC Apl II response, in a manner that depends on the method of application (spaced versus massed). Here, we develop a mathematical model of this response in order to gain insight into how neurons sense these different training protocols. The model was developed incrementally, and each component was experimentally validated, leading to two novel findings: First, the increased desensitization due to PKA-mediated heterologous desensitization is coupled to a faster recovery than the homologous desensitization that occurs in the absence of PKA activity. Second, the model suggests that increased spacing leads to greater desensitization due to the short half-life of a hypothetical protein, whose production prevents homologous desensitization. Thus, we predict that the effects of differential spacing are largely driven by the rates of production and degradation of proteins. This prediction suggests a powerful mechanism by which information about time is incorporated into neuronal processing.'),
(85296, 2011, 'plos', 'Using multiple microenvironments to find similar ligand-binding sites: application to kinase inhibitor binding', 'Liu, Tianyun|Altman, Russ B', 'Department of Genetics, Stanford University, Stanford, California, United States of America.|Department of Genetics, Stanford University, Stanford, California, United States of America.', 'United States|United States', 45, 'Adenosine Triphosphate|Algorithms|Animals|Area Under Curve|Binding Sites|Biochemistry|Biophysics|Computational Biology|False Positive Reactions|Flavin-Adenine Dinucleotide|Humans|Kinetics|Ligands|Models, Molecular|Models, Theoretical|Molecular Conformation|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1002326', '22219723', 'The recognition of cryptic small-molecular binding sites in protein structures is important for understanding off-target side effects and for recognizing potential new indications for existing drugs. Current methods focus on the geometry and detailed chemical interactions within putative binding pockets, but may not recognize distant similarities where dynamics or modified interactions allow one ligand to bind apparently divergent binding pockets. In this paper, we introduce an algorithm that seeks similar microenvironments within two binding sites, and assesses overall binding site similarity by the presence of multiple shared microenvironments. The method has relatively weak geometric requirements (to allow for conformational change or dynamics in both the ligand and the pocket) and uses multiple biophysical and biochemical measures to characterize the microenvironments (to allow for diverse modes of ligand binding). We term the algorithm PocketFEATURE, since it focuses on pockets using the FEATURE system for characterizing microenvironments. We validate PocketFEATURE first by showing that it can better discriminate sites that bind similar ligands from those that do not, and by showing that we can recognize FAD-binding sites on a proteome scale with Area Under the Curve (AUC) of 92%. We then apply PocketFEATURE to evolutionarily distant kinases, for which the method recognizes several proven distant relationships, and predicts unexpected shared ligand binding. Using experimental data from ChEMBL and Ambit, we show that at high significance level, 40 kinase pairs are predicted to share ligands. Some of these pairs offer new opportunities for inhibiting two proteins in a single pathway.'),
(85297, 2011, 'plos', 'Radial and spiral stream formation in Proteus mirabilis colonies', 'Xue, Chuan|Budrene, Elena O|Othmer, Hans G', 'Mathematical Biosciences Institute, the Ohio State University, Columbus, Ohio, United States of America. cxue@mbi.osu.edu|Mathematical Biosciences Institute, the Ohio State University, Columbus, Ohio, United States of America. cxue@mbi.osu.edu|Mathematical Biosciences Institute, the Ohio State University, Columbus, Ohio, United States of America. cxue@mbi.osu.edu', 'United States|United States|United States', 0, 'Algorithms|Bacillus subtilis|Biofilms|Chemotaxis|Computational Biology|Escherichia coli|Models, Biological|Models, Statistical|Movement|Proteus mirabilis|Salmonella typhimurium', 'Journal Article', '10.1371/journal.pcbi.1002332', '22219724', 'The enteric bacterium Proteus mirabilis, which is a pathogen that forms biofilms in vivo, can swarm over hard surfaces and form a variety of spatial patterns in colonies. Colony formation involves two distinct cell types: swarmer cells that dominate near the surface and the leading edge, and swimmer cells that prefer a less viscous medium, but the mechanisms underlying pattern formation are not understood. New experimental investigations reported here show that swimmer cells in the center of the colony stream inward toward the inoculation site and in the process form many complex patterns, including radial and spiral streams, in addition to previously-reported concentric rings. These new observations suggest that swimmers are motile and that indirect interactions between them are essential in the pattern formation. To explain these observations we develop a hybrid model comprising cell-based and continuum components that incorporates a chemotactic response of swimmers to a chemical they produce. The model predicts that formation of radial streams can be explained as the modulation of the local attractant concentration by the cells, and that the chirality of the spiral streams results from a swimming bias of the cells near the surface of the substrate. The spatial patterns generated from the model are in qualitative agreement with the experimental observations.'),
(85298, 2011, 'plos', 'Genetic co-occurrence network across sequenced microbes', 'Kim, Pan-Jun|Price, Nathan D', 'Institute for Genomic Biology, University of Illinois, Urbana, Illinois, United States of America.|Institute for Genomic Biology, University of Illinois, Urbana, Illinois, United States of America.', 'United States|United States', 22, 'Bacteria|Computational Biology|Environment|Evolution, Molecular|Gastrointestinal Tract|Gene Expression Profiling|Gene Regulatory Networks|Genes, Bacterial|Genome, Bacterial|Humans|Models, Biological|Phenotype|Phylogeny|Sequence Analysis, DNA|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.1002340', '22219725', 'The phenotype of any organism on earth is, in large part, the consequence of interplay between numerous gene products encoded in the genome, and such interplay between gene products affects the evolutionary fate of the genome itself through the resulting phenotype. In this regard, contemporary genomes can be used as molecular records that reveal associations of various genes working in their natural lifestyles. By analyzing thousands of orthologs across xe2x88xbc600 bacterial species, we constructed a map of gene-gene co-occurrence across much of the sequenced biome. If genes preferentially co-occur in the same organisms, they were called herein correlogs, in the opposite case, called anti-correlogs. To quantify correlogy and anti-correlogy, we alleviated the contribution of indirect correlations between genes by adapting ideas developed for reverse engineering of transcriptional regulatory networks. Resultant correlogous associations are highly enriched for physically interacting proteins and for co-expressed transcripts, clearly differentiating a subgroup of functionally-obligatory protein interactions from conditional or transient interactions. Other biochemical and phylogenetic properties were also found to be reflected in correlogous and anti-correlogous relationships. Additionally, our study elucidates the global organization of the gene association map, in which various modules of correlogous genes are strikingly interconnected by anti-correlogous crosstalk between the modules. We then demonstrate the effectiveness of such associations along different domains of life and environmental microbial communities. These phylogenetic profiling approaches infer functional coupling of genes regardless of mechanistic details, and may be useful to guide exogenous gene import in synthetic biology.'),
(85299, 2012, 'plos', 'A dynamical model of oocyte maturation unveils precisely orchestrated meiotic decisions', 'Pfeuty, Benjamin|Bodart, Jean-Francois|Blossey, Ralf|Lefranc, Marc', 'Laboratoire de Physique des Lasers, Atomes, et Molécules, CNRS, UMR8523, Université Lille 1 Sciences et Technologies, Villeneuve dAscq, France. benjamin.pfeuty@phlam.univ-lille1.fr|Laboratoire de Physique des Lasers, Atomes, et Molécules, CNRS, UMR8523, Université Lille 1 Sciences et Technologies, Villeneuve dAscq, France. benjamin.pfeuty@phlam.univ-lille1.fr|Laboratoire de Physique des Lasers, Atomes, et Molécules, CNRS, UMR8523, Université Lille 1 Sciences et Technologies, Villeneuve dAscq, France. benjamin.pfeuty@phlam.univ-lille1.fr|Laboratoire de Physique des Lasers, Atomes, et Molécules, CNRS, UMR8523, Université Lille 1 Sciences et Technologies, Villeneuve dAscq, France. benjamin.pfeuty@phlam.univ-lille1.fr', 'France|France|France|France', 0, 'Animals|Cell Cycle|Cyclin-Dependent Kinases|Feedback, Physiological|Meiosis|Models, Biological|Oocytes|Oogenesis|Phenotype|Signal Transduction|Xenopus laevis', 'Journal Article', '10.1371/journal.pcbi.1002329', '22238511', 'Maturation of vertebrate oocytes into haploid gametes relies on two consecutive meioses without intervening DNA replication. The temporal sequence of cellular transitions driving eggs from G2 arrest to meiosis I (MI) and then to meiosis II (MII) is controlled by the interplay between cyclin-dependent and mitogen-activated protein kinases. In this paper, we propose a dynamical model of the molecular network that orchestrates maturation of Xenopus laevis oocytes. Our model reproduces the core features of maturation progression, including the characteristic non-monotonous time course of cyclin-Cdks, and unveils the network design principles underlying a precise sequence of meiotic decisions, as captured by bifurcation and sensitivity analyses. Firstly, a coherent and sharp meiotic resumption is triggered by the concerted action of positive feedback loops post-translationally activating cyclin-Cdks. Secondly, meiotic transition is driven by the dynamic antagonism between positive and negative feedback loops controlling cyclin turnover. Our findings reveal a highly modular network in which the coordination of distinct regulatory schemes ensures both reliable and flexible cell-cycle decisions.'),
(85300, 2012, 'plos', 'Short conduction delays cause inhibition rather than excitation to favor synchrony in hybrid neuronal networks of the entorhinal cortex', 'Wang, Shuoguo|Chandrasekaran, Lakshmi|Fernandez, Fernando R|White, John A|Canavier, Carmen C', 'Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA. swang1@lsuhsc.edu|Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA. swang1@lsuhsc.edu|Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA. swang1@lsuhsc.edu|Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA. swang1@lsuhsc.edu|Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA. swang1@lsuhsc.edu', 'United States|United States|United States|United States|United States', 0, 'Animals|Biological Clocks|Computer Simulation|Entorhinal Cortex|Excitatory Postsynaptic Potentials|Humans|Models, Neurological|Nerve Net|Neural Conduction|Neural Inhibition|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002306', '22241969', 'How stable synchrony in neuronal networks is sustained in the presence of conduction delays is an open question. The Dynamic Clamp was used to measure phase resetting curves (PRCs) for entorhinal cortical cells, and then to construct networks of two such neurons. PRCs were in general Type I (all advances or all delays) or weakly type II with a small region at early phases with the opposite type of resetting. We used previously developed theoretical methods based on PRCs under the assumption of pulsatile coupling to predict the delays that synchronize these hybrid circuits. For excitatory coupling, synchrony was predicted and observed only with no delay and for delays greater than half a network period that cause each neuron to receive an input late in its firing cycle and almost immediately fire an action potential. Synchronization for these long delays was surprisingly tight and robust to the noise and heterogeneity inherent in a biological system. In contrast to excitatory coupling, inhibitory coupling led to antiphase for no delay, very short delays and delays close to a network period, but to near-synchrony for a wide range of relatively short delays. PRC-based methods show that conduction delays can stabilize synchrony in several ways, including neutralizing a discontinuity introduced by strong inhibition, favoring synchrony in the case of noisy bistability, and avoiding an initial destabilizing region of a weakly type II PRC. PRCs can identify optimal conduction delays favoring synchronization at a given frequency, and also predict robustness to noise and heterogeneity.'),
(85301, 2012, 'plos', 'Multi-scale inference of interaction rules in animal groups using Bayesian model selection', 'Mann, Richard P|Perna, Andrea|Strömbom, Daniel|Garnett, Roman|Herbert-Read, James E|Sumpter, David J T|Ward, Ashley J W', 'Department of Mathematics, Uppsala University, Uppsala, Sweden. rmann@math.uu.se|Department of Mathematics, Uppsala University, Uppsala, Sweden. rmann@math.uu.se|Department of Mathematics, Uppsala University, Uppsala, Sweden. rmann@math.uu.se|Department of Mathematics, Uppsala University, Uppsala, Sweden. rmann@math.uu.se|Department of Mathematics, Uppsala University, Uppsala, Sweden. rmann@math.uu.se|Department of Mathematics, Uppsala University, Uppsala, Sweden. rmann@math.uu.se|Department of Mathematics, Uppsala University, Uppsala, Sweden. rmann@math.uu.se', 'Sweden|Sweden|Sweden|Sweden|Sweden|Sweden|Sweden', 9, 'Animals|Bayes Theorem|Behavior, Animal|Computer Simulation|Group Processes|Models, Biological|Models, Statistical|Palaemonidae|Social Behavior|Spatial Behavior', 'Journal Article', '10.1371/journal.pcbi.1002308', '22241970', 'Inference of interaction rules of animals moving in groups usually relies on an analysis of large scale system behaviour. Models are tuned through repeated simulation until they match the observed behaviour. More recent work has used the fine scale motions of animals to validate and fit the rules of interaction of animals in groups. Here, we use a Bayesian methodology to compare a variety of models to the collective motion of glass prawns (Paratya australiensis). We show that these exhibit a stereotypical phase transition, whereby an increase in density leads to the onset of collective motion in one direction. We fit models to this data, which range from: a mean-field model where all prawns interact globally, to a spatial Markovian model where prawns are self-propelled particles influenced only by the current positions and directions of their neighbours, up to non-Markovian models where prawns have memory of previous interactions, integrating their experiences over time when deciding to change behaviour. We show that the mean-field model fits the large scale behaviour of the system, but does not capture fine scale rules of interaction, which are primarily mediated by physical contact. Conversely, the Markovian self-propelled particle model captures the fine scale rules of interaction but fails to reproduce global dynamics. The most sophisticated model, the non-Markovian model, provides a good match to the data at both the fine scale and in terms of reproducing global dynamics. We conclude that prawns movements are influenced by not just the current direction of nearby conspecifics, but also those encountered in the recent past. Given the simplicity of prawns as a study system our research suggests that self-propelled particle models of collective motion should, if they are to be realistic at multiple biological scales, include memory of previous interactions and other non-Markovian effects.'),
(85302, 2012, 'plos', 'Failure of adaptive self-organized criticality during epileptic seizure attacks', 'Meisel, Christian|Storch, Alexander|Hallmeyer-Elgner, Susanne|Bullmore, Ed|Gross, Thilo', 'Biological Physics Section, Max Planck Institute for the Physics of Complex Systems, Dresden, Germany. meisel@mpipks-dresden.mpg.de|Biological Physics Section, Max Planck Institute for the Physics of Complex Systems, Dresden, Germany. meisel@mpipks-dresden.mpg.de|Biological Physics Section, Max Planck Institute for the Physics of Complex Systems, Dresden, Germany. meisel@mpipks-dresden.mpg.de|Biological Physics Section, Max Planck Institute for the Physics of Complex Systems, Dresden, Germany. meisel@mpipks-dresden.mpg.de|Biological Physics Section, Max Planck Institute for the Physics of Complex Systems, Dresden, Germany. meisel@mpipks-dresden.mpg.de', 'Germany|Germany|Germany|Germany|Germany', 76, 'Adaptation, Physiological|Brain|Computer Simulation|Epilepsy|Humans|Models, Neurological|Nerve Net|Neuronal Plasticity', 'Journal Article', '10.1371/journal.pcbi.1002312', '22241971', 'Critical dynamics are assumed to be an attractive mode for normal brain functioning as information processing and computational capabilities are found to be optimal in the critical state. Recent experimental observations of neuronal activity patterns following power-law distributions, a hallmark of systems at a critical state, have led to the hypothesis that human brain dynamics could be poised at a phase transition between ordered and disordered activity. A so far unresolved question concerns the medical significance of critical brain activity and how it relates to pathological conditions. Using data from invasive electroencephalogram recordings from humans we show that during epileptic seizure attacks neuronal activity patterns deviate from the normally observed power-law distribution characterizing critical dynamics. The comparison of these observations to results from a computational model exhibiting self-organized criticality (SOC) based on adaptive networks allows further insights into the underlying dynamics. Together these results suggest that brain dynamics deviates from criticality during seizures caused by the failure of adaptive SOC.'),
(85303, 2012, 'plos', 'Dopamine, affordance and active inference', 'Friston, Karl J|Shiner, Tamara|FitzGerald, Thomas|Galea, Joseph M|Adams, Rick|Brown, Harriet|Dolan, Raymond J|Moran, Rosalyn|Stephan, Klaas Enno|Bestmann, Sven', 'The Wellcome Trust Centre for Neuroimaging, University College London, Queen Square, London, United Kingdom. k.friston@fil.ion.ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, Queen Square, London, United Kingdom. k.friston@fil.ion.ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, Queen Square, London, United Kingdom. k.friston@fil.ion.ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, Queen Square, London, United Kingdom. k.friston@fil.ion.ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, Queen Square, London, United Kingdom. k.friston@fil.ion.ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, Queen Square, London, United Kingdom. k.friston@fil.ion.ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, Queen Square, London, United Kingdom. k.friston@fil.ion.ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, Queen Square, London, United Kingdom. k.friston@fil.ion.ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, Queen Square, London, United Kingdom. k.friston@fil.ion.ucl.ac.uk|The Wellcome Trust Centre for Neuroimaging, University College London, Queen Square, London, United Kingdom. k.friston@fil.ion.ucl.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Brain|Computer Simulation|Cues|Decision Making|Dopamine|Humans|Models, Neurological|Nerve Net|Perceptual Masking|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002327', '22241972', 'The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinsons disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level.'),
(85304, 2012, 'plos', 'Landscape epidemiology and control of pathogens with cryptic and long-distance dispersal: sudden oak death in northern Californian forests', 'Filipe, João A N|Cobb, Richard C|Meentemeyer, Ross K|Lee, Christopher A|Valachovic, Yana S|Cook, Alex R|Rizzo, David M|Gilligan, Christopher A', 'Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom. jf263@cam.ac.uk|Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom. jf263@cam.ac.uk|Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom. jf263@cam.ac.uk|Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom. jf263@cam.ac.uk|Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom. jf263@cam.ac.uk|Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom. jf263@cam.ac.uk|Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom. jf263@cam.ac.uk|Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom. jf263@cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 58, 'California|Computer Simulation|Ecosystem|Models, Biological|Plant Diseases|Trees', 'Journal Article', '10.1371/journal.pcbi.1002328', '22241973', 'Exotic pathogens and pests threaten ecosystem service, biodiversity, and crop security globally. If an invasive agent can disperse asymptomatically over long distances, multiple spatial and temporal scales interplay, making identification of effective strategies to regulate, monitor, and control disease extremely difficult. The management of outbreaks is also challenged by limited data on the actual area infested and the dynamics of spatial spread, due to financial, technological, or social constraints. We examine principles of landscape epidemiology important in designing policy to prevent or slow invasion by such organisms, and use Phytophthora ramorum, the cause of sudden oak death, to illustrate how shortfalls in their understanding can render management applications inappropriate. This pathogen has invaded forests in coastal California, USA, and an isolated but fast-growing epidemic focus in northern California (Humboldt County) has the potential for extensive spread. The risk of spread is enhanced by the pathogens generalist nature and survival. Additionally, the extent of cryptic infection is unknown due to limited surveying resources and access to private land. Here, we use an epidemiological model for transmission in heterogeneous landscapes and Bayesian Markov-chain-Monte-Carlo inference to estimate dispersal and life-cycle parameters of P. ramorum and forecast the distribution of infection and speed of the epidemic front in Humboldt County. We assess the viability of management options for containing the pathogens northern spread and local impacts. Implementing a stand-alone host-free barrier had limited efficacy due to long-distance dispersal, but combining curative with preventive treatments ahead of the front reduced local damage and contained spread. While the large size of this focus makes effective control expensive, early synchronous treatment in newly-identified disease foci should be more cost-effective. We show how the successful management of forest ecosystems depends on estimating the spatial scales of invasion and treatment of pathogens and pests with cryptic long-distance dispersal.'),
(85305, 2012, 'plos', 'Joint modelling of confounding factors and prominent genetic regulators provides increased accuracy in genetical genomics studies', 'Fusi, Nicoló|Stegle, Oliver|Lawrence, Neil D', 'Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom. nicolo.fusi@sheffield.ac.uk|Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom. nicolo.fusi@sheffield.ac.uk|Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom. nicolo.fusi@sheffield.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 66, 'Algorithms|Animals|Chromosome Mapping|Computer Simulation|Confounding Factors (Epidemiology)|Data Interpretation, Statistical|Gene Expression Regulation|Genetic Variation|Humans|Models, Genetic|Models, Statistical|Quantitative Trait Loci|Sensitivity and Specificity', 'Journal Article', '10.1371/journal.pcbi.1002330', '22241974', 'Expression quantitative trait loci (eQTL) studies are an integral tool to investigate the genetic component of gene expression variation. A major challenge in the analysis of such studies are hidden confounding factors, such as unobserved covariates or unknown subtle environmental perturbations. These factors can induce a pronounced artifactual correlation structure in the expression profiles, which may create spurious false associations or mask real genetic association signals. Here, we report PANAMA (Probabilistic ANAlysis of genoMic dAta), a novel probabilistic model to account for confounding factors within an eQTL analysis. In contrast to previous methods, PANAMA learns hidden factors jointly with the effect of prominent genetic regulators. As a result, this new model can more accurately distinguish true genetic association signals from confounding variation. We applied our model and compared it to existing methods on different datasets and biological systems. PANAMA consistently performs better than alternative methods, and finds in particular substantially more trans regulators. Importantly, our approach not only identifies a greater number of associations, but also yields hits that are biologically more plausible and can be better reproduced between independent studies. A software implementation of PANAMA is freely available online at http://ml.sheffield.ac.uk/qtl/.'),
(85306, 2012, 'plos', 'A model of ant route navigation driven by scene familiarity', 'Baddeley, Bart|Graham, Paul|Husbands, Philip|Philippides, Andrew', 'Centre for Computational Neuroscience and Robotics, Department of Informatics, University of Sussex, Brighton, United Kingdom. b.t.baddeley@sussex.ac.uk|Centre for Computational Neuroscience and Robotics, Department of Informatics, University of Sussex, Brighton, United Kingdom. b.t.baddeley@sussex.ac.uk|Centre for Computational Neuroscience and Robotics, Department of Informatics, University of Sussex, Brighton, United Kingdom. b.t.baddeley@sussex.ac.uk|Centre for Computational Neuroscience and Robotics, Department of Informatics, University of Sussex, Brighton, United Kingdom. b.t.baddeley@sussex.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Animals|Ants|Behavior, Animal|Computer Simulation|Learning|Locomotion|Models, Biological|Orientation|Pattern Recognition, Visual', 'Journal Article', '10.1371/journal.pcbi.1002336', '22241975', 'In this paper we propose a model of visually guided route navigation in ants that captures the known properties of real behaviour whilst retaining mechanistic simplicity and thus biological plausibility. For an ant, the coupling of movement and viewing direction means that a familiar view specifies a familiar direction of movement. Since the views experienced along a habitual route will be more familiar, route navigation can be re-cast as a search for familiar views. This search can be performed with a simple scanning routine, a behaviour that ants have been observed to perform. We test this proposed route navigation strategy in simulation, by learning a series of routes through visually cluttered environments consisting of objects that are only distinguishable as silhouettes against the sky. In the first instance we determine view familiarity by exhaustive comparison with the set of views experienced during training. In further experiments we train an artificial neural network to perform familiarity discrimination using the training views. Our results indicate that, not only is the approach successful, but also that the routes that are learnt show many of the characteristics of the routes of desert ants. As such, we believe the model represents the only detailed and complete model of insect route guidance to date. What is more, the model provides a general demonstration that visually guided routes can be produced with parsimonious mechanisms that do not specify when or what to learn, nor separate routes into sequences of waypoints.'),
(85307, 2012, 'plos', 'A mathematical methodology for determining the temporal order of pathway alterations arising during gliomagenesis', 'Cheng, Yu-Kang|Beroukhim, Rameen|Levine, Ross L|Mellinghoff, Ingo K|Holland, Eric C|Michor, Franziska', 'Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.', 'United States|United States|United States|United States|United States|United States', 46, 'Algorithms|Cell Transformation, Neoplastic|Computer Simulation|Glioma|Humans|Models, Biological|Neoplasm Proteins|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002337', '22241976', 'Human cancer is caused by the accumulation of genetic alterations in cells. Of special importance are changes that occur early during malignant transformation because they may result in oncogene addiction and thus represent promising targets for therapeutic intervention. We have previously described a computational approach, called Retracing the Evolutionary Steps in Cancer (RESIC), to determine the temporal sequence of genetic alterations during tumorigenesis from cross-sectional genomic data of tumors at their fully transformed stage. Since alterations within a set of genes belonging to a particular signaling pathway may have similar or equivalent effects, we applied a pathway-based systems biology approach to the RESIC methodology. This method was used to determine whether alterations of specific pathways develop early or late during malignant transformation. When applied to primary glioblastoma (GBM) copy number data from The Cancer Genome Atlas (TCGA) project, RESIC identified a temporal order of pathway alterations consistent with the order of events in secondary GBMs. We then further subdivided the samples into the four main GBM subtypes and determined the relative contributions of each subtype to the overall results: we found that the overall ordering applied for the proneural subtype but differed for mesenchymal samples. The temporal sequence of events could not be identified for neural and classical subtypes, possibly due to a limited number of samples. Moreover, for samples of the proneural subtype, we detected two distinct temporal sequences of events: (i) RAS pathway activation was followed by TP53 inactivation and finally PI3K2 activation, and (ii) RAS activation preceded only AKT activation. This extension of the RESIC methodology provides an evolutionary mathematical approach to identify the temporal sequence of pathway changes driving tumorigenesis and may be useful in guiding the understanding of signaling rearrangements in cancer development.'),
(85308, 2012, 'plos', 'A viral dynamic model for treatment regimens with direct-acting antivirals for chronic hepatitis C infection', 'Adiwijaya, Bambang S|Kieffer, Tara L|Henshaw, Joshua|Eisenhauer, Karen|Kimko, Holly|Alam, John J|Kauffman, Robert S|Garg, Varun', 'Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, USA. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, USA. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, USA. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, USA. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, USA. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, USA. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, USA. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, USA. bambang_adiwijaya@vrtx.com', 'United States|United States|United States|United States|United States|United States|United States|United States', 30, 'Antiviral Agents|Computer Simulation|Dose-Response Relationship, Drug|Drug Therapy, Computer-Assisted|Hepacivirus|Hepatitis C|Humans|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1002339', '22241977', 'We propose an integrative, mechanistic model that integrates in vitro virology data, pharmacokinetics, and viral response to a combination regimen of a direct-acting antiviral (telaprevir, an HCV NS3-4A protease inhibitor) and peginterferon alfa-2a/ribavirin (PR) in patients with genotype 1 chronic hepatitis C (CHC). This model, which was parameterized with on-treatment data from early phase clinical studies in treatment-naïve patients, prospectively predicted sustained virologic response (SVR) rates that were comparable to observed rates in subsequent clinical trials of regimens with different treatment durations in treatment-naïve and treatment-experienced populations. The model explains the clinically-observed responses, taking into account the IC50, fitness, and prevalence prior to treatment of viral resistant variants and patient diversity in treatment responses, which result in different eradication times of each variant. The proposed model provides a framework to optimize treatment strategies and to integrate multifaceted mechanistic information and give insight into novel CHC treatments that include direct-acting antiviral agents.'),
(85309, 2012, 'plos', 'Parsimonious higher-order hidden Markov models for improved array-CGH analysis with applications to Arabidopsis thaliana', 'Seifert, Michael|Gohr, André|Strickert, Marc|Grosse, Ivo', 'Department of Molecular Genetics, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany. seifert@ipk-gatersleben.de|Department of Molecular Genetics, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany. seifert@ipk-gatersleben.de|Department of Molecular Genetics, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany. seifert@ipk-gatersleben.de|Department of Molecular Genetics, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany. seifert@ipk-gatersleben.de', 'Germany|Germany|Germany|Germany', 0, 'Arabidopsis|Comparative Genomic Hybridization|Genome, Human|Genome, Plant|Humans|Markov Chains|Polymorphism, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002286', '22253580', 'Array-based comparative genomic hybridization (Array-CGH) is an important technology in molecular biology for the detection of DNA copy number polymorphisms between closely related genomes. Hidden Markov Models (HMMs) are popular tools for the analysis of Array-CGH data, but current methods are only based on first-order HMMs having constrained abilities to model spatial dependencies between measurements of closely adjacent chromosomal regions. Here, we develop parsimonious higher-order HMMs enabling the interpolation between a mixture model ignoring spatial dependencies and a higher-order HMM exhaustively modeling spatial dependencies. We apply parsimonious higher-order HMMs to the analysis of Array-CGH data of the accessions C24 and Col-0 of the model plant Arabidopsis thaliana. We compare these models against first-order HMMs and other existing methods using a reference of known deletions and sequence deviations. We find that parsimonious higher-order HMMs clearly improve the identification of these polymorphisms. Moreover, we perform a functional analysis of identified polymorphisms revealing novel details of genomic differences between C24 and Col-0. Additional model evaluations are done on widely considered Array-CGH data of human cell lines indicating that parsimonious HMMs are also well-suited for the analysis of non-plant specific data. All these results indicate that parsimonious higher-order HMMs are useful for Array-CGH analyses. An implementation of parsimonious higher-order HMMs is available as part of the open source Java library Jstacs (www.jstacs.de/index.php/PHHMM).'),
(85310, 2012, 'plos', 'Lipid exchange mechanism of the cholesteryl ester transfer protein clarified by atomistic and coarse-grained simulations', 'Koivuniemi, Artturi|Vuorela, Timo|Kovanen, Petri T|Vattulainen, Ilpo|Hyvönen, Marja T', 'Department of Physics, Tampere University of Technology, Tampere, Finland. artturi.koivuniemi@vtt.fi|Department of Physics, Tampere University of Technology, Tampere, Finland. artturi.koivuniemi@vtt.fi|Department of Physics, Tampere University of Technology, Tampere, Finland. artturi.koivuniemi@vtt.fi|Department of Physics, Tampere University of Technology, Tampere, Finland. artturi.koivuniemi@vtt.fi|Department of Physics, Tampere University of Technology, Tampere, Finland. artturi.koivuniemi@vtt.fi', 'Finland|Finland|Finland|Finland|Finland', 0, 'Binding Sites|Cholesterol Ester Transfer Proteins|Cholesterol Esters|Computer Simulation|Lipoproteins, HDL|Models, Molecular|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1002299', '22253581', 'Cholesteryl ester transfer protein (CETP) transports cholesteryl esters, triglycerides, and phospholipids between different lipoprotein fractions in blood plasma. The inhibition of CETP has been shown to be a sound strategy to prevent and treat the development of coronary heart disease. We employed molecular dynamics simulations to unravel the mechanisms associated with the CETP-mediated lipid exchange. To this end we used both atomistic and coarse-grained models whose results were consistent with each other. We found CETP to bind to the surface of high density lipoprotein (HDL) -like lipid droplets through its charged and tryptophan residues. Upon binding, CETP rapidly (in about 10 ns) induced the formation of a small hydrophobic patch to the phospholipid surface of the droplet, opening a route from the core of the lipid droplet to the binding pocket of CETP. This was followed by a conformational change of helix X of CETP to an open state, in which we found the accessibility of cholesteryl esters to the C-terminal tunnel opening of CETP to increase. Furthermore, in the absence of helix X, cholesteryl esters rapidly diffused into CETP through the C-terminal opening. The results provide compelling evidence that helix X acts as a lid which conducts lipid exchange by alternating the open and closed states. The findings have potential for the design of novel molecular agents to inhibit the activity of CETP.'),
(85311, 2012, 'plos', 'Global analysis of small molecule binding to related protein targets', 'Kruger, Felix A|Overington, John P', 'European Bioinformatics Institute, Hinxton, United Kingdom.|European Bioinformatics Institute, Hinxton, United Kingdom.', 'United Kingdom|United Kingdom', 0, 'Animals|Binding Sites|Databases, Factual|Drug Discovery|Humans|Ligands|Proteins|Rats', 'Journal Article', '10.1371/journal.pcbi.1002333', '22253582', 'We report on the integration of pharmacological data and homology information for a large scale analysis of small molecule binding to related targets. Differences in small molecule binding have been assessed for curated pairs of human to rat orthologs and also for recently diverged human paralogs. Our analysis shows that in general, small molecule binding is conserved for pairs of human to rat orthologs. Using statistical tests, we identified a small number of cases where small molecule binding is different between human and rat, some of which had previously been reported in the literature. Knowledge of species specific pharmacology can be advantageous for drug discovery, where rats are frequently used as a model system. For human paralogs, we demonstrate a global correlation between sequence identity and the binding of small molecules with equivalent affinity. Our findings provide an initial general model relating small molecule binding and sequence divergence, containing the foundations for a general model to anticipate and predict within-target-family selectivity.'),
(85312, 2012, 'plos', 'A dynamic view of domain-motif interactions', 'Akiva, Eyal|Friedlander, Gilgi|Itzhaki, Zohar|Margalit, Hanah', 'Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.|Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.|Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.|Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.', 'Israel|Israel|Israel|Israel', 45, 'Amino Acid Sequence|Animals|Binding Sites|Evolution, Molecular|Humans|Molecular Sequence Data|Phosphorylation|Protein Processing, Post-Translational|Protein Structure, Tertiary|Proteins|src Homology Domains', 'Journal Article', '10.1371/journal.pcbi.1002341', '22253583', 'Many protein-protein interactions are mediated by domain-motif interaction, where a domain in one protein binds a short linear motif in its interacting partner. Such interactions are often involved in key cellular processes, necessitating their tight regulation. A common strategy of the cell to control protein function and interaction is by post-translational modifications of specific residues, especially phosphorylation. Indeed, there are motifs, such as SH2-binding motifs, in which motif phosphorylation is required for the domain-motif interaction. On the contrary, there are other examples where motif phosphorylation prevents the domain-motif interaction. Here we present a large-scale integrative analysis of experimental human data of domain-motif interactions and phosphorylation events, demonstrating an intriguing coupling between the two. We report such coupling for SH3, PDZ, SH2 and WW domains, where residue phosphorylation within or next to the motif is implied to be associated with switching on or off domain binding. For domains that require motif phosphorylation for binding, such as SH2 domains, we found coupled phosphorylation events other than the ones required for domain binding. Furthermore, we show that phosphorylation might function as a double switch, concurrently enabling interaction of the motif with one domain and disabling interaction with another domain. Evolutionary analysis shows that co-evolution of the motif and the proximal residues capable of phosphorylation predominates over other evolutionary scenarios, in which the motif appeared before the potentially phosphorylated residue, or vice versa. Our findings provide strengthening evidence for coupled interaction-regulation units, defined by a domain-binding motif and a phosphorylated residue.'),
(85313, 2012, 'plos', 'Adjusting phenotypes by noise control', 'Kim, Kyung H|Sauro, Herbert M', 'Department of Bioengineering, University of Washington, Seattle, Washington, United States of America. kkim@uw.edu|Department of Bioengineering, University of Washington, Seattle, Washington, United States of America. kkim@uw.edu', 'United States|United States', 0, 'Computer Simulation|Gene Expression Regulation|Gene Regulatory Networks|HIV|Phenotype|Saccharomyces cerevisiae|Tumor Suppressor Protein p53', 'Journal Article', '10.1371/journal.pcbi.1002344', '22253584', 'Genetically identical cells can show phenotypic variability. This is often caused by stochastic events that originate from randomness in biochemical processes involving in gene expression and other extrinsic cellular processes. From an engineering perspective, there have been efforts focused on theory and experiments to control noise levels by perturbing and replacing gene network components. However, systematic methods for noise control are lacking mainly due to the intractable mathematical structure of noise propagation through reaction networks. Here, we provide a numerical analysis method by quantifying the parametric sensitivity of noise characteristics at the level of the linear noise approximation. Our analysis is readily applicable to various types of noise control and to different types of system, for example, we can orthogonally control the mean and noise levels and can control system dynamics such as noisy oscillations. As an illustration we applied our method to HIV and yeast gene expression systems and metabolic networks. The oscillatory signal control was applied to p53 oscillations from DNA damage. Furthermore, we showed that the efficiency of orthogonal control can be enhanced by applying extrinsic noise and feedback. Our noise control analysis can be applied to any stochastic model belonging to continuous time Markovian systems such as biological and chemical reaction systems, and even computer and social networks. We anticipate the proposed analysis to be a useful tool for designing and controlling synthetic gene networks.');
