INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84470, 2010, 'plos', 'Identification of networks of co-occurring, tumor-related DNA copy number changes using a genome-wide scoring approach', 'Klijn, Christiaan|Bot, Jan|Adams, David J|Reinders, Marcel|Wessels, Lodewyk|Jonkers, Jos', 'Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 0, 'Chromosome Mapping|DNA Copy Number Variations|DNA, Neoplasm|Gene Expression Regulation, Neoplastic|Genome, Human|Humans|Neoplasm Proteins|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000631', '20052266', 'Tumorigenesis is a multi-step process in which normal cells transform into malignant tumors following the accumulation of genetic mutations that enable them to evade the growth control checkpoints that would normally suppress their growth or result in apoptosis. It is therefore important to identify those combinations of mutations that collaborate in cancer development and progression. DNA copy number alterations (CNAs) are one of the ways in which cancer genes are deregulated in tumor cells. We hypothesized that synergistic interactions between cancer genes might be identified by looking for regions of co-occurring gain and/or loss. To this end we developed a scoring framework to separate truly co-occurring aberrations from passenger mutations and dominant single signals present in the data. The resulting regions of high co-occurrence can be investigated for between-region functional interactions. Analysis of high-resolution DNA copy number data from a panel of 95 hematological tumor cell lines correctly identified co-occurring recombinations at the T-cell receptor and immunoglobulin loci in T- and B-cell malignancies, respectively, showing that we can recover truly co-occurring genomic alterations. In addition, our analysis revealed networks of co-occurring genomic losses and gains that are enriched for cancer genes. These networks are also highly enriched for functional relationships between genes. We further examine sub-networks of these networks, core networks, which contain many known cancer genes. The core network for co-occurring DNA losses we find seems to be independent of the canonical cancer genes within the network. Our findings suggest that large-scale, low-intensity copy number alterations may be an important feature of cancer development or maintenance by affecting gene dosage of a large interconnected network of functionally related genes.'),
(84471, 2010, 'plos', 'Modeling mitochondrial bioenergetics with integrated volume dynamics', 'Bazil, Jason N|Buzzard, Gregery T|Rundell, Ann E', 'Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, United States of America.|Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, United States of America.|Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, United States of America.', 'India|India|India', 39, 'Animals|Computer Simulation|Energy Metabolism|Extracellular Matrix|Humans|Mitochondria|Models, Biological|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000632', '20052270', 'Mathematical models of mitochondrial bioenergetics provide powerful analytical tools to help interpret experimental data and facilitate experimental design for elucidating the supporting biochemical and physical processes. As a next step towards constructing a complete physiologically faithful mitochondrial bioenergetics model, a mathematical model was developed targeting the cardiac mitochondrial bioenergetic based upon previous efforts, and corroborated using both transient and steady state data. The model consists of several modified rate functions of mitochondrial bioenergetics, integrated calcium dynamics and a detailed description of the K(+)-cycle and its effect on mitochondrial bioenergetics and matrix volume regulation. Model simulations were used to fit 42 adjustable parameters to four independent experimental data sets consisting of 32 data curves. During the model development, a certain network topology had to be in place and some assumptions about uncertain or unobserved experimental factors and conditions were explicitly constrained in order to faithfully reproduce all the data sets. These realizations are discussed, and their necessity helps contribute to the collective understanding of the mitochondrial bioenergetics.'),
(84472, 2010, 'plos', 'Disentangling direct from indirect co-evolution of residues in protein alignments', 'Burger, Lukas|van Nimwegen, Erik', 'Biozentrum, University of Basel, and Swiss Institute of Bioinformatics, Basel, Switzerland.|Biozentrum, University of Basel, and Swiss Institute of Bioinformatics, Basel, Switzerland.', 'Switzerland|Switzerland', 127, 'Algorithms|Amino Acid Sequence|Binding Sites|Molecular Sequence Data|Protein Binding|Proteins|Sequence Alignment|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1000633', '20052271', 'Predicting protein structure from primary sequence is one of the ultimate challenges in computational biology. Given the large amount of available sequence data, the analysis of co-evolution, i.e., statistical dependency, between columns in multiple alignments of protein domain sequences remains one of the most promising avenues for predicting residues that are contacting in the structure. A key impediment to this approach is that strong statistical dependencies are also observed for many residue pairs that are distal in the structure. Using a comprehensive analysis of protein domains with available three-dimensional structures we show that co-evolving contacts very commonly form chains that percolate through the protein structure, inducing indirect statistical dependencies between many distal pairs of residues. We characterize the distributions of length and spatial distance traveled by these co-evolving contact chains and show that they explain a large fraction of observed statistical dependencies between structurally distal pairs. We adapt a recently developed Bayesian network model into a rigorous procedure for disentangling direct from indirect statistical dependencies, and we demonstrate that this method not only successfully accomplishes this task, but also allows contacts with weak statistical dependency to be detected. To illustrate how additional information can be incorporated into our method, we incorporate a phylogenetic correction, and we develop an informative prior that takes into account that the probability for a pair of residues to contact depends strongly on their primary-sequence distance and the amount of conservation that the corresponding columns in the multiple alignment exhibit. We show that our model including these extensions dramatically improves the accuracy of contact prediction from multiple sequence alignments.'),
(84473, 2010, 'plos', 'Network-free inference of knockout effects in yeast', 'Peleg, Tal|Yosef, Nir|Ruppin, Eytan|Sharan, Roded', 'Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel.|Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel.|Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel.|Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel.', 'Israel|Israel|Israel|Israel', 12, 'Algorithms|Cluster Analysis|Gene Knockout Techniques|Gene Regulatory Networks|Genes, Fungal|Linear Models|Reproducibility of Results|Systems Biology|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1000635', '20066032', 'Perturbation experiments, in which a certain gene is knocked out and the expression levels of other genes are observed, constitute a fundamental step in uncovering the intricate wiring diagrams in the living cell and elucidating the causal roles of genes in signaling and regulation. Here we present a novel framework for analyzing large cohorts of gene knockout experiments and their genome-wide effects on expression levels. We devise clustering-like algorithms that identify groups of genes that behave similarly with respect to the knockout data, and utilize them to predict knockout effects and to annotate physical interactions between proteins as inhibiting or activating. Differing from previous approaches, our prediction approach does not depend on physical network information, the latter is used only for the annotation task. Consequently, it is both more efficient and of wider applicability than previous methods. We evaluate our approach using a large scale collection of gene knockout experiments in yeast, comparing it to the state-of-the-art SPINE algorithm. In cross validation tests, our algorithm exhibits superior prediction accuracy, while at the same time increasing the coverage by over 25-fold. Significant coverage gains are obtained also in the annotation of the physical network.'),
(84474, 2010, 'plos', 'Conformational transitions upon ligand binding: holo-structure prediction from apo conformations', 'Seeliger, Daniel|de Groot, Bert L', 'Computational Biomolecular Dynamics Group, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.|Computational Biomolecular Dynamics Group, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.', 'Germany|Germany', 73, 'Apoproteins|Crystallography, X-Ray|Holoenzymes|Ligands|Molecular Dynamics Simulation|Protein Binding|Protein Conformation|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1000634', '20066034', 'Biological function of proteins is frequently associated with the formation of complexes with small-molecule ligands. Experimental structure determination of such complexes at atomic resolution, however, can be time-consuming and costly. Computational methods for structure prediction of protein/ligand complexes, particularly docking, are as yet restricted by their limited consideration of receptor flexibility, rendering them not applicable for predicting protein/ligand complexes if large conformational changes of the receptor upon ligand binding are involved. Accurate receptor models in the ligand-bound state (holo structures), however, are a prerequisite for successful structure-based drug design. Hence, if only an unbound (apo) structure is available distinct from the ligand-bound conformation, structure-based drug design is severely limited. We present a method to predict the structure of protein/ligand complexes based solely on the apo structure, the ligand and the radius of gyration of the holo structure. The method is applied to ten cases in which proteins undergo structural rearrangements of up to 7.1 A backbone RMSD upon ligand binding. In all cases, receptor models within 1.6 A backbone RMSD to the target were predicted and close-to-native ligand binding poses were obtained for 8 of 10 cases in the top-ranked complex models. A protocol is presented that is expected to enable structure modeling of protein/ligand complexes and structure-based drug design for cases where crystal structures of ligand-bound conformations are not available.'),
(84475, 2010, 'plos', 'Combining structure and sequence information allows automated prediction of substrate specificities within enzyme families', 'Röttig, Marc|Rausch, Christian|Kohlbacher, Oliver', 'Center for Bioinformatics Tübingen, Eberhard-Karls-Universität Tübingen, Tübingen, Germany. roettig@informatik.uni-tuebingen.de|Center for Bioinformatics Tübingen, Eberhard-Karls-Universität Tübingen, Tübingen, Germany. roettig@informatik.uni-tuebingen.de|Center for Bioinformatics Tübingen, Eberhard-Karls-Universität Tübingen, Tübingen, Germany. roettig@informatik.uni-tuebingen.de', 'Germany|Germany|Germany', 25, 'Algorithms|Amino Acid Sequence|Artificial Intelligence|Catalytic Domain|Computational Biology|Databases, Protein|Enzymes|Internet|Models, Molecular|Protein Conformation|Structure-Activity Relationship|Substrate Specificity', 'Journal Article', '10.1371/journal.pcbi.1000636', '20072606', 'An important aspect of the functional annotation of enzymes is not only the type of reaction catalysed by an enzyme, but also the substrate specificity, which can vary widely within the same family. In many cases, prediction of family membership and even substrate specificity is possible from enzyme sequence alone, using a nearest neighbour classification rule. However, the combination of structural information and sequence information can improve the interpretability and accuracy of predictive models. The method presented here, Active Site Classification (ASC), automatically extracts the residues lining the active site from one representative three-dimensional structure and the corresponding residues from sequences of other members of the family. From a set of representatives with known substrate specificity, a Support Vector Machine (SVM) can then learn a model of substrate specificity. Applied to a sequence of unknown specificity, the SVM can then predict the most likely substrate. The models can also be analysed to reveal the underlying structural reasons determining substrate specificities and thus yield valuable insights into mechanisms of enzyme specificity. We illustrate the high prediction accuracy achieved on two benchmark data sets and the structural insights gained from ASC by a detailed analysis of the family of decarboxylating dehydrogenases. The ASC web service is available at http://asc.informatik.uni-tuebingen.de/.'),
(84476, 2010, 'plos', 'Knots: attractive places with high path tortuosity in mouse open field exploration', 'Dvorkin, Anna|Szechtman, Henry|Golani, Ilan', 'Department of Zoology, Tel Aviv University, Tel Aviv, Israel. dvorkin@mcmaster.ca|Department of Zoology, Tel Aviv University, Tel Aviv, Israel. dvorkin@mcmaster.ca|Department of Zoology, Tel Aviv University, Tel Aviv, Israel. dvorkin@mcmaster.ca', 'Israel|Israel|Israel', 13, 'Algorithms|Animals|Behavior, Animal|Computational Biology|Exploratory Behavior|Linear Models|Mice|Mice, Inbred C57BL|Models, Biological|Sodium Chloride|Stress, Physiological', 'Journal Article', '10.1371/journal.pcbi.1000638', '20090825', 'When introduced into a novel environment, mammals establish in it a preferred place marked by the highest number of visits and highest cumulative time spent in it. Examination of exploratory behavior in reference to this home base highlights important features of its organization. It might therefore be fruitful to search for other types of marked places in mouse exploratory behavior and examine their influence on overall behavior.Examination of path curvatures of mice exploring a large empty arena revealed the presence of circumscribed locales marked by the performance of tortuous paths full of twists and turns. We term these places knots, and the behavior performed in them-knot-scribbling. There is typically no more than one knot per session, it has distinct boundaries and it is maintained both within and across sessions. Knots are mostly situated in the place of introduction into the arena, here away from walls. Knots are not characterized by the features of a home base, except for a high speed during inbound and a low speed during outbound paths. The establishment of knots is enhanced by injecting the mouse with saline and placing it in an exposed portion of the arena, suggesting that stress and the arousal associated with it consolidate a long-term contingency between a particular locale and knot-scribbling.In an environment devoid of proximal cues mice mark a locale associated with arousal by twisting and turning in it. This creates a self-generated, often centrally located landmark. The tortuosity of the path traced during the behavior implies almost concurrent multiple views of the environment. Knot-scribbling could therefore function as a way to obtain an overview of the entire environment, allowing re-calibration of the mouses locale map and compass directions. The rich vestibular input generated by scribbling could improve the interpretation of the visual scene.'),
(84477, 2010, 'plos', 'How synchronization protects from noise', 'Tabareau, Nicolas|Slotine, Jean-Jacques|Pham, Quang-Cuong', 'LPPA, Collège de France, Paris, France. nicolas.tabareau@inria.fr|LPPA, Collège de France, Paris, France. nicolas.tabareau@inria.fr|LPPA, Collège de France, Paris, France. nicolas.tabareau@inria.fr', 'France|France|France', 72, 'Algorithms|Computer Simulation|Membrane Potentials|Models, Biological|Neurons|Nonlinear Dynamics|Systems Biology|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1000637', '20090826', 'THE FUNCTIONAL ROLE OF SYNCHRONIZATION HAS ATTRACTED MUCH INTEREST AND DEBATE: in particular, synchronization may allow distant sites in the brain to communicate and cooperate with each other, and therefore may play a role in temporal binding, in attention or in sensory-motor integration mechanisms. In this article, we study another role for synchronization: the so-called collective enhancement of precision. We argue, in a full nonlinear dynamical context, that synchronization may help protect interconnected neurons from the influence of random perturbations-intrinsic neuronal noise-which affect all neurons in the nervous system. More precisely, our main contribution is a mathematical proof that, under specific, quantified conditions, the impact of noise on individual interconnected systems and on their spatial mean can essentially be cancelled through synchronization. This property then allows reliable computations to be carried out even in the presence of significant noise (as experimentally found e.g., in retinal ganglion cells in primates). This in turn is key to obtaining meaningful downstream signals, whether in terms of precisely-timed interaction (temporal coding), population coding, or frequency coding. Similar concepts may be applicable to questions of noise and variability in systems biology.'),
(84478, 2010, 'plos', 'An integrative -omics approach to identify functional sub-networks in human colorectal cancer', 'Nibbe, Rod K|Koyutürk, Mehmet|Chance, Mark R', 'Center for Proteomics & Bioinformatics, Case Western Reserve University, Cleveland, Ohio, United States of America. rkn6@case.edu|Center for Proteomics & Bioinformatics, Case Western Reserve University, Cleveland, Ohio, United States of America. rkn6@case.edu|Center for Proteomics & Bioinformatics, Case Western Reserve University, Cleveland, Ohio, United States of America. rkn6@case.edu', 'United States|United States|United States', 126, 'Colorectal Neoplasms|Databases, Protein|Gene Expression Regulation, Neoplastic|Gene Regulatory Networks|Humans|Models, Genetic|Proteomics|RNA, Messenger|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000639', '20090827', 'Emerging evidence indicates that gene products implicated in human cancers often cluster together in hot spots in protein-protein interaction (PPI) networks. Additionally, small sub-networks within PPI networks that demonstrate synergistic differential expression with respect to tumorigenic phenotypes were recently shown to be more accurate classifiers of disease progression when compared to single targets identified by traditional approaches. However, many of these studies rely exclusively on mRNA expression data, a useful but limited measure of cellular activity. Proteomic profiling experiments provide information at the post-translational level, yet they generally screen only a limited fraction of the proteome. Here, we demonstrate that integration of these complementary data sources with a proteomics-first approach can enhance the discovery of candidate sub-networks in cancer that are well-suited for mechanistic validation in disease. We propose that small changes in the mRNA expression of multiple genes in the neighborhood of a protein-hub can be synergistically associated with significant changes in the activity of that protein and its network neighbors. Further, we hypothesize that proteomic targets with significant fold change between phenotype and control may be used to seed a search for small PPI sub-networks that are functionally associated with these targets. To test this hypothesis, we select proteomic targets having significant expression changes in human colorectal cancer (CRC) from two independent 2-D gel-based screens. Then, we use random walk based models of network crosstalk and develop novel reference models to identify sub-networks that are statistically significant in terms of their functional association with these proteomic targets. Subsequently, using an information-theoretic measure, we evaluate synergistic changes in the activity of identified sub-networks based on genome-wide screens of mRNA expression in CRC. Cross-classification experiments to predict disease class show excellent performance using only a few sub-networks, underwriting the strength of the proposed approach in discovering relevant and reproducible sub-networks.'),
(84479, 2010, 'plos', 'Associating genes and protein complexes with disease via network propagation', 'Vanunu, Oron|Magger, Oded|Ruppin, Eytan|Shlomi, Tomer|Sharan, Roded', '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.|School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel.', 'Israel|Israel|Israel|Israel|Israel', 524, 'Algorithms|Alzheimer Disease|Databases, Genetic|Diabetes Mellitus|Disease|Genes|Humans|Male|Multiprotein Complexes|Prostatic Neoplasms|Protein Interaction Mapping|Proteins|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000641', '20090828', 'A fundamental challenge in human health is the identification of disease-causing genes. Recently, several studies have tackled this challenge via a network-based approach, motivated by the observation that genes causing the same or similar diseases tend to lie close to one another in a network of protein-protein or functional interactions. However, most of these approaches use only local network information in the inference process and are restricted to inferring single gene associations. Here, we provide a global, network-based method for prioritizing disease genes and inferring protein complex associations, which we call PRINCE. The method is based on formulating constraints on the prioritization function that relate to its smoothness over the network and usage of prior information. We exploit this function to predict not only genes but also protein complex associations with a disease of interest. We test our method on gene-disease association data, evaluating both the prioritization achieved and the protein complexes inferred. We show that our method outperforms extant approaches in both tasks. Using data on 1,369 diseases from the OMIM knowledgebase, our method is able (in a cross validation setting) to rank the true causal gene first for 34% of the diseases, and infer 139 disease-related complexes that are highly coherent in terms of the function, expression and conservation of their member proteins. Importantly, we apply our method to study three multi-factorial diseases for which some causal genes have been found already: prostate cancer, alzheimer and type 2 diabetes mellitus. PRINCEs predictions for these diseases highly match the known literature, suggesting several novel causal genes and protein complexes for further investigation.'),
(84480, 2010, 'plos', 'A Bayesian partition method for detecting pleiotropic and epistatic eQTL modules', 'Zhang, Wei|Zhu, Jun|Schadt, Eric E|Liu, Jun S', 'UBS Equities, Stamford, Connecticut, United States of America.|UBS Equities, Stamford, Connecticut, United States of America.|UBS Equities, Stamford, Connecticut, United States of America.|UBS Equities, Stamford, Connecticut, United States of America.', 'United States|United States|United States|United States', 54, 'Bayes Theorem|Cluster Analysis|Computational Biology|Computer Simulation|Genotype|Linkage Disequilibrium|Models, Genetic|Phenotype|Quantitative Trait Loci|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1000642', '20090830', 'Studies of the relationship between DNA variation and gene expression variation, often referred to as expression quantitative trait loci (eQTL) mapping, have been conducted in many species and resulted in many significant findings. Because of the large number of genes and genetic markers in such analyses, it is extremely challenging to discover how a small number of eQTLs interact with each other to affect mRNA expression levels for a set of co-regulated genes. We present a Bayesian method to facilitate the task, in which co-expressed genes mapped to a common set of markers are treated as a module characterized by latent indicator variables. A Markov chain Monte Carlo algorithm is designed to search simultaneously for the module genes and their linked markers. We show by simulations that this method is more powerful for detecting true eQTLs and their target genes than traditional QTL mapping methods. We applied the procedure to a data set consisting of gene expression and genotypes for 112 segregants of S. cerevisiae. Our method identified modules containing genes mapped to previously reported eQTL hot spots, and dissected these large eQTL hot spots into several modules corresponding to possibly different biological functions or primary and secondary responses to regulatory perturbations. In addition, we identified nine modules associated with pairs of eQTLs, of which two have been previously reported. We demonstrated that one of the novel modules containing many daughter-cell expressed genes is regulated by AMN1 and BPH1. In conclusion, the Bayesian partition method which simultaneously considers all traits and all markers is more powerful for detecting both pleiotropic and epistatic effects based on both simulated and empirical data.'),
(84481, 2010, 'plos', 'Optimizing metapopulation sustainability through a checkerboard strategy', 'Zion, Yossi Ben|Yaari, Gur|Shnerb, Nadav M', 'Department of Physics, Bar-Ilan University, Ramat-Gan, Israel. benzioy@mail.biu.ac.il|Department of Physics, Bar-Ilan University, Ramat-Gan, Israel. benzioy@mail.biu.ac.il|Department of Physics, Bar-Ilan University, Ramat-Gan, Israel. benzioy@mail.biu.ac.il', 'Israel|Israel|Israel', 20, 'Computer Simulation|Models, Theoretical|Population Dynamics|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1000643', '20098493', 'The persistence of a spatially structured population is determined by the rate of dispersal among habitat patches. If the local dynamic at the subpopulation level is extinction-prone, the system viability is maximal at intermediate connectivity where recolonization is allowed, but full synchronization that enables correlated extinction is forbidden. Here we developed and used an algorithm for agent-based simulations in order to study the persistence of a stochastic metapopulation. The effect of noise is shown to be dramatic, and the dynamics of the spatial population differs substantially from the predictions of deterministic models. This has been validated for the stochastic versions of the logistic map, the Ricker map and the Nicholson-Bailey host-parasitoid system. To analyze the possibility of extinction, previous studies were focused on the attractiveness (Lyapunov exponent) of stable solutions and the structure of their basin of attraction (dependence on initial population size). Our results suggest that these features are of secondary importance in the presence of stochasticity. Instead, optimal sustainability is achieved when decoherence is maximal. Individual-based simulations of metapopulations of different sizes, dimensions and noise types, show that the systems lifetime peaks when it displays checkerboard spatial patterns. This conclusion is supported by the results of a recently published Drosophila experiment. The checkerboard strategy provides a technique for the manipulation of migration rates (e.g., by constructing corridors) in order to affect the persistence of a metapopulation. It may be used in order to minimize the risk of extinction of an endangered species, or to maximize the efficiency of an eradication campaign.'),
(84482, 2010, 'plos', 'Quantitative modeling of GRK-mediated beta2AR regulation', 'Vayttaden, Sharat J|Friedman, Jacqueline|Tran, Tuan M|Rich, Thomas C|Dessauer, Carmen W|Clark, Richard B', 'Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas, United States of America.|Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas, United States of America.|Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas, United States of America.|Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas, United States of America.|Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas, United States of America.|Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas, United States of America.', 'United States|United States|United States|United States|United States|United States', 16, 'Arrestin|Cells, Cultured|Computational Biology|Computer Simulation|Drug Partial Agonism|G-Protein-Coupled Receptor Kinases|Humans|Kinetics|Models, Biological|Phosphoric Monoester Hydrolases|Phosphorylation|Protein Binding|Receptors, Adrenergic, beta-2|Reproducibility of Results|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000647', '20098494', 'We developed a unified model of the GRK-mediated beta2 adrenergic receptor (beta2AR) regulation that simultaneously accounts for six different biochemical measurements of the system obtained over a wide range of agonist concentrations. Using a single deterministic model we accounted for (1) GRK phosphorylation in response to various full and partial agonists, (2) dephosphorylation of the GRK site on the beta2AR, (3) beta2AR internalization, (4) recycling of the beta2AR post isoproterenol treatment, (5) beta2AR desensitization, and (6) beta2AR resensitization. Simulations of our model show that plasma membrane dephosphorylation and recycling of the phosphorylated receptor are necessary to adequately account for the measured dephosphorylation kinetics. We further used the model to predict the consequences of (1) modifying rates such as GRK phosphorylation of the receptor, arrestin binding and dissociation from the receptor, and receptor dephosphorylation that should reflect effects of knockdowns and overexpressions of these components, and (2) varying concentration and frequency of agonist stimulation seen by the beta2AR to better mimic hormonal, neurophysiological and pharmacological stimulations of the beta2AR. Exploring the consequences of rapid pulsatile agonist stimulation, we found that although resensitization was rapid, the beta2AR system retained the memory of the previous stimuli and desensitized faster and much more strongly in response to subsequent stimuli. The latent memory that we predict is due to slower membrane dephosphorylation, which allows for progressive accumulation of phosphorylated receptor on the surface. This primes the receptor for faster arrestin binding on subsequent agonist activation leading to a greater extent of desensitization. In summary, the model is unique in accounting for the behavior of the beta2AR system across multiple types of biochemical measurements using a single set of experimentally constrained parameters. It also provides insight into how the signaling machinery can retain memory of prior stimulation long after near complete resensitization has been achieved.'),
(84483, 2010, 'plos', 'A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology', 'Durrant, Jacob D|Amaro, Rommie E|Xie, Lei|Urbaniak, Michael D|Ferguson, Michael A J|Haapalainen, Antti|Chen, Zhijun|Di Guilmi, Anne Marie|Wunder, Frank|Bourne, Philip E|McCammon, J Andrew', 'Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America. jdurrant@ucsd.edu|Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America. jdurrant@ucsd.edu|Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America. jdurrant@ucsd.edu|Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America. jdurrant@ucsd.edu|Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America. jdurrant@ucsd.edu|Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America. jdurrant@ucsd.edu|Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America. jdurrant@ucsd.edu|Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America. jdurrant@ucsd.edu|Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America. jdurrant@ucsd.edu|Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America. jdurrant@ucsd.edu|Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America. jdurrant@ucsd.edu', 'United States|United States|United States|United States|United States|United States|United States|Un', 73, 'Algorithms|Catalytic Domain|Cluster Analysis|Computational Biology|Computer Simulation|Databases, Protein|Drug Discovery|Humans|Models, Biological|Proteins|Sequence Homology, Amino Acid|Structural Homology, Protein', 'Journal Article', '10.1371/journal.pcbi.1000648', '20098496', 'Conventional drug design embraces the one gene, one drug, one disease philosophy. Polypharmacology, which focuses on multi-target drugs, has emerged as a new paradigm in drug discovery. The rational design of drugs that act via polypharmacological mechanisms can produce compounds that exhibit increased therapeutic potency and against which resistance is less likely to develop. Additionally, identifying multiple protein targets is also critical for side-effect prediction. One third of potential therapeutic compounds fail in clinical trials or are later removed from the market due to unacceptable side effects often caused by off-target binding. In the current work, we introduce a multidimensional strategy for the identification of secondary targets of known small-molecule inhibitors in the absence of global structural and sequence homology with the primary target protein. To demonstrate the utility of the strategy, we identify several targets of 4,5-dihydroxy-3-(1-naphthyldiazenyl)-2,7-naphthalenedisulfonic acid, a known micromolar inhibitor of Trypanosoma brucei RNA editing ligase 1. As it is capable of identifying potential secondary targets, the strategy described here may play a useful role in future efforts to reduce drug side effects and/or to increase polypharmacology.'),
(84484, 2010, 'plos', 'Blurring of high-resolution data shows that the effect of intrinsic nucleosome occupancy on transcription factor binding is mostly regional, not local', 'Goh, Wee Siong|Orlov, Yuriy|Li, Jingmei|Clarke, Neil D', 'Computational and Systems Biology, Genome Institute of Singapore, Singapore.|Computational and Systems Biology, Genome Institute of Singapore, Singapore.|Computational and Systems Biology, Genome Institute of Singapore, Singapore.|Computational and Systems Biology, Genome Institute of Singapore, Singapore.', 'Singapore|Singapore|Singapore|Singapore', 20, 'Area Under Curve|Binding Sites|Chromatin|Chromatin Immunoprecipitation|Cluster Analysis|Computational Biology|Computer Simulation|DNA|Databases, Protein|Models, Genetic|Nucleosomes|Polymerase Chain Reaction|Protein Interaction Domains and Motifs|ROC Curve|Saccharomyces|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000649', '20098497', 'Genome wide maps of nucleosome occupancy in yeast have recently been produced through deep sequencing of nuclease-protected DNA. These maps have been obtained from both crosslinked and uncrosslinked chromatin in vivo, and from chromatin assembled from genomic DNA and nucleosomes in vitro. Here, we analyze these maps in combination with existing ChIP-chip data, and with new ChIP-qPCR experiments reported here. We show that the apparent nucleosome density in crosslinked chromatin, when compared to uncrosslinked chromatin, is preferentially increased at transcription factor (TF) binding sites, suggesting a strategy for mapping generic transcription factor binding sites that would not require immunoprecipitation of a particular factor. We also confirm previous conclusions that the intrinsic, sequence dependent binding of nucleosomes helps determine the localization of TF binding sites. However, we find that the association between low nucleosome occupancy and TF binding is typically greater if occupancy at a site is averaged over a 600bp window, rather than using the occupancy at the binding site itself. We have also incorporated intrinsic nucleosome binding occupancies as weights in a computational model for TF binding, and by this measure as well we find better prediction if the high resolution nucleosome occupancy data is averaged over 600bp. We suggest that the intrinsic DNA binding specificity of nucleosomes plays a role in TF binding site selection not so much through the specification of precise nucleosome positions that permit or occlude binding, but rather through the creation of low occupancy regions that can accommodate competition from TFs through rearrangement of nucleosomes.'),
(84485, 2010, 'plos', 'Hydrogen-bond driven loop-closure kinetics in unfolded polypeptide chains', 'Daidone, Isabella|Neuweiler, Hannes|Doose, Sören|Sauer, Markus|Smith, Jeremy C', 'Interdisciplinary Center for Scientific Computing, University of Heidelberg, Heidelberg, Germany. Isabella.Daidone@iwr.uni-heidelberg.de|Interdisciplinary Center for Scientific Computing, University of Heidelberg, Heidelberg, Germany. Isabella.Daidone@iwr.uni-heidelberg.de|Interdisciplinary Center for Scientific Computing, University of Heidelberg, Heidelberg, Germany. Isabella.Daidone@iwr.uni-heidelberg.de|Interdisciplinary Center for Scientific Computing, University of Heidelberg, Heidelberg, Germany. Isabella.Daidone@iwr.uni-heidelberg.de|Interdisciplinary Center for Scientific Computing, University of Heidelberg, Heidelberg, Germany. Isabella.Daidone@iwr.uni-heidelberg.de', 'Germany|Germany|Germany|Germany|Germany', 41, 'Hydrogen Bonding|Hydrophobic and Hydrophilic Interactions|Kinetics|Molecular Dynamics Simulation|Peptides|Protein Folding|Protein Structure, Secondary|Spectrometry, Fluorescence', 'Journal Article', '10.1371/journal.pcbi.1000645', '20098498', 'Characterization of the length dependence of end-to-end loop-closure kinetics in unfolded polypeptide chains provides an understanding of early steps in protein folding. Here, loop-closure in poly-glycine-serine peptides is investigated by combining single-molecule fluorescence spectroscopy with molecular dynamics simulation. For chains containing more than 10 peptide bonds loop-closing rate constants on the 20-100 nanosecond time range exhibit a power-law length dependence. However, this scaling breaks down for shorter peptides, which exhibit slower kinetics arising from a perturbation induced by the dye reporter system used in the experimental setup. The loop-closure kinetics in the longer peptides is found to be determined by the formation of intra-peptide hydrogen bonds and transient beta-sheet structure, that accelerate the search for contacts among residues distant in sequence relative to the case of a polypeptide chain in which hydrogen bonds cannot form. Hydrogen-bond-driven polypeptide-chain collapse in unfolded peptides under physiological conditions found here is not only consistent with hierarchical models of protein folding, that highlights the importance of secondary structure formation early in the folding process, but is also shown to speed up the search for productive folding events.'),
(84486, 2010, 'plos', 'A neurophysiologically plausible population code model for feature integration explains visual crowding', 'van den Berg, Ronald|Roerdink, Jos B T M|Cornelissen, Frans W', 'Institute of Mathematics and Computing Science, University of Groningen, Groningen, The Netherlands. rvdberg@cpu.bcm.edu|Institute of Mathematics and Computing Science, University of Groningen, Groningen, The Netherlands. rvdberg@cpu.bcm.edu|Institute of Mathematics and Computing Science, University of Groningen, Groningen, The Netherlands. rvdberg@cpu.bcm.edu', 'Netherlands|Netherlands|Netherlands', 45, 'Anisotropy|Computational Biology|Computer Simulation|Fovea Centralis|Humans|Models, Neurological|Photic Stimulation|Visual Fields', 'Journal Article', '10.1371/journal.pcbi.1000646', '20098499', 'An object in the peripheral visual field is more difficult to recognize when surrounded by other objects. This phenomenon is called crowding. Crowding places a fundamental constraint on human vision that limits performance on numerous tasks. It has been suggested that crowding results from spatial feature integration necessary for object recognition. However, in the absence of convincing models, this theory has remained controversial. Here, we present a quantitative and physiologically plausible model for spatial integration of orientation signals, based on the principles of population coding. Using simulations, we demonstrate that this model coherently accounts for fundamental properties of crowding, including critical spacing, compulsory averaging, and a foveal-peripheral anisotropy. Moreover, we show that the model predicts increased responses to correlated visual stimuli. Altogether, these results suggest that crowding has little immediate bearing on object recognition but is a by-product of a general, elementary integration mechanism in early vision aimed at improving signal quality.'),
(84487, 2010, 'plos', 'SnugDock: paratope structural optimization during antibody-antigen docking compensates for errors in antibody homology models', 'Sircar, Aroop|Gray, Jeffrey J', 'Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.|Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.', 'United States|United States', 71, 'Algorithms|Antibodies|Antigen-Antibody Complex|Antigens|Binding Sites, Antibody|Models, Molecular|Protein Binding|Structural Homology, Protein', 'Journal Article', '10.1371/journal.pcbi.1000644', '20098500', 'High resolution structures of antibody-antigen complexes are useful for analyzing the binding interface and to make rational choices for antibody engineering. When a crystallographic structure of a complex is unavailable, the structure must be predicted using computational tools. In this work, we illustrate a novel approach, named SnugDock, to predict high-resolution antibody-antigen complex structures by simultaneously structurally optimizing the antibody-antigen rigid-body positions, the relative orientation of the antibody light and heavy chains, and the conformations of the six complementarity determining region loops. This approach is especially useful when the crystal structure of the antibody is not available, requiring allowances for inaccuracies in an antibody homology model which would otherwise frustrate rigid-backbone docking predictions. Local docking using SnugDock with the lowest-energy RosettaAntibody homology model produced more accurate predictions than standard rigid-body docking. SnugDock can be combined with ensemble docking to mimic conformer selection and induced fit resulting in increased sampling of diverse antibody conformations. The combined algorithm produced four medium (Critical Assessment of PRediction of Interactions-CAPRI rating) and seven acceptable lowest-interface-energy predictions in a test set of fifteen complexes. Structural analysis shows that diverse paratope conformations are sampled, but docked paratope backbones are not necessarily closer to the crystal structure conformations than the starting homology models. The accuracy of SnugDock predictions suggests a new genre of general docking algorithms with flexible binding interfaces targeted towards making homology models useful for further high-resolution predictions.'),
(84488, 2010, 'plos', 'Getting started in structural phylogenomics', 'Sjölander, Kimmen', 'Department of Bioengineering, University of California, Berkeley, Berkeley, California, United States of America. kimmen@berkeley.edu', 'United States', 9, 'Genomics|Phylogeny', 'Journal Article', '10.1371/journal.pcbi.1000621', '20126522', '-'),
(84489, 2010, 'plos', 'Functional characterization of transcription factor motifs using cross-species comparison across large evolutionary distances', 'Kim, Jaebum|Cunningham, Ryan|James, Brian|Wyder, Stefan|Gibson, Joshua D|Niehuis, Oliver|Zdobnov, Evgeny M|Robertson, Hugh M|Robinson, Gene E|Werren, John H|Sinha, Saurabh', 'Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.|Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Amino Acid Motifs|Amino Acid Sequence|Animals|Bees|Behavior, Animal|Computational Biology|Conserved Sequence|Drosophila melanogaster|Genome, Insect|Insect Proteins|Models, Genetic|Molecular Sequence Data|Species Specificity|Transcription Factors|Wasps', 'Journal Article', '10.1371/journal.pcbi.1000652', '20126523', 'We address the problem of finding statistically significant associations between cis-regulatory motifs and functional gene sets, in order to understand the biological roles of transcription factors. We develop a computational framework for this task, whose features include a new statistical score for motif scanning, the use of different scores for predicting targets of different motifs, and new ways to deal with redundancies among significant motif-function associations. This framework is applied to the recently sequenced genome of the jewel wasp, Nasonia vitripennis, making use of the existing knowledge of motifs and gene annotations in another insect genome, that of the fruitfly. The framework uses cross-species comparison to improve the specificity of its predictions, and does so without relying upon non-coding sequence alignment. It is therefore well suited for comparative genomics across large evolutionary divergences, where existing alignment-based methods are not applicable. We also apply the framework to find motifs associated with socially regulated gene sets in the honeybee, Apis mellifera, using comparisons with Nasonia, a solitary species, to identify honeybee-specific associations.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84490, 2010, 'plos', 'Live Coverage of Intelligent Systems for Molecular Biology/European Conference on computational biology (ISMB/ECCB) 2009', 'Lister, Allyson L|Datta, Ruchira S|Hofmann, Oliver|Krause, Roland|Kuhn, Michael|Roth, Bettina|Schneider, Reinhard', 'Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom.|Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom.|Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom.|Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom.|Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom.|Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom.|Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Artificial Intelligence|Blogging|Computational Biology|Congresses as Topic|Humans|Molecular Biology', 'Journal Article', '10.1371/journal.pcbi.1000640', '20126524', '-'),
(84491, 2010, 'plos', 'Live coverage of scientific conferences using web technologies', 'Lister, Allyson L|Datta, Ruchira S|Hofmann, Oliver|Krause, Roland|Kuhn, Michael|Roth, Bettina|Schneider, Reinhard', 'Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom. a.l.lister@newcastle.ac.uk|Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom. a.l.lister@newcastle.ac.uk|Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom. a.l.lister@newcastle.ac.uk|Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom. a.l.lister@newcastle.ac.uk|Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom. a.l.lister@newcastle.ac.uk|Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom. a.l.lister@newcastle.ac.uk|Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom. a.l.lister@newcastle.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Congresses as Topic|Humans|Internet', 'Journal Article', '10.1371/journal.pcbi.1000563', '20126525', '-'),
(84492, 2010, 'plos', 'Identification of crosstalk between phosphoprotein signaling pathways in RAW 2647 macrophage cells', 'Gupta, Shakti|Maurya, Mano Ram|Subramaniam, Shankar', 'Department of Bioengineering, University of California, San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California, San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California, San Diego, La Jolla, California, United States of America.', 'United States|United States|United States', 0, 'Animals|Cell Line, Tumor|Computational Biology|Gene Regulatory Networks|Macrophages|Mice|Models, Biological|Phosphoproteins|Reproducibility of Results|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000654', '20126526', 'Signaling pathways mediate the effect of external stimuli on gene expression in cells. The signaling proteins in these pathways interact with each other and their phosphorylation levels often serve as indicators for the activity of signaling pathways. Several signaling pathways have been identified in mammalian cells but the crosstalk between them is not well understood. Alliance for Cellular Signaling (AfCS) has measured time-course data in RAW 264.7 macrophage cells on important phosphoproteins, such as the mitogen-activated protein kinases (MAPKs) and signal transducer and activator of transcription (STATs), in single- and double-ligand stimulation experiments for 22 ligands. In the present work, we have used a data-driven approach to analyze the AfCS data to decipher the interactions and crosstalk between signaling pathways in stimulated macrophage cells. We have used dynamic mapping to develop a predictive model using a partial least squares approach. Significant interactions were selected through statistical hypothesis testing and were used to reconstruct the phosphoprotein signaling network. The proposed data-driven approach is able to identify most of the known signaling interactions such as protein kinase B (Akt) --> glycogen synthase kinase 3alpha/beta (GSKalpha/beta) etc., and predicts potential novel interactions such as P38 --> RSK and GSK --> ezrin/radixin/moesin. We have also shown that the model has good predictive power for extrapolation. Our novel approach captures the temporal causality and directionality in intracellular signaling pathways. Further, case specific analysis of the phosphoproteins in the network has led us to propose hypothesis about inhibition (phosphorylation) of GSKalpha/beta via P38.'),
(84493, 2010, 'plos', 'Recombination rate and selection strength in HIV intra-patient evolution', 'Neher, Richard A|Leitner, Thomas', 'Kavli Institute for Theoretical Physics, University of California, Santa Barbara, California, United States of America. neher@kitp.ucsb.edu|Kavli Institute for Theoretical Physics, University of California, Santa Barbara, California, United States of America. neher@kitp.ucsb.edu', 'United States|United States', 109, 'Algorithms|Cluster Analysis|Computational Biology|Evolution, Molecular|HIV|HIV Infections|Host-Pathogen Interactions|Mutation|Recombination, Genetic|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000660', '20126527', 'The evolutionary dynamics of HIV during the chronic phase of infection is driven by the host immune response and by selective pressures exerted through drug treatment. To understand and model the evolution of HIV quantitatively, the parameters governing genetic diversification and the strength of selection need to be known. While mutation rates can be measured in single replication cycles, the relevant effective recombination rate depends on the probability of coinfection of a cell with more than one virus and can only be inferred from population data. However, most population genetic estimators for recombination rates assume absence of selection and are hence of limited applicability to HIV, since positive and purifying selection are important in HIV evolution. Yet, little is known about the distribution of selection differentials between individual viruses and the impact of single polymorphisms on viral fitness. Here, we estimate the rate of recombination and the distribution of selection coefficients from time series sequence data tracking the evolution of HIV within single patients. By examining temporal changes in the genetic composition of the population, we estimate the effective recombination to be rho = 1.4+/-0.6 x 10(-5) recombinations per site and generation. Furthermore, we provide evidence that the selection coefficients of at least 15% of the observed non-synonymous polymorphisms exceed 0.8% per generation. These results provide a basis for a more detailed understanding of the evolution of HIV. A particularly interesting case is evolution in response to drug treatment, where recombination can facilitate the rapid acquisition of multiple resistance mutations. With the methods developed here, more precise and more detailed studies will be possible as soon as data with higher time resolution and greater sample sizes are available.'),
(84494, 2010, 'plos', 'Modeling magnification and anisotropy in the primate foveal confluence', 'Schira, Mark M|Tyler, Christopher W|Spehar, Branka|Breakspear, Michael', 'School of Psychiatry and The Black Dog Institute, University of New South Wales, Sydney Australia. mschira@science.unsw.edu.au|School of Psychiatry and The Black Dog Institute, University of New South Wales, Sydney Australia. mschira@science.unsw.edu.au|School of Psychiatry and The Black Dog Institute, University of New South Wales, Sydney Australia. mschira@science.unsw.edu.au|School of Psychiatry and The Black Dog Institute, University of New South Wales, Sydney Australia. mschira@science.unsw.edu.au', 'Australia|Australia|Australia|Australia', 37, 'Algorithms|Anisotropy|Fovea Centralis|Humans|Models, Neurological|Retina|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1000651', '20126528', 'A basic organizational principle of the primate visual system is that it maps the visual environment repeatedly and retinotopically onto cortex. Simple algebraic models can be used to describe the projection from visual space to cortical space not only for V1, but also for the complex of areas V1, V2 and V3. Typically a conformal (angle-preserving) projection ensuring local isotropy is regarded as ideal and primate visual cortex is often regarded as an approximation of this ideal. However, empirical data show systematic deviations from this ideal that are especially relevant in the foveal projection. The aims of this study were to map the nature of anisotropy predicted by existing models, to investigate the optimization targets faced by different types of retino-cortical maps, and finally to propose a novel map that better models empirical data than other candidates. The retino-cortical map can be optimized towards a space-conserving homogenous representation or a quasi-conformal mapping. The latter would require a significantly enlarged representation of specific parts of the cortical maps. In particular it would require significant enlargement of parafoveal V2 and V3 which is not supported by empirical data. Further, the recently published principal layout of the foveal singularity cannot be explained by existing models. We suggest a new model that accurately describes foveal data, minimizing cortical surface area in the periphery but suggesting that local isotropy dominates the most foveal part at the expense of additional cortical surface. The foveal confluence is an important example of the detailed trade-offs between the compromises required for the mapping of environmental space to a complex of neighboring cortical areas. Our models demonstrate that the organization follows clear morphogenetic principles that are essential for our understanding of foveal vision in daily life.'),
(84495, 2010, 'plos', 'FluTE, a publicly available stochastic influenza epidemic simulation model', 'Chao, Dennis L|Halloran, M Elizabeth|Obenchain, Valerie J|Longini, Ira M', 'Center for Statistics and Quantitative Infectious Diseases/Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. dchao@fhcrc.org|Center for Statistics and Quantitative Infectious Diseases/Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. dchao@fhcrc.org|Center for Statistics and Quantitative Infectious Diseases/Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. dchao@fhcrc.org|Center for Statistics and Quantitative Infectious Diseases/Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. dchao@fhcrc.org', 'United States|United States|United States|United States', 0, 'Computer Simulation|Disease Outbreaks|Humans|Influenza, Human|Models, Biological|Prevalence|Software|Stochastic Processes|United States', 'Journal Article', '10.1371/journal.pcbi.1000656', '20126529', 'Mathematical and computer models of epidemics have contributed to our understanding of the spread of infectious disease and the measures needed to contain or mitigate them. To help prepare for future influenza seasonal epidemics or pandemics, we developed a new stochastic model of the spread of influenza across a large population. Individuals in this model have realistic social contact networks, and transmission and infections are based on the current state of knowledge of the natural history of influenza. The model has been calibrated so that outcomes are consistent with the 1957/1958 Asian A(H2N2) and 2009 pandemic A(H1N1) influenza viruses. We present examples of how this model can be used to study the dynamics of influenza epidemics in the United States and simulate how to mitigate or delay them using pharmaceutical interventions and social distancing measures. Computer simulation models play an essential role in informing public policy and evaluating pandemic preparedness plans. We have made the source code of this model publicly available to encourage its use and further development.'),
(84496, 2010, 'plos', 'Acute effects of sex steroid hormones on susceptibility to cardiac arrhythmias: a simulation study', 'Yang, Pei-Chi|Kurokawa, Junko|Furukawa, Tetsushi|Clancy, Colleen E', 'Department of Pharmacology, University of California, Davis, Davis, California, United States of America.|Department of Pharmacology, University of California, Davis, Davis, California, United States of America.|Department of Pharmacology, University of California, Davis, Davis, California, United States of America.|Department of Pharmacology, University of California, Davis, Davis, California, United States of America.', 'United States|United States|United States|United States', 40, 'Action Potentials|Animals|Anti-Arrhythmia Agents|Arrhythmias, Cardiac|Cells, Cultured|Computer Simulation|Disease Susceptibility|Electrocardiography|Estrogens|Female|Gonadal Steroid Hormones|Guinea Pigs|Male|Markov Chains|Menstrual Cycle|Myocytes, Cardiac|Piperidines|Potassium Channels|Progesterone|Pyridines|Testosterone', 'Journal Article', '10.1371/journal.pcbi.1000658', '20126530', 'Acute effects of sex steroid hormones likely contribute to the observation that post-pubescent males have shorter QT intervals than females. However, the specific role for hormones in modulating cardiac electrophysiological parameters and arrhythmia vulnerability is unclear. Here we use a computational modeling approach to incorporate experimentally measured effects of physiological concentrations of testosterone, estrogen and progesterone on cardiac ion channel targets. We then study the hormone effects on ventricular cell and tissue dynamics comprised of Faber-Rudy computational models. The female model predicts changes in action potential duration (APD) at different stages of the menstrual cycle that are consistent with clinically observed QT interval fluctuations. The male model predicts shortening of APD and QT interval at physiological testosterone concentrations. The model suggests increased susceptibility to drug-induced arrhythmia when estradiol levels are high, while testosterone and progesterone are apparently protective. Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval. The simulations also indicate that acute effects of estrogen are not alone sufficient to cause arrhythmia triggers and explain the increased risk of females to Torsades de Pointes. Our results suggest that acute effects of sex steroid hormones on cardiac ion channels are sufficient to account for some aspects of gender specific susceptibility to long-QT linked arrhythmias.'),
(84497, 2010, 'plos', 'Automatic assignment of EC numbers', 'Egelhofer, Volker|Schomburg, Ida|Schomburg, Dietmar', 'Department of Bioinformatics and Biochemistry, Technical University Braunschweig, Braunschweig, Germany. volker.egelhofer@univie.ac.at|Department of Bioinformatics and Biochemistry, Technical University Braunschweig, Braunschweig, Germany. volker.egelhofer@univie.ac.at|Department of Bioinformatics and Biochemistry, Technical University Braunschweig, Braunschweig, Germany. volker.egelhofer@univie.ac.at', 'Germany|Germany|Germany', 0, 'Computational Biology|Databases, Protein|Enzymes|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000661', '20126531', 'A wide range of research areas in molecular biology and medical biochemistry require a reliable enzyme classification system, e.g., drug design, metabolic network reconstruction and system biology. When research scientists in the above mentioned areas wish to unambiguously refer to an enzyme and its function, the EC number introduced by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (IUBMB) is used. However, each and every one of these applications is critically dependent upon the consistency and reliability of the underlying data for success. We have developed tools for the validation of the EC number classification scheme. In this paper, we present validated data of 3788 enzymatic reactions including 229 sub-subclasses of the EC classification system. Over 80% agreement was found between our assignment and the EC classification. For 61 (i.e., only 2.5%) reactions we found that their assignment was inconsistent with the rules of the nomenclature committee, they have to be transferred to other sub-subclasses. We demonstrate that our validation results can be used to initiate corrections and improvements to the EC number classification scheme.'),
(84498, 2010, 'plos', 'Axonal velocity distributions in neural field equations', 'Bojak, Ingo|Liley, David T J', 'Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Radboud University Nijmegen, Nijmegen, The Netherlands. i.bojak@donders.ru.nl|Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Radboud University Nijmegen, Nijmegen, The Netherlands. i.bojak@donders.ru.nl', 'Netherlands|Netherlands', 42, 'Algorithms|Animals|Axons|Cerebral Cortex|Chi-Square Distribution|Computer Simulation|Corpus Callosum|Humans|Models, Neurological|Nerve Fibers, Myelinated|Rats|Synapses', 'Journal Article', '10.1371/journal.pcbi.1000653', '20126532', 'By modelling the average activity of large neuronal populations, continuum mean field models (MFMs) have become an increasingly important theoretical tool for understanding the emergent activity of cortical tissue. In order to be computationally tractable, long-range propagation of activity in MFMs is often approximated with partial differential equations (PDEs). However, PDE approximations in current use correspond to underlying axonal velocity distributions incompatible with experimental measurements. In order to rectify this deficiency, we here introduce novel propagation PDEs that give rise to smooth unimodal distributions of axonal conduction velocities. We also argue that velocities estimated from fibre diameters in slice and from latency measurements, respectively, relate quite differently to such distributions, a significant point for any phenomenological description. Our PDEs are then successfully fit to fibre diameter data from human corpus callosum and rat subcortical white matter. This allows for the first time to simulate long-range conduction in the mammalian brain with realistic, convenient PDEs. Furthermore, the obtained results suggest that the propagation of activity in rat and human differs significantly beyond mere scaling. The dynamical consequences of our new formulation are investigated in the context of a well known neural field model. On the basis of Turing instability analyses, we conclude that pattern formation is more easily initiated using our more realistic propagator. By increasing characteristic conduction velocities, a smooth transition can occur from self-sustaining bulk oscillations to travelling waves of various wavelengths, which may influence axonal growth during development. Our analytic results are also corroborated numerically using simulations on a large spatial grid. Thus we provide here a comprehensive analysis of empirically constrained activity propagation in the context of MFMs, which will allow more realistic studies of mammalian brain activity in the future.'),
(84499, 2010, 'plos', 'Protein interaction networks--more than mere modules', 'Pinkert, Stefan|Schultz, Jörg|Reichardt, Jörg', 'Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.|Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.|Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.', 'Germany|Germany|Germany', 0, 'Algorithms|Computational Biology|Databases, Protein|Humans|Models, Molecular|Protein Interaction Domains and Motifs|Protein Interaction Mapping|Proteins|Two-Hybrid System Techniques', 'Journal Article', '10.1371/journal.pcbi.1000659', '20126533', 'It is widely believed that the modular organization of cellular function is reflected in a modular structure of molecular networks. A common view is that a module in a network is a cohesively linked group of nodes, densely connected internally and sparsely interacting with the rest of the network. Many algorithms try to identify functional modules in protein-interaction networks (PIN) by searching for such cohesive groups of proteins. Here, we present an alternative approach independent of any prior definition of what actually constitutes a module. In a self-consistent manner, proteins are grouped into functional roles if they interact in similar ways with other proteins according to their functional roles. Such grouping may well result in cohesive modules again, but only if the network structure actually supports this. We applied our method to the PIN from the Human Protein Reference Database (HPRD) and found that a representation of the network in terms of cohesive modules, at least on a global scale, does not optimally represent the networks structure because it focuses on finding independent groups of proteins. In contrast, a decomposition into functional roles is able to depict the structure much better as it also takes into account the interdependencies between roles and even allows groupings based on the absence of interactions between proteins in the same functional role. This, for example, is the case for transmembrane proteins, which could never be recognized as a cohesive group of nodes in a PIN. When mapping experimental methods onto the groups, we identified profound differences in the coverage suggesting that our method is able to capture experimental bias in the data, too. For example yeast-two-hybrid data were highly overrepresented in one particular group. Thus, there is more structure in protein-interaction networks than cohesive modules alone and we believe this finding can significantly improve automated function prediction algorithms.'),
(84500, 2010, 'plos', 'A reaction-diffusion model of ROS-induced ROS release in a mitochondrial network', 'Zhou, Lufang|Aon, Miguel A|Almas, Tabish|Cortassa, Sonia|Winslow, Raimond L|ORourke, Brian', 'Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.', 'United States|United States|United States|United States|United States|United States', 103, 'Algorithms|Animals|Computer Simulation|Guinea Pigs|Membrane Potential, Mitochondrial|Microscopy, Fluorescence, Multiphoton|Mitochondria|Models, Biological|Myocytes, Cardiac|Reactive Oxygen Species|Signal Transduction|Superoxides', 'Journal Article', '10.1371/journal.pcbi.1000657', '20126535', 'Loss of mitochondrial function is a fundamental determinant of cell injury and death. In heart cells under metabolic stress, we have previously described how the abrupt collapse or oscillation of the mitochondrial energy state is synchronized across the mitochondrial network by local interactions dependent upon reactive oxygen species (ROS). Here, we develop a mathematical model of ROS-induced ROS release (RIRR) based on reaction-diffusion (RD-RIRR) in one- and two-dimensional mitochondrial networks. The nodes of the RD-RIRR network are comprised of models of individual mitochondria that include a mechanism of ROS-dependent oscillation based on the interplay between ROS production, transport, and scavenging, and incorporating the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and Ca(2+) handling. Local mitochondrial interaction is mediated by superoxide (O2.-) diffusion and the O2.(-)-dependent activation of an inner membrane anion channel (IMAC). In a 2D network composed of 500 mitochondria, model simulations reveal DeltaPsi(m) depolarization waves similar to those observed when isolated guinea pig cardiomyocytes are subjected to a localized laser-flash or antioxidant depletion. The sensitivity of the propagation rate of the depolarization wave to O(2.-) diffusion, production, and scavenging in the reaction-diffusion model is similar to that observed experimentally. In addition, we present novel experimental evidence, obtained in permeabilized cardiomyocytes, confirming that DeltaPsi(m) depolarization is mediated specifically by O2.-). The present work demonstrates that the observed emergent macroscopic properties of the mitochondrial network can be reproduced in a reaction-diffusion model of RIRR. Moreover, the findings have uncovered a novel aspect of the synchronization mechanism, which is that clusters of mitochondria that are oscillating can entrain mitochondria that would otherwise display stable dynamics. The work identifies the fundamental mechanisms leading from the failure of individual organelles to the whole cell, thus it has important implications for understanding cell death during the progression of heart disease.'),
(84501, 2010, 'plos', 'In silico analysis of the apolipoprotein E and the amyloid beta peptide interaction: misfolding induced by frustration of the salt bridge network', 'Luo, Jinghui|Maréchal, Jean-Didier|Wärmländer, Sebastian|Gräslund, Astrid|Perálvarez-Marín, Alex', 'Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.|Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.|Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.|Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.|Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.', 'Sweden|Sweden|Sweden|Sweden|Sweden', 26, 'Alzheimer Disease|Amyloid beta-Peptides|Apolipoproteins E|Computational Biology|Computer Simulation|Humans|Lipid Metabolism|Models, Molecular|Molecular Dynamics Simulation|Protein Binding|Protein Folding|Static Electricity', 'Journal Article', '10.1371/journal.pcbi.1000663', '20140182', 'The relationship between Apolipoprotein E (ApoE) and the aggregation processes of the amyloid beta (A beta) peptide has been shown to be crucial for Alzheimers disease (AD). The presence of the ApoE4 isoform is considered to be a contributing risk factor for AD. However, the detailed molecular properties of ApoE4 interacting with the A beta peptide are unknown, although various mechanisms have been proposed to explain the physiological and pathological role of this relationship. Here, computer simulations have been used to investigate the process of A beta interaction with the N-terminal domain of the human ApoE isoforms (ApoE2, ApoE3 and ApoE4). Molecular docking combined with molecular dynamics simulations have been undertaken to determine the A beta peptide binding sites and the relative stability of binding to each of the ApoE isoforms. Our results show that from the several ApoE isoforms investigated, only ApoE4 presents a misfolded intermediate when bound to A beta. Moreover, the initial alpha-helix used as the A beta peptide model structure also becomes unstructured due to the interaction with ApoE4. These structural changes appear to be related to a rearrangement of the salt bridge network in ApoE4, for which we propose a model. It seems plausible that ApoE4 in its partially unfolded state is incapable of performing the clearance of A beta, thereby promoting amyloid forming processes. Hence, the proposed model can be used to identify potential drug binding sites in the ApoE4-A beta complex, where the interaction between the two molecules can be inhibited.'),
(84502, 2010, 'plos', 'Explicit kinetic heterogeneity: mathematical models for interpretation of deuterium labeling of heterogeneous cell populations', 'Ganusov, Vitaly V|Borghans, José A M|De Boer, Rob J', 'Theoretical Biology, Utrecht University, Utrecht, The Netherlands. vitaly.ganusov@gmail.com|Theoretical Biology, Utrecht University, Utrecht, The Netherlands. vitaly.ganusov@gmail.com|Theoretical Biology, Utrecht University, Utrecht, The Netherlands. vitaly.ganusov@gmail.com', 'Netherlands|Netherlands|Netherlands', 0, 'Algorithms|Cell Growth Processes|Computational Biology|Computer Simulation|Deuterium|Humans|Isotope Labeling|Kinetics|Lymphocytes|Models, Biological|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000666', '20140186', 'Estimation of division and death rates of lymphocytes in different conditions is vital for quantitative understanding of the immune system. Deuterium, in the form of deuterated glucose or heavy water, can be used to measure rates of proliferation and death of lymphocytes in vivo. Inferring these rates from labeling and delabeling curves has been subject to considerable debate with different groups suggesting different mathematical models for that purpose. We show that the three most common models, which are based on quite different biological assumptions, actually predict mathematically identical labeling curves with one parameter for the exponential up and down slope, and one parameter defining the maximum labeling level. By extending these previous models, we here propose a novel approach for the analysis of data from deuterium labeling experiments. We construct a model of kinetic heterogeneity in which the total cell population consists of many sub-populations with different rates of cell turnover. In this model, for a given distribution of the rates of turnover, the predicted fraction of labeled DNA accumulated and lost can be calculated. Our model reproduces several previously made experimental observations, such as a negative correlation between the length of the labeling period and the rate at which labeled DNA is lost after label cessation. We demonstrate the reliability of the new explicit kinetic heterogeneity model by applying it to artificially generated datasets, and illustrate its usefulness by fitting experimental data. In contrast to previous models, the explicit kinetic heterogeneity model 1) provides a novel way of interpreting labeling data, 2) allows for a non-exponential loss of labeled cells during delabeling, and 3) can be used to describe data with variable labeling length.'),
(84503, 2010, 'plos', 'The overlap of small molecule and protein binding sites within families of protein structures', 'Davis, Fred P|Sali, Andrej', 'Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia, USA. davisf@janelia.hhmi.org|Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia, USA. davisf@janelia.hhmi.org', 'United States|United States', 41, 'Binding Sites|Computational Biology|Ligands|Models, Molecular|Protein Binding|Protein Interaction Domains and Motifs|Proteins|Statistics, Nonparametric', 'Journal Article', '10.1371/journal.pcbi.1000668', '20140189', 'Protein-protein interactions are challenging targets for modulation by small molecules. Here, we propose an approach that harnesses the increasing structural coverage of protein complexes to identify small molecules that may target protein interactions. Specifically, we identify ligand and protein binding sites that overlap upon alignment of homologous proteins. Of the 2,619 protein structure families observed to bind proteins, 1,028 also bind small molecules (250-1000 Da), and 197 exhibit a statistically significant (p<0.01) overlap between ligand and protein binding positions. These bi-functional positions, which bind both ligands and proteins, are particularly enriched in tyrosine and tryptophan residues, similar to energetic hotspots described previously, and are significantly less conserved than mono-functional and solvent exposed positions. Homology transfer identifies ligands whose binding sites overlap at least 20% of the protein interface for 35% of domain-domain and 45% of domain-peptide mediated interactions. The analysis recovered known small-molecule modulators of protein interactions as well as predicted new interaction targets based on the sequence similarity of ligand binding sites. We illustrate the predictive utility of the method by suggesting structural mechanisms for the effects of sanglifehrin A on HIV virion production, bepridil on the cellular entry of anthrax edema factor, and fusicoccin on vertebrate developmental pathways. The results, available at http://pibase.janelia.org, represent a comprehensive collection of structurally characterized modulators of protein interactions, and suggest that homologous structures are a useful resource for the rational design of interaction modulators.'),
(84504, 2010, 'plos', 'A variant of TNFR2-Fc fusion protein exhibits improved efficacy in treating experimental rheumatoid arthritis', 'Yang, Tong|Wang, Zheng|Wu, Fang|Tan, Jingwei|Shen, Yijun|Li, Erguang|Dai, Jingzhi|Shen, Ronghai|Li, Gang|Wu, Jinsong|Wang, Luochun|Wang, Haibo|Liu, Yanjun', 'Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China.|Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China.|Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China.|Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China.|Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China.|Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China.|Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China.|Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China.|Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China.|Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China.|Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China.|Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China.|Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China.', 'China|China|China|China|China|China|China|China|China|China|China|China|China', 14, 'Animals|Arthritis, Experimental|Cell Line|Cell Survival|Computational Biology|Etanercept|Histocytochemistry|Immunoglobulin G|Mice|Mutation|Protein Binding|Rats|Receptors, Tumor Necrosis Factor|Surface Plasmon Resonance|Tumor Necrosis Factor-alpha', 'Journal Article', '10.1371/journal.pcbi.1000669', '20140191', 'Etanercept, a TNF receptor 2-Fc fusion protein, is currently being used for the treatment of rheumatoid arthritis (RA). However, 25% to 38% of patients show no response which is suspected to be partially due to insufficient affinity of this protein to TNFalpha. By using computational protein design, we found that residue W89 and E92 of TNFR2 were critical for ligand binding. Among several mutants tested, W89Y/E92N displayed 1.49-fold higher neutralizing activity to TNFalpha, as compared to that of Etanercept. Surface plasmon resonance (SPR) based binding assay revealed that the equilibrium dissociation constant of W89Y/E92N to TNFalpha was 3.65-fold higher than that of Etanercept. In a rat model of collagen-induced arthritis (CIA), W89Y/E92N showed a significantly better ability than Etanercept in reducing paw swelling and improvement of arthritic joint histopathologically. These data demonstrate that W89Y/E92N is potentially a better candidate with improved efficacy in treating RA and other autoimmune diseases.'),
(84505, 2010, 'plos', 'Network-based elucidation of human disease similarities reveals common functional modules enriched for pluripotent drug targets', 'Suthram, Silpa|Dudley, Joel T|Chiang, Annie P|Chen, Rong|Hastie, Trevor J|Butte, Atul J', 'Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, California, USA.|Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, California, USA.|Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, California, USA.|Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, California, USA.|Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, California, USA.|Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, California, USA.', 'United States|United States|United States|United States|United States|United States', 0, 'Cluster Analysis|Computational Biology|Databases, Genetic|Disease|Drug Delivery Systems|Gene Expression Profiling|Humans|Linear Models|Oligonucleotide Array Sequence Analysis|Random Allocation|Statistics, Nonparametric', 'Journal Article', '10.1371/journal.pcbi.1000662', '20140234', 'Current work in elucidating relationships between diseases has largely been based on pre-existing knowledge of disease genes. Consequently, these studies are limited in their discovery of new and unknown disease relationships. We present the first quantitative framework to compare and contrast diseases by an integrated analysis of disease-related mRNA expression data and the human protein interaction network. We identified 4,620 functional modules in the human protein network and provided a quantitative metric to record their responses in 54 diseases leading to 138 significant similarities between diseases. Fourteen of the significant disease correlations also shared common drugs, supporting the hypothesis that similar diseases can be treated by the same drugs, allowing us to make predictions for new uses of existing drugs. Finally, we also identified 59 modules that were dysregulated in at least half of the diseases, representing a common disease-state signature. These modules were significantly enriched for genes that are known to be drug targets. Interestingly, drugs known to target these genes/proteins are already known to treat significantly more diseases than drugs targeting other genes/proteins, highlighting the importance of these core modules as prime therapeutic opportunities.'),
(84506, 2010, 'plos', 'A universal trend of reduced mRNA stability near the translation-initiation site in prokaryotes and eukaryotes', 'Gu, Wanjun|Zhou, Tong|Wilke, Claus O', 'Key Laboratory of Child Development and Learning Science of Ministry of Education of China, Southeast University, Nanjing, Jiangsu, China.|Key Laboratory of Child Development and Learning Science of Ministry of Education of China, Southeast University, Nanjing, Jiangsu, China.|Key Laboratory of Child Development and Learning Science of Ministry of Education of China, Southeast University, Nanjing, Jiangsu, China.', 'China|China|China', 0, 'Animals|Bacteria|Base Composition|Computational Biology|Eukaryota|Genome|Genome, Bacterial|Mutation|Peptide Chain Initiation, Translational|RNA Stability|RNA, Messenger|Temperature|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000664', '20140241', 'Recent studies have suggested that the thermodynamic stability of mRNA secondary structure near the start codon can regulate translation efficiency in Escherichia coli, and that translation is more efficient the less stable the secondary structure. We survey the complete genomes of 340 species for signals of reduced mRNA secondary structure near the start codon. Our analysis includes bacteria, archaea, fungi, plants, insects, fishes, birds, and mammals. We find that nearly all species show evidence for reduced mRNA stability near the start codon. The reduction in stability generally increases with increasing genomic GC content. In prokaryotes, the reduction also increases with decreasing optimal growth temperature. Within genomes, there is variation in the stability among genes, and this variation correlates with gene GC content, codon bias, and gene expression level. For birds and mammals, however, we do not find a genome-wide trend of reduced mRNA stability near the start codon. Yet the most GC rich genes in these organisms do show such a signal. We conclude that reduced stability of the mRNA secondary structure near the start codon is a universal feature of all cellular life. We suggest that the origin of this reduction is selection for efficient recognition of the start codon by initiator-tRNA.'),
(84507, 2010, 'plos', 'A dynamic model of interactions of Ca2+, calmodulin, and catalytic subunits of Ca2+/calmodulin-dependent protein kinase II', 'Pepke, Shirley|Kinzer-Ursem, Tamara|Mihalas, Stefan|Kennedy, Mary B', 'Center for Advanced Computing Research, California Institute of Technology, Pasadena, California, USA.|Center for Advanced Computing Research, California Institute of Technology, Pasadena, California, USA.|Center for Advanced Computing Research, California Institute of Technology, Pasadena, California, USA.|Center for Advanced Computing Research, California Institute of Technology, Pasadena, California, USA.', 'United States|United States|United States|United States', 47, 'Calcium|Calcium-Calmodulin-Dependent Protein Kinase Type 2|Calmodulin|Kinetics|Models, Chemical|Molecular Dynamics Simulation|Multiprotein Complexes|Phosphorylation|Protein Binding|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000675', '20168991', 'During the acquisition of memories, influx of Ca2+ into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca2+influx during the first few seconds of activity is interpreted within the Ca2+-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity,including Ca2+/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bindup to 4 Ca2+ ions. As a first step toward clarifying how the Ca2+-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca2+, calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca2+ play a significant role in activation of CaMKII in the physiological regime,supporting the notion that processing of Ca2+ signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca2+ is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca2+ transients arises from the kinetics of interaction of fluctuating Ca2+with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning.'),
(84508, 2010, 'plos', 'Conditions for the evolution of gene clusters in bacterial genomes', 'Ballouz, Sara|Francis, Andrew R|Lan, Ruiting|Tanaka, Mark M', 'School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, New South Wales, Australia.|School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, New South Wales, Australia.|School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, New South Wales, Australia.|School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, New South Wales, Australia.', 'Australia|Australia|Australia|Australia', 30, 'Bacterial Proteins|Cluster Analysis|Computational Biology|Evolution, Molecular|Gene Rearrangement|Genome, Bacterial|Models, Genetic|Multigene Family|Operon', 'Journal Article', '10.1371/journal.pcbi.1000672', '20168992', 'Genes encoding proteins in a common pathway are often found near each other along bacterial chromosomes. Several explanations have been proposed to account for the evolution of these structures. For instance, natural selection may directly favour gene clusters through a variety of mechanisms, such as increased efficiency of coregulation. An alternative and controversial hypothesis is the selfish operon model, which asserts that clustered arrangements of genes are more easily transferred to other species, thus improving the prospects for survival of the cluster. According to another hypothesis (the persistence model), genes that are in close proximity are less likely to be disrupted by deletions. Here we develop computational models to study the conditions under which gene clusters can evolve and persist. First, we examine the selfish operon model by re-implementing the simulation and running it under a wide range of conditions. Second, we introduce and study a Moran process in which there is natural selection for gene clustering and rearrangement occurs by genome inversion events. Finally, we develop and study a model that includes selection and inversion, which tracks the occurrence and fixation of rearrangements. Surprisingly, gene clusters fail to evolve under a wide range of conditions. Factors that promote the evolution of gene clusters include a low number of genes in the pathway, a high population size, and in the case of the selfish operon model, a high horizontal transfer rate. The computational analysis here has shown that the evolution of gene clusters can occur under both direct and indirect selection as long as certain conditions hold. Under these conditions the selfish operon model is still viable as an explanation for the evolution of gene clusters.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84509, 2010, 'plos', 'Minimization of biosynthetic costs in adaptive gene expression responses of yeast to environmental changes', 'Vilaprinyo, Ester|Alves, Rui|Sorribas, Albert', 'Fundació Dr Ferràn-Hospital de Tortosa Verge de la Cinta, Tortosa, Spain. evilaprinyo@cmb.udl.cat|Fundació Dr Ferràn-Hospital de Tortosa Verge de la Cinta, Tortosa, Spain. evilaprinyo@cmb.udl.cat|Fundació Dr Ferràn-Hospital de Tortosa Verge de la Cinta, Tortosa, Spain. evilaprinyo@cmb.udl.cat', 'Spain|Spain|Spain', 0, 'Cellular Structures|Cluster Analysis|Databases, Genetic|Fungal Proteins|Gene Expression Profiling|Gene Expression Regulation, Fungal|Image Processing, Computer-Assisted|Oligonucleotide Array Sequence Analysis|Signal Transduction|Statistics, Nonparametric|Stress, Physiological|Systems Biology|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1000674', '20168993', 'Yeast successfully adapts to an environmental stress by altering physiology and fine-tuning metabolism. This fine-tuning is achieved through regulation of both gene expression and protein activity, and it is shaped by various physiological requirements. Such requirements impose a sustained evolutionary pressure that ultimately selects a specific gene expression profile, generating a suitable adaptive response to each environmental change. Although some of the requirements are stress specific, it is likely that others are common to various situations. We hypothesize that an evolutionary pressure for minimizing biosynthetic costs might have left signatures in the physicochemical properties of proteins whose gene expression is fine-tuned during adaptive responses. To test this hypothesis we analyze existing yeast transcriptomic data for such responses and investigate how several properties of proteins correlate to changes in gene expression. Our results reveal signatures that are consistent with a selective pressure for economy in protein synthesis during adaptive response of yeast to various types of stress. These signatures differentiate two groups of adaptive responses with respect to how cells manage expenditure in protein biosynthesis. In one group, significant trends towards downregulation of large proteins and upregulation of small ones are observed. In the other group we find no such trends. These results are consistent with resource limitation being important in the evolution of the first group of stress responses.'),
(84510, 2010, 'plos', 'Characterizing dynamic changes in the human blood transcriptional network', 'Zhu, Jun|Chen, Yanqing|Leonardson, Amy S|Wang, Kai|Lamb, John R|Emilsson, Valur|Schadt, Eric E', 'Department of Genetics, Rosetta Inpharmatics, LLC, a wholly owned subsidiary of Merck & Co., Inc., Seattle, Washington, USA. junzhu_99@yahoo.com|Department of Genetics, Rosetta Inpharmatics, LLC, a wholly owned subsidiary of Merck & Co., Inc., Seattle, Washington, USA. junzhu_99@yahoo.com|Department of Genetics, Rosetta Inpharmatics, LLC, a wholly owned subsidiary of Merck & Co., Inc., Seattle, Washington, USA. junzhu_99@yahoo.com|Department of Genetics, Rosetta Inpharmatics, LLC, a wholly owned subsidiary of Merck & Co., Inc., Seattle, Washington, USA. junzhu_99@yahoo.com|Department of Genetics, Rosetta Inpharmatics, LLC, a wholly owned subsidiary of Merck & Co., Inc., Seattle, Washington, USA. junzhu_99@yahoo.com|Department of Genetics, Rosetta Inpharmatics, LLC, a wholly owned subsidiary of Merck & Co., Inc., Seattle, Washington, USA. junzhu_99@yahoo.com|Department of Genetics, Rosetta Inpharmatics, LLC, a wholly owned subsidiary of Merck & Co., Inc., Seattle, Washington, USA. junzhu_99@yahoo.com', 'United States|United States|United States|United States|United States|United States|United States', 45, 'Analysis of Variance|Bayes Theorem|Blood|Blood Physiological Phenomena|Circadian Rhythm|Cluster Analysis|Eating|Fasting|Gene Expression Profiling|Humans|Metabolic Networks and Pathways|Obesity|Random Allocation', 'Journal Article', '10.1371/journal.pcbi.1000671', '20168994', 'Gene expression data generated systematically in a given system over multiple time points provides a source of perturbation that can be leveraged to infer causal relationships among genes explaining network changes. Previously, we showed that food intake has a large impact on blood gene expression patterns and that these responses, either in terms of gene expression level or gene-gene connectivity, are strongly associated with metabolic diseases. In this study, we explored which genes drive the changes of gene expression patterns in response to time and food intake. We applied the Granger causality test and the dynamic Bayesian network to gene expression data generated from blood samples collected at multiple time points during the course of a day. The simulation result shows that combining many short time series together is as powerful to infer Granger causality as using a single long time series. Using the Granger causality test, we identified genes that were supported as the most likely causal candidates for the coordinated temporal changes in the network. These results show that PER1 is a key regulator of the blood transcriptional network, in which multiple biological processes are under circadian rhythm regulation. The fasted and fed dynamic Bayesian networks showed that over 72% of dynamic connections are self links. Finally, we show that different processes such as inflammation and lipid metabolism, which are disconnected in the static network, become dynamically linked in response to food intake, which would suggest that increasing nutritional load leads to coordinate regulation of these biological processes. In conclusion, our results suggest that food intake has a profound impact on the dynamic co-regulation of multiple biological processes, such as metabolism, immune response, apoptosis and circadian rhythm. The results could have broader implications for the design of studies of disease association and drug response in clinical trials.'),
(84511, 2010, 'plos', 'Design of a trichromatic cone array', 'Garrigan, Patrick|Ratliff, Charles P|Klein, Jennifer M|Sterling, Peter|Brainard, David H|Balasubramanian, Vijay', 'Department of Psychology, Saint Josephs University, Philadelphia, Pennsylvania, USA. patrick.garrigan@sju.edu|Department of Psychology, Saint Josephs University, Philadelphia, Pennsylvania, USA. patrick.garrigan@sju.edu|Department of Psychology, Saint Josephs University, Philadelphia, Pennsylvania, USA. patrick.garrigan@sju.edu|Department of Psychology, Saint Josephs University, Philadelphia, Pennsylvania, USA. patrick.garrigan@sju.edu|Department of Psychology, Saint Josephs University, Philadelphia, Pennsylvania, USA. patrick.garrigan@sju.edu|Department of Psychology, Saint Josephs University, Philadelphia, Pennsylvania, USA. patrick.garrigan@sju.edu', 'United States|United States|United States|United States|United States|United States', 0, 'Algorithms|Computational Biology|Databases, Factual|Humans|Light|Models, Biological|Photography|Retinal Cone Photoreceptor Cells|Vision, Ocular', 'Journal Article', '10.1371/journal.pcbi.1000677', '20168996', 'Cones with peak sensitivity to light at long (L), medium (M) and short (S) wavelengths are unequal in number on the human retina: S cones are rare (<10%) while increasing in fraction from center to periphery, and the L/M cone proportions are highly variable between individuals. What optical properties of the eye, and statistical properties of natural scenes, might drive this organization? We found that the spatial-chromatic structure of natural scenes was largely symmetric between the L, M and S sensitivity bands. Given this symmetry, short wavelength attenuation by ocular media gave L/M cones a modest signal-to-noise advantage, which was amplified, especially in the denser central retina, by long-wavelength accommodation of the lens. Meanwhile, total information represented by the cone mosaic remained relatively insensitive to L/M proportions. Thus, the observed cone array design along with a long-wavelength accommodated lens provides a selective advantage: it is maximally informative.'),
(84512, 2010, 'plos', 'Adaptable functionality of transcriptional feedback in bacterial two-component systems', 'Ray, J Christian J|Igoshin, Oleg A', 'Department of Bioengineering, Rice University, Houston, Texas, USA.|Department of Bioengineering, Rice University, Houston, Texas, USA.', 'United States|United States', 38, 'Algorithms|Bacterial Physiological Phenomena|Bacterial Proteins|Computational Biology|Feedback, Physiological|Models, Biological|Monte Carlo Method|Signal Transduction|Transcription, Genetic|Two-Hybrid System Techniques', 'Journal Article', '10.1371/journal.pcbi.1000676', '20168997', 'A widespread mechanism of bacterial signaling occurs through two-component systems, comprised of a sensor histidine kinase (SHK) and a transcriptional response regulator (RR). The SHK activates RR by phosphorylation. The most common two-component system structure involves expression from a single operon, the transcription of which is activated by its own phosphorylated RR. The role of this feedback is poorly understood, but it has been associated with an overshooting kinetic response and with fast recovery of previous interrupted signaling events in different systems. Mathematical models show that overshoot is only attainable with negative feedback that also improves response time. Our models also predict that fast recovery of previous interrupted signaling depends on high accumulation of SHK and RR, which is more likely in a positive feedback regime. We use Monte Carlo sampling of the parameter space to explore the range of attainable model behaviors. The model predicts that the effective feedback sign can change from negative to positive depending on the signal level. Variations in two-component system architectures and parameters may therefore have evolved to optimize responses in different bacterial lifestyles. We propose a conceptual model where low signal conditions result in a responsive system with effectively negative feedback while high signal conditions with positive feedback favor persistence of system output.'),
(84513, 2010, 'plos', 'A kinetic model of dopamine- and calcium-dependent striatal synaptic plasticity', 'Nakano, Takashi|Doi, Tomokazu|Yoshimoto, Junichiro|Doya, Kenji', 'Graduate School of Information Science, Nara Institute of Science and Technology, Ikoma, Japan.|Graduate School of Information Science, Nara Institute of Science and Technology, Ikoma, Japan.|Graduate School of Information Science, Nara Institute of Science and Technology, Ikoma, Japan.|Graduate School of Information Science, Nara Institute of Science and Technology, Ikoma, Japan.', 'Japan|Japan|Japan|Japan', 63, 'Basal Ganglia|Calcium|Computer Simulation|Cyclic AMP-Dependent Protein Kinases|Dopamine|Feedback, Physiological|Kinetics|Models, Neurological|Neuronal Plasticity|Protein Phosphatase 2|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000670', '20169176', 'Corticostriatal synapse plasticity of medium spiny neurons is regulated by glutamate input from the cortex and dopamine input from the substantia nigra. While cortical stimulation alone results in long-term depression (LTD), the combination with dopamine switches LTD to long-term potentiation (LTP), which is known as dopamine-dependent plasticity. LTP is also induced by cortical stimulation in magnesium-free solution, which leads to massive calcium influx through NMDA-type receptors and is regarded as calcium-dependent plasticity. Signaling cascades in the corticostriatal spines are currently under investigation. However, because of the existence of multiple excitatory and inhibitory pathways with loops, the mechanisms regulating the two types of plasticity remain poorly understood. A signaling pathway model of spines that express D1-type dopamine receptors was constructed to analyze the dynamic mechanisms of dopamine- and calcium-dependent plasticity. The model incorporated all major signaling molecules, including dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP32), as well as AMPA receptor trafficking in the post-synaptic membrane. Simulations with dopamine and calcium inputs reproduced dopamine- and calcium-dependent plasticity. Further in silico experiments revealed that the positive feedback loop consisted of protein kinase A (PKA), protein phosphatase 2A (PP2A), and the phosphorylation site at threonine 75 of DARPP-32 (Thr75) served as the major switch for inducing LTD and LTP. Calcium input modulated this loop through the PP2B (phosphatase 2B)-CK1 (casein kinase 1)-Cdk5 (cyclin-dependent kinase 5)-Thr75 pathway and PP2A, whereas calcium and dopamine input activated the loop via PKA activation by cyclic AMP (cAMP). The positive feedback loop displayed robust bi-stable responses following changes in the reaction parameters. Increased basal dopamine levels disrupted this dopamine-dependent plasticity. The present model elucidated the mechanisms involved in bidirectional regulation of corticostriatal synapses and will allow for further exploration into causes and therapies for dysfunctions such as drug addiction.'),
(84514, 2010, 'plos', 'Spatial and topological organization of DNA chains induced by gene co-localization', 'Junier, Ivan|Martin, Olivier|Képès, François', 'Epigenomics Project, Genopole, CNRS UPS 3201, UniverSud Paris, University of Evry, Genopole Campus 1-Genavenir 6, Evry, France.|Epigenomics Project, Genopole, CNRS UPS 3201, UniverSud Paris, University of Evry, Genopole Campus 1-Genavenir 6, Evry, France.|Epigenomics Project, Genopole, CNRS UPS 3201, UniverSud Paris, University of Evry, Genopole Campus 1-Genavenir 6, Evry, France.', 'France|France|France', 66, 'Binding Sites|Chromosomes|Computer Simulation|DNA|Genome|Models, Genetic|Models, Molecular|Models, Statistical|Monte Carlo Method|Nucleic Acid Conformation|Thermodynamics|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000678', '20169181', 'Transcriptional activity has been shown to relate to the organization of chromosomes in the eukaryotic nucleus and in the bacterial nucleoid. In particular, highly transcribed genes, RNA polymerases and transcription factors gather into discrete spatial foci called transcription factories. However, the mechanisms underlying the formation of these foci and the resulting topological order of the chromosome remain to be elucidated. Here we consider a thermodynamic framework based on a worm-like chain model of chromosomes where sparse designated sites along the DNA are able to interact whenever they are spatially close by. This is motivated by recurrent evidence that there exist physical interactions between genes that operate together. Three important results come out of this simple framework. First, the resulting formation of transcription foci can be viewed as a micro-phase separation of the interacting sites from the rest of the DNA. In this respect, a thermodynamic analysis suggests transcription factors to be appropriate candidates for mediating the physical interactions between genes. Next, numerical simulations of the polymer reveal a rich variety of phases that are associated with different topological orderings, each providing a way to increase the local concentrations of the interacting sites. Finally, the numerical results show that both one-dimensional clustering and periodic location of the binding sites along the DNA, which have been observed in several organisms, make the spatial co-localization of multiple families of genes particularly efficient.'),
(84515, 2010, 'plos', 'Self versus environment motion in postural control', 'Dokka, Kalpana|Kenyon, Robert V|Keshner, Emily A|Kording, Konrad P', 'Department of Anatomy and Neurobiology, Washington University, Saint Louis, Missouri, United States of America. kalpana@pcg.wustl.edu|Department of Anatomy and Neurobiology, Washington University, Saint Louis, Missouri, United States of America. kalpana@pcg.wustl.edu|Department of Anatomy and Neurobiology, Washington University, Saint Louis, Missouri, United States of America. kalpana@pcg.wustl.edu|Department of Anatomy and Neurobiology, Washington University, Saint Louis, Missouri, United States of America. kalpana@pcg.wustl.edu', 'United States|United States|United States|United States', 33, 'Adult|Bayes Theorem|Humans|Models, Biological|Motor Activity|Nonlinear Dynamics|Photic Stimulation|Posture|Vestibular Nerve|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1000680', '20174552', 'To stabilize our position in space we use visual information as well as non-visual physical motion cues. However, visual cues can be ambiguous: visually perceived motion may be caused by self-movement, movement of the environment, or both. The nervous system must combine the ambiguous visual cues with noisy physical motion cues to resolve this ambiguity and control our body posture. Here we have developed a Bayesian model that formalizes how the nervous system could solve this problem. In this model, the nervous system combines the sensory cues to estimate the movement of the body. We analytically demonstrate that, as long as visual stimulation is fast in comparison to the uncertainty in our perception of body movement, the optimal strategy is to weight visually perceived movement velocities proportional to a power law. We find that this model accounts for the nonlinear influence of experimentally induced visual motion on human postural behavior both in our data and in previously published results.'),
(84516, 2010, 'plos', 'Numerical modelling of the V-J combinations of the T cell receptor TRA/TRD locus', 'Thuderoz, Florence|Simonet, Maria-Ana|Hansen, Olivier|Pasqual, Nicolas|Dariz, Aurélie|Baum, Thierry Pascal|Hierle, Vivien|Demongeot, Jacques|Marche, Patrice Noël|Jouvin-Marche, Evelyne', 'CNRS, Laboratoire TIMC-IMAG, UMR 5525, Grenoble, France.|CNRS, Laboratoire TIMC-IMAG, UMR 5525, Grenoble, France.|CNRS, Laboratoire TIMC-IMAG, UMR 5525, Grenoble, France.|CNRS, Laboratoire TIMC-IMAG, UMR 5525, Grenoble, France.|CNRS, Laboratoire TIMC-IMAG, UMR 5525, Grenoble, France.|CNRS, Laboratoire TIMC-IMAG, UMR 5525, Grenoble, France.|CNRS, Laboratoire TIMC-IMAG, UMR 5525, Grenoble, France.|CNRS, Laboratoire TIMC-IMAG, UMR 5525, Grenoble, France.|CNRS, Laboratoire TIMC-IMAG, UMR 5525, Grenoble, France.|CNRS, Laboratoire TIMC-IMAG, UMR 5525, Grenoble, France.', 'France|France|France|France|France|France|France|France|France|France', 14, 'Animals|Computer Simulation|Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor|Gene Rearrangement, delta-Chain T-Cell Antigen Receptor|Genes, T-Cell Receptor alpha|Genes, T-Cell Receptor delta|Mice|Mice, Inbred BALB C|Models, Immunological|Receptors, Antigen, T-Cell, alpha-beta|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000682', '20174554', 'T-Cell antigen Receptor (TR) repertoire is generated through rearrangements of V and J genes encoding alpha and beta chains. The quantification and frequency for every V-J combination during ontogeny and development of the immune system remain to be precisely established. We have addressed this issue by building a model able to account for Valpha-Jalpha gene rearrangements during thymus development of mice. So we developed a numerical model on the whole TRA/TRD locus, based on experimental data, to estimate how Valpha and Jalpha genes become accessible to rearrangements. The progressive opening of the locus to V-J gene recombinations is modeled through windows of accessibility of different sizes and with different speeds of progression. Furthermore, the possibility of successive secondary V-J rearrangements was included in the modelling. The model points out some unbalanced V-J associations resulting from a preferential access to gene rearrangements and from a non-uniform partition of the accessibility of the J genes, depending on their location in the locus. The model shows that 3 to 4 successive rearrangements are sufficient to explain the use of all the V and J genes of the locus. Finally, the model provides information on both the kinetics of rearrangements and frequencies of each V-J associations. The model accounts for the essential features of the observed rearrangements on the TRA/TRD locus and may provide a reference for the repertoire of the V-J combinatorial diversity.'),
(84517, 2010, 'plos', 'Amplification of asynchronous inhibition-mediated synchronization by feedback in recurrent networks', 'Marella, Sashi|Ermentrout, Bard', 'Center for Neuroscience/Center for Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Center for Neuroscience/Center for Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.', 'United States|United States', 8, 'Action Potentials|Algorithms|Animals|Cortical Synchronization|Feedback, Physiological|Humans|Models, Neurological|Olfactory Pathways|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1000679', '20174555', 'Synchronization of 30-80 Hz oscillatory activity of the principle neurons in the olfactory bulb (mitral cells) is believed to be important for odor discrimination. Previous theoretical studies of these fast rhythms in other brain areas have proposed that principle neuron synchrony can be mediated by short-latency, rapidly decaying inhibition. This phasic inhibition provides a narrow time window for the principle neurons to fire, thus promoting synchrony. However, in the olfactory bulb, the inhibitory granule cells produce long lasting, small amplitude, asynchronous and aperiodic inhibitory input and thus the narrow time window that is required to synchronize spiking does not exist. Instead, it has been suggested that correlated output of the granule cells could serve to synchronize uncoupled mitral cells through a mechanism called stochastic synchronization, wherein the synchronization arises through correlation of inputs to two neural oscillators. Almost all work on synchrony due to correlations presumes that the correlation is imposed and fixed. Building on theory and experiments that we and others have developed, we show that increased synchrony in the mitral cells could produce an increase in granule cell activity for those granule cells that share a synchronous group of mitral cells. Common granule cell input increases the input correlation to the mitral cells and hence their synchrony by providing a positive feedback loop in correlation. Thus we demonstrate the emergence and temporal evolution of input correlation in recurrent networks with feedback. We explore several theoretical models of this idea, ranging from spiking models to an analytically tractable model.'),
(84518, 2010, 'plos', 'Predicted functions of MdmX in fine-tuning the response of p53 to DNA damage', 'Kim, Sohyoung|Aladjem, Mirit I|McFadden, Geoffrey B|Kohn, Kurt W', 'Laboratory of Molecular Pharmacology, National Cancer Institute, National Institute of Health, Bethesda, Maryland, United States of America.|Laboratory of Molecular Pharmacology, National Cancer Institute, National Institute of Health, Bethesda, Maryland, United States of America.|Laboratory of Molecular Pharmacology, National Cancer Institute, National Institute of Health, Bethesda, Maryland, United States of America.|Laboratory of Molecular Pharmacology, National Cancer Institute, National Institute of Health, Bethesda, Maryland, United States of America.', 'United States|United States|United States|United States', 11, 'DNA Damage|Kinetics|Metabolic Networks and Pathways|Models, Biological|Molecular Dynamics Simulation|Proto-Oncogene Proteins c-mdm2|Tumor Suppressor Protein p53|Ubiquitination', 'Journal Article', '10.1371/journal.pcbi.1000665', '20174603', 'Tumor suppressor protein p53 is regulated by two structurally homologous proteins, Mdm2 and MdmX. In contrast to Mdm2, MdmX lacks ubiquitin ligase activity. Although the essential interactions of MdmX are known, it is not clear how they function to regulate p53. The regulation of tumor suppressor p53 by Mdm2 and MdmX in response to DNA damage was investigated by mathematical modeling of a simplified network. The simplified network model was derived from a detailed molecular interaction map (MIM) that exhibited four coherent DNA damage response pathways. The results suggest that MdmX may amplify or stabilize DNA damage-induced p53 responses via non-enzymatic interactions. Transient effects of MdmX are mediated by reservoirs of p53ratioMdmX and Mdm2ratioMdmX heterodimers, with MdmX buffering the concentrations of p53 and/or Mdm2. A survey of kinetic parameter space disclosed regions of switch-like behavior stemming from such reservoir-based transients. During an early response to DNA damage, MdmX positively or negatively regulated p53 activity, depending on the level of Mdm2, this led to amplification of p53 activity and switch-like response. During a late response to DNA damage, MdmX could dampen oscillations of p53 activity. A possible role of MdmX may be to dampen such oscillations that otherwise could produce erratic cell behavior. Our study suggests how MdmX may participate in the response of p53 to DNA damage either by increasing dependency of p53 on Mdm2 or by dampening oscillations of p53 activity and presents a model for experimental investigation.'),
(84519, 2010, 'plos', 'A Bayesian approach to quantifying the effects of mass poultry vaccination upon the spatial and temporal dynamics of H5N1 in Northern Vietnam', 'Walker, Patrick G T|Cauchemez, Simon|Métras, Raphaëlle|Dung, Do Huu|Pfeiffer, Dirk|Ghani, Azra C', 'MRC Centre for Outbreak Analysis Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom. patrick.walker@imperial.ac.uk|MRC Centre for Outbreak Analysis Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom. patrick.walker@imperial.ac.uk|MRC Centre for Outbreak Analysis Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom. patrick.walker@imperial.ac.uk|MRC Centre for Outbreak Analysis Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom. patrick.walker@imperial.ac.uk|MRC Centre for Outbreak Analysis Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom. patrick.walker@imperial.ac.uk|MRC Centre for Outbreak Analysis Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom. patrick.walker@imperial.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 23, 'Animals|Bayes Theorem|Computer Simulation|Disease Outbreaks|Geography|Influenza A Virus, H5N1 Subtype|Influenza Vaccines|Influenza in Birds|Mass Vaccination|Poultry|Poultry Diseases|Vietnam', 'Journal Article', '10.1371/journal.pcbi.1000683', '20174604', 'Outbreaks of H5N1 in poultry in Vietnam continue to threaten the livelihoods of those reliant on poultry production whilst simultaneously posing a severe public health risk given the high mortality associated with human infection. Authorities have invested significant resources in order to control these outbreaks. Of particular interest is the decision, following a second wave of outbreaks, to move from a stamping out approach to the implementation of a nationwide mass vaccination campaign. Outbreaks which occurred around this shift in policy provide a unique opportunity to evaluate the relative effectiveness of these approaches and to help other countries make informed judgements when developing control strategies. Here we use Bayesian Markov Chain Monte Carlo (MCMC) data augmentation techniques to derive the first quantitative estimates of the impact of the vaccination campaign on the spread of outbreaks of H5N1 in northern Vietnam. We find a substantial decrease in the transmissibility of infection between communes following vaccination. This was coupled with a significant increase in the time from infection to detection of the outbreak. Using a cladistic approach we estimated that, according to the posterior mean effect of pruning the reconstructed epidemic tree, two thirds of the outbreaks in 2007 could be attributed to this decrease in the rate of reporting. The net impact of these two effects was a less intense but longer-lasting wave and, whilst not sufficient to prevent the sustained spread of outbreaks, an overall reduction in the likelihood of the transmission of infection between communes. These findings highlight the need for more effectively targeted surveillance in order to help ensure that the effective coverage achieved by mass vaccination is converted into a reduction in the likelihood of outbreaks occurring which is sufficient to control the spread of H5N1 in Vietnam.'),
(84520, 2010, 'plos', 'Identifying the rules of engagement enabling leukocyte rolling, activation, and adhesion', 'Tang, Jonathan|Hunt, C Anthony', 'UCSF/UC Berkeley Joint Graduate Group in Bioengineering, University of California, Berkeley, Berkeley, California, United States of America.|UCSF/UC Berkeley Joint Graduate Group in Bioengineering, University of California, Berkeley, Berkeley, California, United States of America.', 'United States|United States', 20, 'Animals|Cell Adhesion|Class Ib Phosphatidylinositol 3-Kinase|Computer Simulation|Intercellular Adhesion Molecule-1|Isoenzymes|Leukocyte Rolling|Leukocytes|Lymphocyte Activation|Lymphocyte Function-Associated Antigen-1|Mice|Mice, Knockout|Models, Biological|P-Selectin|Phenotype|Phosphatidylinositol 3-Kinases|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000681', '20174606', 'The LFA-1 integrin plays a pivotal role in sustained leukocyte adhesion to the endothelial surface, which is a precondition for leukocyte recruitment into inflammation sites. Strong correlative evidence implicates LFA-1 clustering as being essential for sustained adhesion, and it may also facilitate rebinding events with its ligand ICAM-1. We cannot challenge those hypotheses directly because it is infeasible to measure either process during leukocyte adhesion following rolling. The alternative approach undertaken was to challenge the hypothesized mechanisms by experimenting on validated, working counterparts: simulations in which diffusible, LFA1 objects on the surfaces of quasi-autonomous leukocytes interact with simulated, diffusible, ICAM1 objects on endothelial surfaces during simulated adhesion following rolling. We used object-oriented, agent-based methods to build and execute multi-level, multi-attribute analogues of leukocytes and endothelial surfaces. Validation was achieved across different experimental conditions, in vitro, ex vivo, and in vivo, at both the individual cell and population levels. Because those mechanisms exhibit all of the characteristics of biological mechanisms, they can stand as a concrete, working theory about detailed events occurring at the leukocyte-surface interface during leukocyte rolling and adhesion experiments. We challenged mechanistic hypotheses by conducting experiments in which the consequences of multiple mechanistic events were tracked. We quantified rebinding events between individual components under different conditions, and the role of LFA1 clustering in sustaining leukocyte-surface adhesion and in improving adhesion efficiency. Early during simulations ICAM1 rebinding (to LFA1) but not LFA1 rebinding (to ICAM1) was enhanced by clustering. Later, clustering caused both types of rebinding events to increase. We discovered that clustering was not necessary to achieve adhesion as long as LFA1 and ICAM1 object densities were above a critical level. Importantly, at low densities LFA1 clustering enabled improved efficiency: adhesion exhibited measurable, cell level positive cooperativity.'),
(84521, 2010, 'plos', 'Molecular predictors of 3D morphogenesis by breast cancer cell lines in 3D culture', 'Han, Ju|Chang, Hang|Giricz, Orsi|Lee, Genee Y|Baehner, Frederick L|Gray, Joe W|Bissell, Mina J|Kenny, Paraic A|Parvin, Bahram', 'Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.|Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.|Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.|Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.|Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.|Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.|Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.|Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.|Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 62, 'Biomarkers, Tumor|Breast Neoplasms|Cell Culture Techniques|Cell Line, Tumor|Female|Gene Expression Profiling|Histocytochemistry|Humans|Image Processing, Computer-Assisted|Models, Biological|PPAR gamma|Phenotype|Receptor, ErbB-2|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000684', '20195492', 'Correlative analysis of molecular markers with phenotypic signatures is the simplest model for hypothesis generation. In this paper, a panel of 24 breast cell lines was grown in 3D culture, their morphology was imaged through phase contrast microscopy, and computational methods were developed to segment and represent each colony at multiple dimensions. Subsequently, subpopulations from these morphological responses were identified through consensus clustering to reveal three clusters of round, grape-like, and stellate phenotypes. In some cases, cell lines with particular pathobiological phenotypes clustered together (e.g., ERBB2 amplified cell lines sharing the same morphometric properties as the grape-like phenotype). Next, associations with molecular features were realized through (i) differential analysis within each morphological cluster, and (ii) regression analysis across the entire panel of cell lines. In both cases, the dominant genes that are predictive of the morphological signatures were identified. Specifically, PPARgamma has been associated with the invasive stellate morphological phenotype, which corresponds to triple-negative pathobiology. PPARgamma has been validated through two supporting biological assays.'),
(84522, 2010, 'plos', 'Spatial simulations of myxobacterial development', 'Holmes, Antony B|Kalvala, Sara|Whitworth, David E', 'MOAC Doctoral Training Centre, University of Warwick, Coventry, United Kingdom. antony.holmes@dbmi.columbia.edu|MOAC Doctoral Training Centre, University of Warwick, Coventry, United Kingdom. antony.holmes@dbmi.columbia.edu|MOAC Doctoral Training Centre, University of Warwick, Coventry, United Kingdom. antony.holmes@dbmi.columbia.edu', 'United Kingdom|United Kingdom|United Kingdom', 19, 'Algorithms|Cell Physiological Phenomena|Computational Biology|Computer Simulation|Gravitation|Models, Biological|Monte Carlo Method|Myxococcus xanthus|Signal Transduction|Spores, Bacterial|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000686', '20195493', 'Many bacteria exhibit multicellular behaviour, with individuals within a colony coordinating their actions for communal benefit. One example of complex multicellular phenotypes is myxobacterial fruiting body formation, where thousands of cells aggregate into large three-dimensional structures, within which sporulation occurs. Here we describe a novel theoretical model, which uses Monte Carlo dynamics to simulate and explain multicellular development. The model captures multiple behaviours observed during fruiting, including the spontaneous formation of aggregation centres and the formation and dissolution of fruiting bodies. We show that a small number of physical properties in the model is sufficient to explain the most frequently documented population-level behaviours observed during development in Myxococcus xanthus.'),
(84523, 2010, 'plos', 'Stochastic model of integrin-mediated signaling and adhesion dynamics at the leading edges of migrating cells', 'Cirit, Murat|Krajcovic, Matej|Choi, Colin K|Welf, Erik S|Horwitz, Alan F|Haugh, Jason M', 'Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, United States of America.|Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, United States of America.|Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, United States of America.|Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, United States of America.|Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, United States of America.|Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, United States of America.', 'United States|United States|United States|United States|United States|United States', 40, 'Animals|CHO Cells|Cell Adhesion|Cell Movement|Cell Surface Extensions|Computational Biology|Computer Simulation|Cricetinae|Cricetulus|Extracellular Matrix|Green Fluorescent Proteins|Integrins|Models, Biological|Myosins|Paxillin|Signal Transduction|Stochastic Processes|rac GTP-Binding Proteins', 'Journal Article', '10.1371/journal.pcbi.1000688', '20195494', 'Productive cell migration requires the spatiotemporal coordination of cell adhesion, membrane protrusion, and actomyosin-mediated contraction. Integrins, engaged by the extracellular matrix (ECM), nucleate the formation of adhesive contacts at the cells leading edge(s), and maturation of nascent adhesions to form stable focal adhesions constitutes a functional switch between protrusive and contractile activities. To shed additional light on the coupling between integrin-mediated adhesion and membrane protrusion, we have formulated a quantitative model of leading edge dynamics combining mechanistic and phenomenological elements and studied its features through classical bifurcation analysis and stochastic simulation. The model describes in mathematical terms the feedback loops driving, on the one hand, Rac-mediated membrane protrusion and rapid turnover of nascent adhesions, and on the other, myosin-dependent maturation of adhesions that inhibit protrusion at high ECM density. Our results show that the qualitative behavior of the model is most sensitive to parameters characterizing the influence of stable adhesions and myosin. The major predictions of the model, which we subsequently confirmed, are that persistent leading edge protrusion is optimal at an intermediate ECM density, whereas depletion of myosin IIA relieves the repression of protrusion at higher ECM density.'),
(84524, 2010, 'plos', 'How to understand the cell by breaking it: network analysis of gene perturbation screens', 'Markowetz, Florian', 'Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom.', 'United Kingdom', 42, 'Animals|Cell Physiological Phenomena|Cluster Analysis|Gene Regulatory Networks|Genomics|Humans|Models, Genetic|Models, Statistical|Phenotype|Signal Transduction|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000655', '20195495', '-'),
(84525, 2010, 'plos', 'Decoupling Environment-Dependent and Independent Genetic Robustness across Bacterial Species', 'Freilich, Shiri|Kreimer, Anat|Borenstein, Elhanan|Gophna, Uri|Sharan, Roded|Ruppin, Eytan', 'The Blavatnik School of Computer Sciences, Faculty of Life Sciences, Ramat Aviv, Israel. shiri.freilich@gmail.com|The Blavatnik School of Computer Sciences, Faculty of Life Sciences, Ramat Aviv, Israel. shiri.freilich@gmail.com|The Blavatnik School of Computer Sciences, Faculty of Life Sciences, Ramat Aviv, Israel. shiri.freilich@gmail.com|The Blavatnik School of Computer Sciences, Faculty of Life Sciences, Ramat Aviv, Israel. shiri.freilich@gmail.com|The Blavatnik School of Computer Sciences, Faculty of Life Sciences, Ramat Aviv, Israel. shiri.freilich@gmail.com|The Blavatnik School of Computer Sciences, Faculty of Life Sciences, Ramat Aviv, Israel. shiri.freilich@gmail.com', 'Israel|Israel|Israel|Israel|Israel|Israel', 24, 'Bacteria|Bacterial Physiological Phenomena|Computational Biology|Computer Simulation|Environment|Genetic Variation|Metabolic Networks and Pathways|Models, Genetic|Selection, Genetic|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000690', '20195496', 'The evolutionary origins of genetic robustness are still under debate: it may arise as a consequence of requirements imposed by varying environmental conditions, due to intrinsic factors such as metabolic requirements, or directly due to an adaptive selection in favor of genes that allow a species to endure genetic perturbations. Stratifying the individual effects of each origin requires one to study the pertaining evolutionary forces across many species under diverse conditions. Here we conduct the first large-scale computational study charting the level of robustness of metabolic networks of hundreds of bacterial species across many simulated growth environments. We provide evidence that variations among species in their level of robustness reflect ecological adaptations. We decouple metabolic robustness into two components and quantify the extents of each: the first, environmental-dependent, is responsible for at least 20% of the non-essential reactions and its extent is associated with the species lifestyle (specialized/generalist), the second, environmental-independent, is associated (correlation = approximately 0.6) with the intrinsic metabolic capacities of a species-higher robustness is observed in fast growers or in organisms with an extensive production of secondary metabolites. Finally, we identify reactions that are uniquely susceptible to perturbations in human pathogens, potentially serving as novel drug-targets.'),
(84526, 2010, 'plos', 'Unfolding simulations reveal the mechanism of extreme unfolding cooperativity in the kinetically stable alpha-lytic protease', 'Salimi, Neema L|Ho, Bosco|Agard, David A', 'Graduate Group in Biophysics, University of California San Francisco, San Francisco, California, United States of America.|Graduate Group in Biophysics, University of California San Francisco, San Francisco, California, United States of America.|Graduate Group in Biophysics, University of California San Francisco, San Francisco, California, United States of America.', 'United States|United States|United States', 20, 'Cluster Analysis|Computational Biology|Molecular Dynamics Simulation|Principal Component Analysis|Protein Folding|Protein Stability|Protein Structure, Tertiary|Serine Endopeptidases|Temperature|Trypsin', 'Journal Article', '10.1371/journal.pcbi.1000689', '20195497', 'Kinetically stable proteins, those whose stability is derived from their slow unfolding kinetics and not thermodynamics, are examples of evolutions best attempts at suppressing unfolding. Especially in highly proteolytic environments, both partially and fully unfolded proteins face potential inactivation through degradation and/or aggregation, hence, slowing unfolding can greatly extend a proteins functional lifetime. The prokaryotic serine protease alpha-lytic protease (alphaLP) has done just that, as its unfolding is both very slow (t(1/2) approximately 1 year) and so cooperative that partial unfolding is negligible, providing a functional advantage over its thermodynamically stable homologs, such as trypsin. Previous studies have identified regions of the domain interface as critical to alphaLP unfolding, though a complete description of the unfolding pathway is missing. In order to identify the alphaLP unfolding pathway and the mechanism for its extreme cooperativity, we performed high temperature molecular dynamics unfolding simulations of both alphaLP and trypsin. The simulated alphaLP unfolding pathway produces a robust transition state ensemble consistent with prior biochemical experiments and clearly shows that unfolding proceeds through a preferential disruption of the domain interface. Through a novel method of calculating unfolding cooperativity, we show that alphaLP unfolds extremely cooperatively while trypsin unfolds gradually. Finally, by examining the behavior of both domain interfaces, we propose a model for the differential unfolding cooperativity of alphaLP and trypsin involving three key regions that differ between the kinetically stable and thermodynamically stable classes of serine proteases.'),
(84527, 2010, 'plos', 'Temporal sensitivity of protein kinase a activation in late-phase long term potentiation', 'Kim, MyungSook|Huang, Ted|Abel, Ted|Blackwell, Kim T', 'George Mason University, The Krasnow Institute for Advanced Studies, Fairfax, Virginia, United States of America.|George Mason University, The Krasnow Institute for Advanced Studies, Fairfax, Virginia, United States of America.|George Mason University, The Krasnow Institute for Advanced Studies, Fairfax, Virginia, United States of America.|George Mason University, The Krasnow Institute for Advanced Studies, Fairfax, Virginia, United States of America.', 'United States|United States|United States|United States', 43, 'Animals|CA1 Region, Hippocampal|Calcium|Calcium-Calmodulin-Dependent Protein Kinase Type 2|Computational Biology|Computer Simulation|Cyclic AMP|Cyclic AMP-Dependent Protein Kinases|Dopamine|Enzyme Activation|Long-Term Potentiation|Mice|Models, Neurological|Signal Transduction|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1000691', '20195498', 'Protein kinases play critical roles in learning and memory and in long term potentiation (LTP), a form of synaptic plasticity. The induction of late-phase LTP (L-LTP) in the CA1 region of the hippocampus requires several kinases, including CaMKII and PKA, which are activated by calcium-dependent signaling processes and other intracellular signaling pathways. The requirement for PKA is limited to L-LTP induced using spaced stimuli, but not massed stimuli. To investigate this temporal sensitivity of PKA, a computational biochemical model of L-LTP induction in CA1 pyramidal neurons was developed. The model describes the interactions of calcium and cAMP signaling pathways and is based on published biochemical measurements of two key synaptic signaling molecules, PKA and CaMKII. The model is stimulated using four 100 Hz tetani separated by 3 sec (massed) or 300 sec (spaced), identical to experimental L-LTP induction protocols. Simulations show that spaced stimulation activates more PKA than massed stimulation, and makes a key experimental prediction, that L-LTP is PKA-dependent for intervals larger than 60 sec. Experimental measurements of L-LTP demonstrate that intervals of 80 sec, but not 40 sec, produce PKA-dependent L-LTP, thereby confirming the model prediction. Examination of CaMKII reveals that its temporal sensitivity is opposite that of PKA, suggesting that PKA is required after spaced stimulation to compensate for a decrease in CaMKII. In addition to explaining the temporal sensitivity of PKA, these simulations suggest that the use of several kinases for memory storage allows each to respond optimally to different temporal patterns.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84528, 2010, 'plos', 'A primer on metagenomics', 'Wooley, John C|Godzik, Adam|Friedberg, Iddo', 'Community Cyberinfrastructure for Marine Microbial Ecology Research and Analysis, California Institute for Telecommunications and Information Technology, University of California San Diego, La Jolla, California, United States of America.|Community Cyberinfrastructure for Marine Microbial Ecology Research and Analysis, California Institute for Telecommunications and Information Technology, University of California San Diego, La Jolla, California, United States of America.|Community Cyberinfrastructure for Marine Microbial Ecology Research and Analysis, California Institute for Telecommunications and Information Technology, University of California San Diego, La Jolla, California, United States of America.', 'United States|United States|United States', 360, 'Computational Biology|Metagenomics|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1000667', '20195499', 'Metagenomics is a discipline that enables the genomic study of uncultured microorganisms. Faster, cheaper sequencing technologies and the ability to sequence uncultured microbes sampled directly from their habitats are expanding and transforming our view of the microbial world. Distilling meaningful information from the millions of new genomic sequences presents a serious challenge to bioinformaticians. In cultured microbes, the genomic data come from a single clone, making sequence assembly and annotation tractable. In metagenomics, the data come from heterogeneous microbial communities, sometimes containing more than 10,000 species, with the sequence data being noisy and partial. From sampling, to assembly, to gene calling and function prediction, bioinformatics faces new demands in interpreting voluminous, noisy, and often partial sequence data. Although metagenomics is a relative newcomer to science, the past few years have seen an explosion in computational methods applied to metagenomic-based research. It is therefore not within the scope of this article to provide an exhaustive review. Rather, we provide here a concise yet comprehensive introduction to the current computational requirements presented by metagenomics, and review the recent progress made. We also note whether there is software that implements any of the methods presented here, and briefly review its utility. Nevertheless, it would be useful if readers of this article would avail themselves of the comment section provided by this journal, and relate their own experiences. Finally, the last section of this article provides a few representative studies illustrating different facets of recent scientific discoveries made using metagenomics.'),
(84529, 2010, 'plos', 'Interpreting metabolomic profiles using unbiased pathway models', 'Deo, Rahul C|Hunter, Luke|Lewis, Gregory D|Pare, Guillaume|Vasan, Ramachandran S|Chasman, Daniel|Wang, Thomas J|Gerszten, Robert E|Roth, Frederick P', 'Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Amino Acid Transport Systems|Carrier Proteins|Cluster Analysis|Computational Biology|Extracellular Space|Glucose|Glucose Metabolism Disorders|Glucose Tolerance Test|Humans|Intracellular Space|Metabolic Networks and Pathways|Metabolome|Models, Biological|Principal Component Analysis', 'Journal Article', '10.1371/journal.pcbi.1000692', '20195502', 'Human disease is heterogeneous, with similar disease phenotypes resulting from distinct combinations of genetic and environmental factors. Small-molecule profiling can address disease heterogeneity by evaluating the underlying biologic state of individuals through non-invasive interrogation of plasma metabolite levels. We analyzed metabolite profiles from an oral glucose tolerance test (OGTT) in 50 individuals, 25 with normal (NGT) and 25 with impaired glucose tolerance (IGT). Our focus was to elucidate underlying biologic processes. Although we initially found little overlap between changed metabolites and preconceived definitions of metabolic pathways, the use of unbiased network approaches identified significant concerted changes. Specifically, we derived a metabolic network with edges drawn between reactant and product nodes in individual reactions and between all substrates of individual enzymes and transporters. We searched for active modules--regions of the metabolic network enriched for changes in metabolite levels. Active modules identified relationships among changed metabolites and highlighted the importance of specific solute carriers in metabolite profiles. Furthermore, hierarchical clustering and principal component analysis demonstrated that changed metabolites in OGTT naturally grouped according to the activities of the System A and L amino acid transporters, the osmolyte carrier SLC6A12, and the mitochondrial aspartate-glutamate transporter SLC25A13. Comparison between NGT and IGT groups supported blunted glucose- and/or insulin-stimulated activities in the IGT group. Using unbiased pathway models, we offer evidence supporting the important role of solute carriers in the physiologic response to glucose challenge and conclude that carrier activities are reflected in individual metabolite profiles of perturbation experiments. Given the involvement of transporters in human disease, metabolite profiling may contribute to improved disease classification via the interrogation of specific transporter activities.'),
(84530, 2010, 'plos', 'Ten simple rules for organizing a virtual conference--anywhere', 'Gichora, Nelson N|Fatumo, Segun A|Ngara, Mtakai V|Chelbat, Noura|Ramdayal, Kavisha|Opap, Kenneth B|Siwo, Geoffrey H|Adebiyi, Marion O|El Gonnouni, Amina|Zofou, Denis|Maurady, Amal A M|Adebiyi, Ezekiel F|de Villiers, Etienne P|Masiga, Daniel K|Bizzaro, Jeffrey W|Suravajhala, Prashanth|Ommeh, Sheila C|Hide, Winston', 'International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.|International Institute of Tropical Agriculture, Nairobi, Kenya.', 'Kenya|Kenya|Kenya|Kenya|Kenya|Kenya|Kenya|Kenya|Kenya|Kenya|Kenya|Kenya|Kenya|Kenya|Kenya|Kenya|Keny', 0, 'Congresses as Topic|Guidelines as Topic|Humans|Internet|Videoconferencing', 'Editorial', '10.1371/journal.pcbi.1000650', '20195548', '-'),
(84531, 2010, 'plos', 'Will widgets and semantic tagging change computational biology?', 'Bourne, Philip E|Beran, Bojan|Bi, Chunxiao|Bluhm, Wolfgang|Dunbrack, Roland|Prlixc4x87, Andreas|Quinn, Greg|Rose, Peter|Shah, Raship|Tao, Wendy|Weitzner, Brian|Yukich, Ben', 'Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America. pbourne@ucsd.edu|Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America. pbourne@ucsd.edu|Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America. pbourne@ucsd.edu|Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America. pbourne@ucsd.edu|Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America. pbourne@ucsd.edu|Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America. pbourne@ucsd.edu|Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America. pbourne@ucsd.edu|Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America. pbourne@ucsd.edu|Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America. pbourne@ucsd.edu|Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America. pbourne@ucsd.edu|Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America. pbourne@ucsd.edu|Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America. pbourne@ucsd.edu', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Computational Biology|Information Systems|Internet|Semantics|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1000673', '20195550', '-'),
(84532, 2010, 'plos', 'Computational complementation: a modelling approach to study signalling mechanisms during legume autoregulation of nodulation', 'Han, Liqi|Hanan, Jim|Gresshoff, Peter M', 'ARC Centre of Excellence for Integrative Legume Research, The University of Queensland, Brisbane, Queensland, Australia.|ARC Centre of Excellence for Integrative Legume Research, The University of Queensland, Brisbane, Queensland, Australia.|ARC Centre of Excellence for Integrative Legume Research, The University of Queensland, Brisbane, Queensland, Australia.', 'Australia|Australia|Australia', 10, 'Computer Simulation|Cotyledon|Genetic Complementation Test|Models, Biological|Plant Physiological Phenomena|Plant Shoots|Root Nodules, Plant|Signal Transduction|Soybean Proteins|Soybeans', 'Journal Article', '10.1371/journal.pcbi.1000685', '20195551', 'Autoregulation of nodulation (AON) is a long-distance signalling regulatory system maintaining the balance of symbiotic nodulation in legume plants. However, the intricacy of internal signalling and absence of flux and biochemical data, are a bottleneck for investigation of AON. To address this, a new computational modelling approach called Computational Complementation has been developed. The main idea is to use functional-structural modelling to complement the deficiency of an empirical model of a loss-of-function (non-AON) mutant with hypothetical AON mechanisms. If computational complementation demonstrates a phenotype similar to the wild-type plant, the signalling hypothesis would be suggested as reasonable. Our initial case for application of this approach was to test whether or not wild-type soybean cotyledons provide the shoot-derived inhibitor (SDI) to regulate nodule progression. We predicted by computational complementation that the cotyledon is part of the shoot in terms of AON and that it produces the SDI signal, a result that was confirmed by reciprocal epicotyl-and-hypocotyl grafting in a real-plant experiment. This application demonstrates the feasibility of computational complementation and shows its usefulness for applications where real-plant experimentation is either difficult or impossible.'),
(84533, 2010, 'plos', 'Molecular structures of quiescently grown and brain-derived polymorphic fibrils of the Alzheimer amyloid abeta9-40 peptide: a comparison to agitated fibrils', 'Wu, Chun|Bowers, Michael T|Shea, Joan-Emma', 'Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, California, United States of America.|Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, California, United States of America.|Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, California, United States of America.', 'United States|United States|United States', 0, 'Amyloid beta-Peptides|Brain Chemistry|Computer Simulation|Models, Chemical|Models, Molecular|Peptides|Protein Conformation|Protein Folding', 'Comparative Study', '10.1371/journal.pcbi.1000693', '20221247', 'The presence of amyloid deposits consisting primarily of Amyloid-beta (Abeta) fibril in the brain is a hallmark of Alzheimers disease (AD). The morphologies of these fibrils are exquisitely sensitive to environmental conditions. Using molecular dynamics simulations combined with data from previously published solid-state NMR experiments, we propose the first atomically detailed structures of two asymmetric polymorphs of the Abeta(9-40) peptide fibril. The first corresponds to synthetic fibrils grown under quiescent conditions and the second to fibrils derived from AD patients brain-extracts. Our core structure in both fibril structures consists of a layered structure in which three cross-beta subunits are arranged in six tightly stacked beta-sheet layers with an antiparallel hydrophobic-hydrophobic and an antiparallel polar-polar interface. The synthetic and brain-derived structures differ primarily in the side-chain orientation of one beta-strand. The presence of a large and continually exposed hydrophobic surface (buried in the symmetric agitated Abeta fibrils) may account for the higher toxicity of the asymmetric fibrils. Our model explains the effects of external perturbations on the fibril lateral architecture as well as the fibrillogenesis inhibiting action of amphiphilic molecules.'),
(84534, 2010, 'plos', 'Diffusion, crowding & protein stability in a dynamic molecular model of the bacterial cytoplasm', 'McGuffee, Sean R|Elcock, Adrian H', 'Department of Biochemistry, University of Iowa, Iowa City, Iowa, United States of America.|Department of Biochemistry, University of Iowa, Iowa City, Iowa, United States of America.', 'United States|United States', 446, 'Computer Simulation|Cytoplasm|Escherichia coli|Escherichia coli Proteins|Models, Chemical|Models, Molecular|Protein Conformation|Protein Folding', 'Journal Article', '10.1371/journal.pcbi.1000694', '20221255', 'A longstanding question in molecular biology is the extent to which the behavior of macromolecules observed in vitro accurately reflects their behavior in vivo. A number of sophisticated experimental techniques now allow the behavior of individual types of macromolecule to be studied directly in vivo, none, however, allow a wide range of molecule types to be observed simultaneously. In order to tackle this issue we have adopted a computational perspective, and, having selected the model prokaryote Escherichia coli as a test system, have assembled an atomically detailed model of its cytoplasmic environment that includes 50 of the most abundant types of macromolecules at experimentally measured concentrations. Brownian dynamics (BD) simulations of the cytoplasm model have been calibrated to reproduce the translational diffusion coefficients of Green Fluorescent Protein (GFP) observed in vivo, and snapshots of the simulation trajectories have been used to compute the cytoplasms effects on the thermodynamics of protein folding, association and aggregation events. The simulation model successfully describes the relative thermodynamic stabilities of proteins measured in E. coli, and shows that effects additional to the commonly cited crowding effect must be included in attempts to understand macromolecular behavior in vivo.'),
(84535, 2010, 'plos', 'Mathematical modelling of cell-fate decision in response to death receptor engagement', 'Calzone, Laurence|Tournier, Laurent|Fourquet, Simon|Thieffry, Denis|Zhivotovsky, Boris|Barillot, Emmanuel|Zinovyev, Andrei', 'Institut Curie, Paris, France. Laurence.Calzone@curie.fr|Institut Curie, Paris, France. Laurence.Calzone@curie.fr|Institut Curie, Paris, France. Laurence.Calzone@curie.fr|Institut Curie, Paris, France. Laurence.Calzone@curie.fr|Institut Curie, Paris, France. Laurence.Calzone@curie.fr|Institut Curie, Paris, France. Laurence.Calzone@curie.fr|Institut Curie, Paris, France. Laurence.Calzone@curie.fr', 'France|France|France|France|France|France|France', 118, 'Animals|Apoptosis|Computer Simulation|Humans|Models, Biological|Receptors, Death Domain', 'Journal Article', '10.1371/journal.pcbi.1000702', '20221256', 'Cytokines such as TNF and FASL can trigger death or survival depending on cell lines and cellular conditions. The mechanistic details of how a cell chooses among these cell fates are still unclear. The understanding of these processes is important since they are altered in many diseases, including cancer and AIDS. Using a discrete modelling formalism, we present a mathematical model of cell fate decision recapitulating and integrating the most consistent facts extracted from the literature. This model provides a generic high-level view of the interplays between NFkappaB pro-survival pathway, RIP1-dependent necrosis, and the apoptosis pathway in response to death receptor-mediated signals. Wild type simulations demonstrate robust segregation of cellular responses to receptor engagement. Model simulations recapitulate documented phenotypes of protein knockdowns and enable the prediction of the effects of novel knockdowns. In silico experiments simulate the outcomes following ligand removal at different stages, and suggest experimental approaches to further validate and specialise the model for particular cell types. We also propose a reduced conceptual model implementing the logic of the decision process. This analysis gives specific predictions regarding cross-talks between the three pathways, as well as the transient role of RIP1 protein in necrosis, and confirms the phenotypes of novel perturbations. Our wild type and mutant simulations provide novel insights to restore apoptosis in defective cells. The model analysis expands our understanding of how cell fate decision is made. Moreover, our current model can be used to assess contradictory or controversial data from the literature. Ultimately, it constitutes a valuable reasoning tool to delineate novel experiments.'),
(84536, 2010, 'plos', 'Systematic planning of genome-scale experiments in poorly studied species', 'Guan, Yuanfang|Dunham, Maitreya|Caudy, Amy|Troyanskaya, Olga', 'Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.|Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.|Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.|Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.', 'Jersey|Jersey|Jersey|Jersey', 20, 'Chromosome Mapping|Computer Simulation|Gene Expression Profiling|Models, Biological|Oligonucleotide Array Sequence Analysis|Proteome|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Signal Transduction|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.1000698', '20221257', 'Genome-scale datasets have been used extensively in model organisms to screen for specific candidates or to predict functions for uncharacterized genes. However, despite the availability of extensive knowledge in model organisms, the planning of genome-scale experiments in poorly studied species is still based on the intuition of experts or heuristic trials. We propose that computational and systematic approaches can be applied to drive the experiment planning process in poorly studied species based on available data and knowledge in closely related model organisms. In this paper, we suggest a computational strategy for recommending genome-scale experiments based on their capability to interrogate diverse biological processes to enable protein function assignment. To this end, we use the data-rich functional genomics compendium of the model organism to quantify the accuracy of each dataset in predicting each specific biological process and the overlap in such coverage between different datasets. Our approach uses an optimized combination of these quantifications to recommend an ordered list of experiments for accurately annotating most proteins in the poorly studied related organisms to most biological processes, as well as a set of experiments that target each specific biological process. The effectiveness of this experiment- planning system is demonstrated for two related yeast species: the model organism Saccharomyces cerevisiae and the comparatively poorly studied Saccharomyces bayanus. Our system recommended a set of S. bayanus experiments based on an S. cerevisiae microarray data compendium. In silico evaluations estimate that less than 10% of the experiments could achieve similar functional coverage to the whole microarray compendium. This estimation was confirmed by performing the recommended experiments in S. bayanus, therefore significantly reducing the labor devoted to characterize the poorly studied genome. This experiment-planning framework could readily be adapted to the design of other types of large-scale experiments as well as other groups of organisms.'),
(84537, 2010, 'plos', 'Designing focused chemical libraries enriched in protein-protein interaction inhibitors using machine-learning methods', 'Reynès, Christelle|Host, Hélène|Camproux, Anne-Claude|Laconde, Guillaume|Leroux, Florence|Mazars, Anne|Deprez, Benoit|Fahraeus, Robin|Villoutreix, Bruno O|Sperandio, Olivier', 'Inserm UMR-S 973/MTi, University Paris Diderot, Paris, France.|Inserm UMR-S 973/MTi, University Paris Diderot, Paris, France.|Inserm UMR-S 973/MTi, University Paris Diderot, Paris, France.|Inserm UMR-S 973/MTi, University Paris Diderot, Paris, France.|Inserm UMR-S 973/MTi, University Paris Diderot, Paris, France.|Inserm UMR-S 973/MTi, University Paris Diderot, Paris, France.|Inserm UMR-S 973/MTi, University Paris Diderot, Paris, France.|Inserm UMR-S 973/MTi, University Paris Diderot, Paris, France.|Inserm UMR-S 973/MTi, University Paris Diderot, Paris, France.|Inserm UMR-S 973/MTi, University Paris Diderot, Paris, France.', 'France|France|France|France|France|France|France|France|France|France', 92, 'Artificial Intelligence|Humans|Information Storage and Retrieval|Pattern Recognition, Automated|Protein Interaction Mapping|Proteome|Small Molecule Libraries|Software', 'Journal Article', '10.1371/journal.pcbi.1000695', '20221258', 'Protein-protein interactions (PPIs) may represent one of the next major classes of therapeutic targets. So far, only a minute fraction of the estimated 650,000 PPIs that comprise the human interactome are known with a tiny number of complexes being drugged. Such intricate biological systems cannot be cost-efficiently tackled using conventional high-throughput screening methods. Rather, time has come for designing new strategies that will maximize the chance for hit identification through a rationalization of the PPI inhibitor chemical space and the design of PPI-focused compound libraries (global or target-specific). Here, we train machine-learning-based models, mainly decision trees, using a dataset of known PPI inhibitors and of regular drugs in order to determine a global physico-chemical profile for putative PPI inhibitors. This statistical analysis unravels two important molecular descriptors for PPI inhibitors characterizing specific molecular shapes and the presence of a privileged number of aromatic bonds. The best model has been transposed into a computer program, PPI-HitProfiler, that can output from any drug-like compound collection a focused chemical library enriched in putative PPI inhibitors. Our PPI inhibitor profiler is challenged on the experimental screening results of 11 different PPIs among which the p53/MDM2 interaction screened within our own CDithem platform, that in addition to the validation of our concept led to the identification of 4 novel p53/MDM2 inhibitors. Collectively, our tool shows a robust behavior on the 11 experimental datasets by correctly profiling 70% of the experimentally identified hits while removing 52% of the inactive compounds from the initial compound collections. We strongly believe that this new tool can be used as a global PPI inhibitor profiler prior to screening assays to reduce the size of the compound collections to be experimentally screened while keeping most of the true PPI inhibitors. PPI-HitProfiler is freely available on request from our CDithem platform website, www.CDithem.com.'),
(84538, 2010, 'plos', 'Estimating the stochastic bifurcation structure of cellular networks', 'Song, Carl|Phenix, Hilary|Abedi, Vida|Scott, Matthew|Ingalls, Brian P|Kaern, Mads|Perkins, Theodore J', 'Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.', 'Canada|Canada|Canada|Canada|Canada|Canada|Canada', 26, 'Computer Simulation|Gene Expression Profiling|Models, Biological|Models, Statistical|Proteome|Signal Transduction|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1000699', '20221261', 'High throughput measurement of gene expression at single-cell resolution, combined with systematic perturbation of environmental or cellular variables, provides information that can be used to generate novel insight into the properties of gene regulatory networks by linking cellular responses to external parameters. In dynamical systems theory, this information is the subject of bifurcation analysis, which establishes how system-level behaviour changes as a function of parameter values within a given deterministic mathematical model. Since cellular networks are inherently noisy, we generalize the traditional bifurcation diagram of deterministic systems theory to stochastic dynamical systems. We demonstrate how statistical methods for density estimation, in particular, mixture density and conditional mixture density estimators, can be employed to establish empirical bifurcation diagrams describing the bistable genetic switch network controlling galactose utilization in yeast Saccharomyces cerevisiae. These approaches allow us to make novel qualitative and quantitative observations about the switching behavior of the galactose network, and provide a framework that might be useful to extract information needed for the development of quantitative network models.'),
(84539, 2010, 'plos', 'Parameter estimation and model selection in computational biology', 'Lillacci, Gabriele|Khammash, Mustafa', 'Center for Control, Dynamical Systems and Computation, University of California at Santa Barbara, Santa Barbara, California, United States of America.|Center for Control, Dynamical Systems and Computation, University of California at Santa Barbara, Santa Barbara, California, United States of America.', 'United States|United States', 186, 'Algorithms|Animals|Computer Simulation|Gene Expression Regulation|Humans|Models, Biological|Proteome|Signal Transduction|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000696', '20221262', 'A central challenge in computational modeling of biological systems is the determination of the model parameters. Typically, only a fraction of the parameters (such as kinetic rate constants) are experimentally measured, while the rest are often fitted. The fitting process is usually based on experimental time course measurements of observables, which are used to assign parameter values that minimize some measure of the error between these measurements and the corresponding model prediction. The measurements, which can come from immunoblotting assays, fluorescent markers, etc., tend to be very noisy and taken at a limited number of time points. In this work we present a new approach to the problem of parameter selection of biological models. We show how one can use a dynamic recursive estimator, known as extended Kalman filter, to arrive at estimates of the model parameters. The proposed method follows. First, we use a variation of the Kalman filter that is particularly well suited to biological applications to obtain a first guess for the unknown parameters. Secondly, we employ an a posteriori identifiability test to check the reliability of the estimates. Finally, we solve an optimization problem to refine the first guess in case it should not be accurate enough. The final estimates are guaranteed to be statistically consistent with the measurements. Furthermore, we show how the same tools can be used to discriminate among alternate models of the same biological process. We demonstrate these ideas by applying our methods to two examples, namely a model of the heat shock response in E. coli, and a model of a synthetic gene regulation system. The methods presented are quite general and may be applied to a wide class of biological systems where noisy measurements are used for parameter estimation or model selection.'),
(84540, 2010, 'plos', 'Within- and cross-modal distance information disambiguate visual size-change perception', 'Battaglia, Peter W|Di Luca, Massimiliano|Ernst, Marc O|Schrater, Paul R|Machulla, Tonja|Kersten, Daniel', 'Brain and Cognitive Sciences and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. pbatt@mit.edu|Brain and Cognitive Sciences and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. pbatt@mit.edu|Brain and Cognitive Sciences and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. pbatt@mit.edu|Brain and Cognitive Sciences and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. pbatt@mit.edu|Brain and Cognitive Sciences and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. pbatt@mit.edu|Brain and Cognitive Sciences and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. pbatt@mit.edu', 'United States|United States|United States|United States|United States|United States', 7, 'Cues|Decision Making|Form Perception|Humans|Task Performance and Analysis|Touch|Vision, Binocular', 'Journal Article', '10.1371/journal.pcbi.1000697', '20221263', 'Perception is fundamentally underconstrained because different combinations of object properties can generate the same sensory information. To disambiguate sensory information into estimates of scene properties, our brains incorporate prior knowledge and additional auxiliary (i.e., not directly relevant to desired scene property) sensory information to constrain perceptual interpretations. For example, knowing the distance to an object helps in perceiving its size. The literature contains few demonstrations of the use of prior knowledge and auxiliary information in combined visual and haptic disambiguation and almost no examination of haptic disambiguation of vision beyond bistable stimuli. Previous studies have reported humans integrate multiple unambiguous sensations to perceive single, continuous object properties, like size or position. Here we test whether humans use visual and haptic information, individually and jointly, to disambiguate size from distance. We presented participants with a ball moving in depth with a changing diameter. Because no unambiguous distance information is available under monocular viewing, participants rely on prior assumptions about the balls distance to disambiguate their -size percept. Presenting auxiliary binocular and/or haptic distance information augments participants prior distance assumptions and improves their size judgment accuracy-though binocular cues were trusted more than haptic. Our results suggest both visual and haptic distance information disambiguate size perception, and we interpret these results in the context of probabilistic perceptual reasoning.'),
(84541, 2010, 'plos', 'Effects of transcriptional pausing on gene expression dynamics', 'Rajala, Tiina|Häkkinen, Antti|Healy, Shannon|Yli-Harja, Olli|Ribeiro, Andre S', 'Computational Systems Biology Research Group, Department of Signal Processing, Tampere University of Technology, Tampere, Finland.|Computational Systems Biology Research Group, Department of Signal Processing, Tampere University of Technology, Tampere, Finland.|Computational Systems Biology Research Group, Department of Signal Processing, Tampere University of Technology, Tampere, Finland.|Computational Systems Biology Research Group, Department of Signal Processing, Tampere University of Technology, Tampere, Finland.|Computational Systems Biology Research Group, Department of Signal Processing, Tampere University of Technology, Tampere, Finland.', 'Finland|Finland|Finland|Finland|Finland', 34, 'Computer Simulation|DNA-Directed RNA Polymerases|Gene Expression|Gene Expression Regulation|Models, Genetic|RNA|Transcription, Genetic|Transcriptional Activation', 'Journal Article', '10.1371/journal.pcbi.1000704', '20300642', 'Stochasticity in gene expression affects many cellular processes and is a source of phenotypic diversity between genetically identical individuals. Events in elongation, particularly RNA polymerase pausing, are a source of this noise. Since the rate and duration of pausing are sequence-dependent, this regulatory mechanism of transcriptional dynamics is evolvable. The dependency of pause propensity on regulatory molecules makes pausing a response mechanism to external stress. Using a delayed stochastic model of bacterial transcription at the single nucleotide level that includes the promoter open complex formation, pausing, arrest, misincorporation and editing, pyrophosphorolysis, and premature termination, we investigate how RNA polymerase pausing affects a genes transcriptional dynamics and gene networks. We show that pauses duration and rate of occurrence affect the bursting in RNA production, transcriptional and translational noise, and the transient to reach mean RNA and protein levels. In a genetic repressilator, increasing the pausing rate and the duration of pausing events increases the period length but does not affect the robustness of the periodicity. We conclude that RNA polymerase pausing might be an important evolvable feature of genetic networks.'),
(84542, 2010, 'plos', 'Detailed simulations of cell biology with Smoldyn 21', 'Andrews, Steven S|Addy, Nathan J|Brent, Roger|Arkin, Adam P', 'Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America. sandrews@fhcrc.org|Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America. sandrews@fhcrc.org|Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America. sandrews@fhcrc.org|Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America. sandrews@fhcrc.org', 'United States|United States|United States|United States', 207, 'Algorithms|Computer Simulation|Models, Biological|Proteome|Signal Transduction|Software', 'Journal Article', '10.1371/journal.pcbi.1000705', '20300644', 'Most cellular processes depend on intracellular locations and random collisions of individual protein molecules. To model these processes, we developed algorithms to simulate the diffusion, membrane interactions, and reactions of individual molecules, and implemented these in the Smoldyn program. Compared to the popular MCell and ChemCell simulators, we found that Smoldyn was in many cases more accurate, more computationally efficient, and easier to use. Using Smoldyn, we modeled pheromone response system signaling among yeast cells of opposite mating type. This model showed that secreted Bar1 protease might help a cell identify the fittest mating partner by sharpening the pheromone concentration gradient. This model involved about 200,000 protein molecules, about 7000 cubic microns of volume, and about 75 minutes of simulated time, it took about 10 hours to run. Over the next several years, as faster computers become available, Smoldyn will allow researchers to model and explore systems the size of entire bacterial and smaller eukaryotic cells.'),
(84543, 2010, 'plos', 'A multiscale model to investigate circadian rhythmicity of pacemaker neurons in the suprachiasmatic nucleus', 'Vasalou, Christina|Henson, Michael A', 'Department of Chemical Engineering, University of Massachusetts, Amherst, Massachusetts, United States of America.|Department of Chemical Engineering, University of Massachusetts, Amherst, Massachusetts, United States of America.', 'United States|United States', 0, 'Animals|Biological Clocks|Circadian Rhythm|Computer Simulation|Humans|Models, Neurological|Nerve Net|Neurons|Suprachiasmatic Nucleus', 'Journal Article', '10.1371/journal.pcbi.1000706', '20300645', 'The suprachiasmatic nucleus (SCN) of the hypothalamus is a multicellular system that drives daily rhythms in mammalian behavior and physiology. Although the gene regulatory network that produces daily oscillations within individual neurons is well characterized, less is known about the electrophysiology of the SCN cells and how firing rate correlates with circadian gene expression. We developed a firing rate code model to incorporate known electrophysiological properties of SCN pacemaker cells, including circadian dependent changes in membrane voltage and ion conductances. Calcium dynamics were included in the model as the putative link between electrical firing and gene expression. Individual ion currents exhibited oscillatory patterns matching experimental data both in current levels and phase relationships. VIP and GABA neurotransmitters, which encode synaptic signals across the SCN, were found to play critical roles in daily oscillations of membrane excitability and gene expression. Blocking various mechanisms of intracellular calcium accumulation by simulated pharmacological agents (nimodipine, IP3- and ryanodine-blockers) reproduced experimentally observed trends in firing rate dynamics and core-clock gene transcription. The intracellular calcium concentration was shown to regulate diverse circadian processes such as firing frequency, gene expression and system periodicity. The model predicted a direct relationship between firing frequency and gene expression amplitudes, demonstrated the importance of intracellular pathways for single cell behavior and provided a novel multiscale framework which captured characteristics of the SCN at both the electrophysiological and gene regulatory levels.'),
(84544, 2010, 'plos', 'Modeling co-expression across species for complex traits: insights to the difference of human and mouse embryonic stem cells', 'Cai, Jun|Xie, Dan|Fan, Zhewen|Chipperfield, Hiram|Marden, John|Wong, Wing H|Zhong, Sheng', 'Department of Bioengineering, University of Illinois at Urbana Champaign, Urbana, Illinois, United States of America.|Department of Bioengineering, University of Illinois at Urbana Champaign, Urbana, Illinois, United States of America.|Department of Bioengineering, University of Illinois at Urbana Champaign, Urbana, Illinois, United States of America.|Department of Bioengineering, University of Illinois at Urbana Champaign, Urbana, Illinois, United States of America.|Department of Bioengineering, University of Illinois at Urbana Champaign, Urbana, Illinois, United States of America.|Department of Bioengineering, University of Illinois at Urbana Champaign, Urbana, Illinois, United States of America.|Department of Bioengineering, University of Illinois at Urbana Champaign, Urbana, Illinois, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 21, 'Animals|Computer Simulation|Embryonic Stem Cells|Gene Expression Regulation|Humans|Mice|Models, Biological|Proteome|Signal Transduction|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.1000707', '20300647', 'Complex interactions between genes or proteins contribute substantially to phenotypic evolution. We present a probabilistic model and a maximum likelihood approach for cross-species clustering analysis and for identification of conserved as well as species-specific co-expression modules. This model enables a soft cross-species clustering (SCSC) approach by encouraging but not enforcing orthologous genes to be grouped into the same cluster. SCSC is therefore robust to obscure orthologous relationships and can reflect different functional roles of orthologous genes in different species. We generated a time-course gene expression dataset for differentiating mouse embryonic stem (ES) cells, and compiled a dataset of published gene expression data on differentiating human ES cells. Applying SCSC to analyze these datasets, we identified conserved and species-specific gene regulatory modules. Together with protein-DNA binding data, an SCSC cluster specifically induced in murine ES cells indicated that the KLF2/4/5 transcription factors, although critical to maintaining the pluripotent phenotype in mouse ES cells, were decoupled from the OCT4/SOX2/NANOG regulatory module in human ES cells. Two of the target genes of murine KLF2/4/5, LIN28 and NODAL, were rewired to be targets of OCT4/SOX2/NANOG in human ES cells. Moreover, by mapping SCSC clusters onto KEGG signaling pathways, we identified the signal transduction components that were induced in pluripotent ES cells in either a conserved or a species-specific manner. These results suggest that the pluripotent cell identity can be established and maintained through more than one gene regulatory network.'),
(84545, 2010, 'plos', 'Slower visuomotor corrections with unchanged latency are consistent with optimal adaptation to increased endogenous noise in the elderly', 'Sherback, Michael|Valero-Cuevas, Francisco J|DAndrea, Raffaello', 'Institute for Dynamic Systems and Control, ETH-Zurich, Zurich, Switzerland. sherback@idsc.mavt.ethz.ch|Institute for Dynamic Systems and Control, ETH-Zurich, Zurich, Switzerland. sherback@idsc.mavt.ethz.ch|Institute for Dynamic Systems and Control, ETH-Zurich, Zurich, Switzerland. sherback@idsc.mavt.ethz.ch', 'Switzerland|Switzerland|Switzerland', 8, 'Adaptation, Physiological|Aged|Aged, 80 and over|Aging|Computer Simulation|Female|Humans|Male|Middle Aged|Models, Neurological|Movement|Reaction Time|Task Performance and Analysis|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1000708', '20300648', 'We analyzed age-related changes in motor response in a visuomotor compensatory tracking task. Subjects used a manipulandum to attempt to keep a displayed cursor at the center of a screen despite random perturbations to its location. Cross-correlation analysis of the perturbation and the subject response showed no age-related increase in latency until the onset of response to the perturbation, but substantial slowing of the response itself. Results are consistent with age-related deterioration in the ratio of signal to noise in visuomotor response. The task is such that it is tractable to use Bayesian and quadratic optimality assumptions to construct a model for behavior. This model assumes that behavior resembles an optimal controller subject to noise, and parametrizes response in terms of latency, willingness to expend effort, noise intensity, and noise bandwidth. The model is consistent with the data for all young (n = 12, age 20-30) and most elderly (n = 12, age 65-92) subjects. The model reproduces the latency result from the cross-correlation method. When presented with increased noise, the computational model reproduces the experimentally observed age-related slowing and the observed lack of increased latency. The model provides a precise way to quantitatively formulate the long-standing hypothesis that age-related slowing is an adaptation to increased noise.'),
(84546, 2010, 'plos', 'Comparing families of dynamic causal models', 'Penny, Will D|Stephan, Klaas E|Daunizeau, Jean|Rosa, Maria J|Friston, Karl J|Schofield, Thomas M|Leff, Alex P', 'Wellcome Trust Centre for Neuroimaging, University College, London, United Kingdom. w.penny@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, University College, London, United Kingdom. w.penny@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, University College, London, United Kingdom. w.penny@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, University College, London, United Kingdom. w.penny@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, University College, London, United Kingdom. w.penny@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, University College, London, United Kingdom. w.penny@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, University College, London, United Kingdom. w.penny@fil.ion.ucl.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Bayes Theorem|Brain|Causality|Computer Simulation|Models, Neurological|Models, Statistical|Nerve Net|Pattern Recognition, Automated', 'Journal Article', '10.1371/journal.pcbi.1000709', '20300649', 'Mathematical models of scientific data can be formally compared using Bayesian model evidence. Previous applications in the biological sciences have mainly focussed on model selection in which one first selects the model with the highest evidence and then makes inferences based on the parameters of that model. This best model approach is very useful but can become brittle if there are a large number of models to compare, and if different subjects use different models. To overcome this shortcoming we propose the combination of two further approaches: (i) family level inference and (ii) Bayesian model averaging within families. Family level inference removes uncertainty about aspects of model structure other than the characteristic of interest. For example: What are the inputs to the system? Is processing serial or parallel? Is it linear or nonlinear? Is it mediated by a single, crucial connection? We apply Bayesian model averaging within families to provide inferences about parameters that are independent of further assumptions about model structure. We illustrate the methods using Dynamic Causal Models of brain imaging data.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84547, 2010, 'plos', 'Interplay between pleiotropy and secondary selection determines rise and fall of mutators in stress response', 'Heo, Muyoung|Shakhnovich, Eugene I', 'Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.', 'United States|United States', 14, 'Adaptation, Physiological|Animals|Base Pair Mismatch|Computer Simulation|Genetics, Population|Humans|Models, Genetic|Mutation|Selection, Genetic|Stress, Physiological', 'Journal Article', '10.1371/journal.pcbi.1000710', '20300650', 'Mutators are clones whose mutation rate is about two to three orders of magnitude higher than the rate of wild-type clones and their roles in adaptive evolution of asexual populations have been controversial. Here we address this problem by using an ab initio microscopic model of living cells, which combines population genetics with a physically realistic presentation of protein stability and protein-protein interactions. The genome of model organisms encodes replication controlling genes (RCGs) and genes modeling the mismatch repair (MMR) complexes. The genotype-phenotype relationship posits that the replication rate of an organism is proportional to protein copy numbers of RCGs in their functional form and there is a production cost penalty for protein overexpression. The mutation rate depends linearly on the concentration of homodimers of MMR proteins. By simulating multiple runs of evolution of populations under various environmental stresses--stationary phase, starvation or temperature-jump--we find that adaptation most often occurs through transient fixation of a mutator phenotype, regardless of the nature of stress. By contrast, the fixation mechanism does depend on the nature of stress. In temperature jump stress, mutators take over the population due to loss of stability of MMR complexes. In contrast, in starvation and stationary phase stresses, a small number of mutators are supplied to the population via epigenetic stochastic noise in production of MMR proteins (a pleiotropic effect), and their net supply is higher due to reduced genetic drift in slowly growing populations under stressful environments. Subsequently, mutators in stationary phase or starvation hitchhike to fixation with a beneficial mutation in the RCGs, (second order selection) and finally a mutation stabilizing the MMR complex arrives, returning the population to a non-mutator phenotype. Our results provide microscopic insights into the rise and fall of mutators in adapting finite asexual populations.'),
(84548, 2010, 'plos', 'Neocortical axon arbors trade-off material and conduction delay conservation', 'Budd, Julian M L|Kovács, Krisztina|Ferecskó, Alex S|Buzás, Péter|Eysel, Ulf T|Kisvárday, Zoltán F', 'School of Informatics, University of Sussex, Brighton, United Kingdom. j.m.l.budd@susx.ac.uk|School of Informatics, University of Sussex, Brighton, United Kingdom. j.m.l.budd@susx.ac.uk|School of Informatics, University of Sussex, Brighton, United Kingdom. j.m.l.budd@susx.ac.uk|School of Informatics, University of Sussex, Brighton, United Kingdom. j.m.l.budd@susx.ac.uk|School of Informatics, University of Sussex, Brighton, United Kingdom. j.m.l.budd@susx.ac.uk|School of Informatics, University of Sussex, Brighton, United Kingdom. j.m.l.budd@susx.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 32, 'Animals|Axons|Humans|Models, Anatomic|Models, Neurological|Neocortex|Nerve Net|Neural Conduction|Reaction Time|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1000711', '20300651', 'The brain contains a complex network of axons rapidly communicating information between billions of synaptically connected neurons. The morphology of individual axons, therefore, defines the course of information flow within the brain. More than a century ago, Ramón y Cajal proposed that conservation laws to save material (wire) length and limit conduction delay regulate the design of individual axon arbors in cerebral cortex. Yet the spatial and temporal communication costs of single neocortical axons remain undefined. Here, using reconstructions of in vivo labelled excitatory spiny cell and inhibitory basket cell intracortical axons combined with a variety of graph optimization algorithms, we empirically investigated Cajals conservation laws in cerebral cortex for whole three-dimensional (3D) axon arbors, to our knowledge the first study of its kind. We found intracortical axons were significantly longer than optimal. The temporal cost of cortical axons was also suboptimal though far superior to wire-minimized arbors. We discovered that cortical axon branching appears to promote a low temporal dispersion of axonal latencies and a tight relationship between cortical distance and axonal latency. In addition, inhibitory basket cell axonal latencies may occur within a much narrower temporal window than excitatory spiny cell axons, which may help boost signal detection. Thus, to optimize neuronal network communication we find that a modest excess of axonal wire is traded-off to enhance arbor temporal economy and precision. Our results offer insight into the principles of brain organization and communication in and development of grey matter, where temporal precision is a crucial prerequisite for coincidence detection, synchronization and rapid network oscillations.'),
(84549, 2010, 'plos', 'Quantitative comparison of catalytic mechanisms and overall reactions in convergently evolved enzymes: implications for classification of enzyme function', 'Almonacid, Daniel E|Yera, Emmanuel R|Mitchell, John B O|Babbitt, Patricia C', 'Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.|Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.|Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.|Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.', 'United States|United States|United States|United States', 0, 'Amino Acid Sequence|Binding Sites|Catalysis|Computer Simulation|Databases, Protein|Enzyme Activation|Enzymes|Models, Chemical|Molecular Sequence Data|Protein Binding|Sequence Analysis, Protein|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1000700', '20300652', 'Functionally analogous enzymes are those that catalyze similar reactions on similar substrates but do not share common ancestry, providing a window on the different structural strategies nature has used to evolve required catalysts. Identification and use of this information to improve reaction classification and computational annotation of enzymes newly discovered in the genome projects would benefit from systematic determination of reaction similarities. Here, we quantified similarity in bond changes for overall reactions and catalytic mechanisms for 95 pairs of functionally analogous enzymes (non-homologous enzymes with identical first three numbers of their EC codes) from the MACiE database. Similarity of overall reactions was computed by comparing the sets of bond changes in the transformations from substrates to products. For similarity of mechanisms, sets of bond changes occurring in each mechanistic step were compared, these similarities were then used to guide global and local alignments of mechanistic steps. Using this metric, only 44% of pairs of functionally analogous enzymes in the dataset had significantly similar overall reactions. For these enzymes, convergence to the same mechanism occurred in 33% of cases, with most pairs having at least one identical mechanistic step. Using our metric, overall reaction similarity serves as an upper bound for mechanistic similarity in functional analogs. For example, the four carbon-oxygen lyases acting on phosphates (EC 4.2.3) show neither significant overall reaction similarity nor significant mechanistic similarity. By contrast, the three carboxylic-ester hydrolases (EC 3.1.1) catalyze overall reactions with identical bond changes and have converged to almost identical mechanisms. The large proportion of enzyme pairs that do not show significant overall reaction similarity (56%) suggests that at least for the functionally analogous enzymes studied here, more stringent criteria could be used to refine definitions of EC sub-subclasses for improved discrimination in their classification of enzyme reactions. The results also indicate that mechanistic convergence of reaction steps is widespread, suggesting that quantitative measurement of mechanistic similarity can inform approaches for functional annotation.'),
(84550, 2010, 'plos', 'Non-linear neuronal responses as an emergent property of afferent networks: a case study of the locust lobula giant movement detector', 'Bermúdez i Badia, Sergi|Bernardet, Ulysses|Verschure, Paul F M J', 'Laboratory for Synthetic Perceptive, Emotive and Cognitive Systems, Universitat Pompeu Fabra, Barcelona, Spain. sergi.bermudez@upf.edu|Laboratory for Synthetic Perceptive, Emotive and Cognitive Systems, Universitat Pompeu Fabra, Barcelona, Spain. sergi.bermudez@upf.edu|Laboratory for Synthetic Perceptive, Emotive and Cognitive Systems, Universitat Pompeu Fabra, Barcelona, Spain. sergi.bermudez@upf.edu', 'Spain|Spain|Spain', 26, 'Action Potentials|Animals|Computer Simulation|Grasshoppers|Models, Neurological|Motion Perception|Nerve Net|Neurons, Afferent|Nonlinear Dynamics|Sense Organs', 'Journal Article', '10.1371/journal.pcbi.1000701', '20300653', 'In principle it appears advantageous for single neurons to perform non-linear operations. Indeed it has been reported that some neurons show signatures of such operations in their electrophysiological response. A particular case in point is the Lobula Giant Movement Detector (LGMD) neuron of the locust, which is reported to locally perform a functional multiplication. Given the wide ramifications of this suggestion with respect to our understanding of neuronal computations, it is essential that this interpretation of the LGMD as a local multiplication unit is thoroughly tested. Here we evaluate an alternative model that tests the hypothesis that the non-linear responses of the LGMD neuron emerge from the interactions of many neurons in the opto-motor processing structure of the locust. We show, by exposing our model to standard LGMD stimulation protocols, that the properties of the LGMD that were seen as a hallmark of local non-linear operations can be explained as emerging from the dynamics of the pre-synaptic network. Moreover, we demonstrate that these properties strongly depend on the details of the synaptic projections from the medulla to the LGMD. From these observations we deduce a number of testable predictions. To assess the real-time properties of our model we applied it to a high-speed robot. These robot results show that our model of the locust opto-motor system is able to reliably stabilize the movement trajectory of the robot and can robustly support collision avoidance. In addition, these behavioural experiments suggest that the emergent non-linear responses of the LGMD neuron enhance the systems collision detection acuity. We show how all reported properties of this neuron are consistently reproduced by this alternative model, and how they emerge from the overall opto-motor processing structure of the locust. Hence, our results propose an alternative view on neuronal computation that emphasizes the network properties as opposed to the local transformations that can be performed by single neurons.'),
(84551, 2010, 'plos', 'Predicting transmembrane helix packing arrangements using residue contacts and a force-directed algorithm', 'Nugent, Timothy|Jones, David T', 'Bioinformatics Group, Department of Computer Science, University College London, London, United Kingdom.|Bioinformatics Group, Department of Computer Science, University College London, London, United Kingdom.', 'United Kingdom|United Kingdom', 0, 'Algorithms|Amino Acids|Binding Sites|Computer Simulation|Membrane Proteins|Models, Chemical|Models, Molecular|Protein Binding|Protein Conformation|Stress, Mechanical', 'Journal Article', '10.1371/journal.pcbi.1000714', '20333233', 'Alpha-helical transmembrane proteins constitute roughly 30% of a typical genome and are involved in a wide variety of important biological processes including cell signalling, transport of membrane-impermeable molecules and cell recognition. Despite significant efforts to predict transmembrane protein topology, comparatively little attention has been directed toward developing a method to pack the helices together. Here, we present a novel approach to predict lipid exposure, residue contacts, helix-helix interactions and finally the optimal helical packing arrangement of transmembrane proteins. Using molecular dynamics data, we have trained and cross-validated a support vector machine (SVM) classifier to predict per residue lipid exposure with 69% accuracy. This information is combined with additional features to train a second SVM to predict residue contacts which are then used to determine helix-helix interaction with up to 65% accuracy under stringent cross-validation on a non-redundant test set. Our method is also able to discriminate native from decoy helical packing arrangements with up to 70% accuracy. Finally, we employ a force-directed algorithm to construct the optimal helical packing arrangement which demonstrates success for proteins containing up to 13 transmembrane helices. This software is freely available as source code from http://bioinf.cs.ucl.ac.uk/memsat/mempack/.'),
(84552, 2010, 'plos', 'Predicted auxiliary navigation mechanism of peritrichously flagellated chemotactic bacteria', 'Vladimirov, Nikita|Lebiedz, Dirk|Sourjik, Victor', 'Interdisziplinäres Zentrum für Wissenschaftliches Rechnen (IWR) der Universität Heidelberg, Heidelberg, Germany. nikita.vladimirov@gmail.com|Interdisziplinäres Zentrum für Wissenschaftliches Rechnen (IWR) der Universität Heidelberg, Heidelberg, Germany. nikita.vladimirov@gmail.com|Interdisziplinäres Zentrum für Wissenschaftliches Rechnen (IWR) der Universität Heidelberg, Heidelberg, Germany. nikita.vladimirov@gmail.com', 'Germany|Germany|Germany', 27, 'Bacterial Physiological Phenomena|Chemotaxis|Computer Simulation|Flagella|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1000717', '20333235', 'Chemotactic movement of Escherichia coli is one of the most thoroughly studied paradigms of simple behavior. Due to significant competitive advantage conferred by chemotaxis and to high evolution rates in bacteria, the chemotaxis system is expected to be strongly optimized. Bacteria follow gradients by performing temporal comparisons of chemoeffector concentrations along their runs, a strategy which is most efficient given their size and swimming speed. Concentration differences are detected by a sensory system and transmitted to modulate rotation of flagellar motors, decreasing the probability of a tumble and reorientation if the perceived concentration change during a run is positive. Such regulation of tumble probability is of itself sufficient to explain chemotactic drift of a population up the gradient, and is commonly assumed to be the only navigation mechanism of chemotactic E. coli. Here we use computer simulations to predict existence of an additional mechanism of gradient navigation in E. coli. Based on the experimentally observed dependence of cell tumbling angle on the number of switching motors, we suggest that not only the tumbling probability but also the degree of reorientation during a tumble depend on the swimming direction along the gradient. Although the difference in mean tumbling angles up and down the gradient predicted by our model is small, it results in a dramatic enhancement of the cellular drift velocity along the gradient. We thus demonstrate a new level of optimization in E. coli chemotaxis, which arises from the switching of several flagellar motors and a resulting fine tuning of tumbling angle. Similar strategy is likely to be used by other peritrichously flagellated bacteria, and indicates yet another level of evolutionary development of bacterial chemotaxis.'),
(84553, 2010, 'plos', 'Patient referral patterns and the spread of hospital-acquired infections through national health care networks', 'Donker, Tjibbe|Wallinga, Jacco|Grundmann, Hajo', 'Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands. tjibbe.donker@rivm.nl|Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands. tjibbe.donker@rivm.nl|Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands. tjibbe.donker@rivm.nl', 'Netherlands|Netherlands|Netherlands', 0, 'Community Networks|Computer Simulation|Cross Infection|Female|Humans|Incidence|Male|Methicillin-Resistant Staphylococcus aureus|Models, Biological|National Health Programs|Netherlands|Population Dynamics|Referral and Consultation|Risk Assessment|Risk Factors|Staphylococcal Infections', 'Journal Article', '10.1371/journal.pcbi.1000715', '20333236', 'Rates of hospital-acquired infections, such as methicillin-resistant Staphylococcus aureus (MRSA), are increasingly used as quality indicators for hospital hygiene. Alternatively, these rates may vary between hospitals, because hospitals differ in admission and referral of potentially colonized patients. We assessed if different referral patterns between hospitals in health care networks can influence rates of hospital-acquired infections like MRSA. We used the Dutch medical registration of 2004 to measure the connectedness between hospitals. This allowed us to reconstruct the network of hospitals in the Netherlands. We used mathematical models to assess the effect of different patient referral patterns on the potential spread of hospital-acquired infections between hospitals, and between categories of hospitals (University medical centers, top clinical hospitals and general hospitals). University hospitals have a higher number of shared patients than teaching or general hospitals, and are therefore more likely to be among the first to receive colonized patients. Moreover, as the network is directional towards university hospitals, they have a higher prevalence, even when infection control measures are equally effective in all hospitals. Patient referral patterns have a profound effect on the spread of health care-associated infections like hospital-acquired MRSA. The MRSA prevalence therefore differs between hospitals with the position of each hospital within the health care network. Any comparison of MRSA rates between hospitals, as a benchmark for hospital hygiene, should therefore take the position of a hospital within the network into account.'),
(84554, 2010, 'plos', 'Emergence of spatial structure in cell groups and the evolution of cooperation', 'Nadell, Carey D|Foster, Kevin R|Xavier, João B', 'Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America.|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America.|Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America.', 'Jersey|Jersey|Jersey', 199, 'Animals|Biological Evolution|Cell Communication|Computer Simulation|Cooperative Behavior|Humans|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1000716', '20333237', 'On its own, a single cell cannot exert more than a microscopic influence on its immediate surroundings. However, via strength in numbers and the expression of cooperative phenotypes, such cells can enormously impact their environments. Simple cooperative phenotypes appear to abound in the microbial world, but explaining their evolution is challenging because they are often subject to exploitation by rapidly growing, non-cooperative cell lines. Population spatial structure may be critical for this problem because it influences the extent of interaction between cooperative and non-cooperative individuals. It is difficult for cooperative cells to succeed in competition if they become mixed with non-cooperative cells, which can exploit the public good without themselves paying a cost. However, if cooperative cells are segregated in space and preferentially interact with each other, they may prevail. Here we use a multi-agent computational model to study the origin of spatial structure within growing cell groups. Our simulations reveal that the spatial distribution of genetic lineages within these groups is linked to a small number of physical and biological parameters, including cell growth rate, nutrient availability, and nutrient diffusivity. Realistic changes in these parameters qualitatively alter the emergent structure of cell groups, and thereby determine whether cells with cooperative phenotypes can locally and globally outcompete exploitative cells. We argue that cooperative and exploitative cell lineages will spontaneously segregate in space under a wide range of conditions and, therefore, that cellular cooperation may evolve more readily than naively expected.'),
(84555, 2010, 'plos', 'Tumor growth rate determines the timing of optimal chronomodulated treatment schedules', 'Bernard, Samuel|Cajavec Bernard, Branka|Lévi, Francis|Herzel, Hanspeter', 'Institute for Theoretical Biology, Humboldt University and Charité, Berlin, Germany. bernard@math.univ-lyon1.fr|Institute for Theoretical Biology, Humboldt University and Charité, Berlin, Germany. bernard@math.univ-lyon1.fr|Institute for Theoretical Biology, Humboldt University and Charité, Berlin, Germany. bernard@math.univ-lyon1.fr|Institute for Theoretical Biology, Humboldt University and Charité, Berlin, Germany. bernard@math.univ-lyon1.fr', 'Germany|Germany|Germany|Germany', 34, 'Antineoplastic Agents|Cell Cycle|Circadian Rhythm|Computer Simulation|Drug Chronotherapy|Humans|Models, Biological|Neoplasms|Outcome Assessment (Health Care)|Treatment Outcome', 'Journal Article', '10.1371/journal.pcbi.1000712', '20333244', 'In host and cancer tissues, drug metabolism and susceptibility to drugs vary in a circadian (24 h) manner. In particular, the efficacy of a cell cycle specific (CCS) cytotoxic agent is affected by the daily modulation of cell cycle activity in the target tissues. Anti-cancer chronotherapy, in which treatments are administered at a particular time each day, aims at exploiting these biological rhythms to reduce toxicity and improve efficacy of the treatment. The circadian status, which is the timing of physiological and behavioral activity relative to daily environmental cues, largely determines the best timing of treatments. However, the influence of variations in tumor kinetics has not been considered in determining appropriate treatment schedules. We used a simple model for cell populations under chronomodulated treatment to identify which biological parameters are important for the successful design of a chronotherapy strategy. We show that the duration of the phase of the cell cycle targeted by the treatment and the cell proliferation rate are crucial in determining the best times to administer CCS drugs. Thus, optimal treatment times depend not only on the circadian status of the patient but also on the cell cycle kinetics of the tumor. Then, we developed a theoretical analysis of treatment outcome (TATO) to relate the circadian status and cell cycle kinetic parameters to the treatment outcomes. We show that the best and the worst CCS drug administration schedules are those with 24 h intervals, implying that 24 h chronomodulated treatments can be ineffective or even harmful if administered at wrong circadian times. We show that for certain tumors, administration times at intervals different from 24 h may reduce these risks without compromising overall efficacy.'),
(84556, 2010, 'plos', 'Estimating the stoichiometry of HIV neutralization', 'Magnus, Carsten|Regoes, Roland R', 'Integrative Biology, ETH Zurich, Zurich, Switzerland. carsten.magnus@env.ethz.ch|Integrative Biology, ETH Zurich, Zurich, Switzerland. carsten.magnus@env.ethz.ch', 'Switzerland|Switzerland', 27, 'Animals|Cell Membrane|Computer Simulation|HIV|Humans|Models, Chemical|Models, Immunological|Virus Activation|Virus Internalization', 'Journal Article', '10.1371/journal.pcbi.1000713', '20333245', 'HIV-1 virions infect target cells by first establishing contact between envelope glycoprotein trimers on the virions surface and CD4 receptors on a target cell, recruiting co-receptors, fusing with the cell membrane and finally releasing the genetic material into the target cell. Specific experimental setups allow the study of the number of trimer-receptor-interactions needed for infection, i.e., the stoichiometry of entry and also the number of antibodies needed to prevent one trimer from engaging successfully in the entry process, i.e., the stoichiometry of (trimer) neutralization. Mathematical models are required to infer the stoichiometric parameters from these experimental data. Recently, we developed mathematical models for the estimations of the stoichiometry of entry [1]. In this article, we show how our models can be extended to investigate the stoichiometry of trimer neutralization. We study how various biological parameters affect the estimate of the stoichiometry of neutralization. We find that the distribution of trimer numbers-which is also an important determinant of the stoichiometry of entry-influences the estimated value of the stoichiometry of neutralization. In contrast, other parameters, which characterize the experimental system, diminish the information we can extract from the data about the stoichiometry of neutralization, and thus reduce our confidence in the estimate. We illustrate the use of our models by re-analyzing previously published data on the neutralization sensitivity [2], which contains measurements of neutralization sensitivity of viruses with different envelope proteins to antibodies with various specificities. Our mathematical framework represents the formal basis for the estimation of the stoichiometry of neutralization. Together with the stoichiometry of entry, the stoichiometry of trimer neutralization will allow one to calculate how many antibodies are required to neutralize a virion or even an entire population of virions.'),
(84557, 2010, 'plos', 'Specialization can drive the evolution of modularity', 'Espinosa-Soto, Carlos|Wagner, Andreas', 'Department of Biochemistry, University of Zurich, Zurich, Switzerland. c.espinosa@bioc.uzh.ch|Department of Biochemistry, University of Zurich, Zurich, Switzerland. c.espinosa@bioc.uzh.ch', 'Switzerland|Switzerland', 117, 'Biological Evolution|Computer Simulation|Environment|Evolution, Molecular|Gene Expression Regulation|Genes|Models, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000719', '20360969', 'Organismal development and many cell biological processes are organized in a modular fashion, where regulatory molecules form groups with many interactions within a group and few interactions between groups. Thus, the activity of elements within a module depends little on elements outside of it. Modularity facilitates the production of heritable variation and of evolutionary innovations. There is no consensus on how modularity might evolve, especially for modules in development. We show that modularity can increase in gene regulatory networks as a byproduct of specialization in gene activity. Such specialization occurs after gene regulatory networks are selected to produce new gene activity patterns that appear in a specific body structure or under a specific environmental condition. Modules that arise after specialization in gene activity comprise genes that show concerted changes in gene activities. This and other observations suggest that modularity evolves because it decreases interference between different groups of genes. Our work can explain the appearance and maintenance of modularity through a mechanism that is not contingent on environmental change. We also show how modularity can facilitate co-option, the utilization of existing gene activity to build new gene activity patterns, a frequent feature of evolutionary innovations.'),
(84558, 2010, 'plos', 'Using pre-existing microarray datasets to increase experimental power: application to insulin resistance', 'Daigle, Bernie J|Deng, Alicia|McLaughlin, Tracey|Cushman, Samuel W|Cam, Margaret C|Reaven, Gerald|Tsao, Philip S|Altman, Russ B', 'Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 9, 'Algorithms|Artificial Intelligence|Databases, Protein|Gene Expression Profiling|Information Storage and Retrieval|Insulin Resistance|Oligonucleotide Array Sequence Analysis|Pattern Recognition, Automated|Proteome', 'Journal Article', '10.1371/journal.pcbi.1000718', '20361040', 'Although they have become a widely used experimental technique for identifying differentially expressed (DE) genes, DNA microarrays are notorious for generating noisy data. A common strategy for mitigating the effects of noise is to perform many experimental replicates. This approach is often costly and sometimes impossible given limited resources, thus, analytical methods are needed which increase accuracy at no additional cost. One inexpensive source of microarray replicates comes from prior work: to date, data from hundreds of thousands of microarray experiments are in the public domain. Although these data assay a wide range of conditions, they cannot be used directly to inform any particular experiment and are thus ignored by most DE gene methods. We present the SVD Augmented Gene expression Analysis Tool (SAGAT), a mathematically principled, data-driven approach for identifying DE genes. SAGAT increases the power of a microarray experiment by using observed coexpression relationships from publicly available microarray datasets to reduce uncertainty in individual genes expression measurements. We tested the method on three well-replicated human microarray datasets and demonstrate that use of SAGAT increased effective sample sizes by as many as 2.72 arrays. We applied SAGAT to unpublished data from a microarray study investigating transcriptional responses to insulin resistance, resulting in a 50% increase in the number of significant genes detected. We evaluated 11 (58%) of these genes experimentally using qPCR, confirming the directions of expression change for all 11 and statistical significance for three. Use of SAGAT revealed coherent biological changes in three pathways: inflammation, differentiation, and fatty acid synthesis, furthering our molecular understanding of a type 2 diabetes risk factor. We envision SAGAT as a means to maximize the potential for biological discovery from subtle transcriptional responses, and we provide it as a freely available software package that is immediately applicable to any human microarray study.'),
(84559, 2010, 'plos', 'Getting started in gene orthology and functional analysis', 'Fang, Gang|Bhardwaj, Nitin|Robilotto, Rebecca|Gerstein, Mark B', 'Department of Molecular Biophysics and Biophysics, Medical School, Yale University, New Haven, Connecticut, United States of America.|Department of Molecular Biophysics and Biophysics, Medical School, Yale University, New Haven, Connecticut, United States of America.|Department of Molecular Biophysics and Biophysics, Medical School, Yale University, New Haven, Connecticut, United States of America.|Department of Molecular Biophysics and Biophysics, Medical School, Yale University, New Haven, Connecticut, United States of America.', 'United States|United States|United States|United States', 0, 'Base Sequence|Evolution, Molecular|Genes|Molecular Sequence Data|Proteins|Sequence Alignment|Sequence Analysis, DNA|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1000703', '20361041', '-'),
(84560, 2010, 'plos', 'Drug-class specific impact of antivirals on the reproductive capacity of HIV', 'von Kleist, Max|Menz, Stephan|Huisinga, Wilhelm', 'Hamilton Institute, Computational Physiology Group, National University of Ireland Maynooth, Kildare, Ireland. vkleist@zedat.fu-berlin.de|Hamilton Institute, Computational Physiology Group, National University of Ireland Maynooth, Kildare, Ireland. vkleist@zedat.fu-berlin.de|Hamilton Institute, Computational Physiology Group, National University of Ireland Maynooth, Kildare, Ireland. vkleist@zedat.fu-berlin.de', 'Ireland|Ireland|Ireland', 0, 'Anti-HIV Agents|Computer Simulation|HIV|Models, Biological|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.1000720', '20361047', 'Predictive markers linking drug efficacy to clinical outcome are a key component in the drug discovery and development process. In HIV infection, two different measures, viral load decay and phenotypic assays, are used to assess drug efficacy in vivo and in vitro. For the newly introduced class of integrase inhibitors, a huge discrepancy between these two measures of efficacy was observed. Hence, a thorough understanding of the relation between these two measures of drug efficacy is imperative for guiding future drug discovery and development activities in HIV. In this article, we developed a novel viral dynamics model, which allows for a mechanistic integration of the mode of action of all approved drugs and drugs in late clinical trials. Subsequently, we established a link between in vivo and in vitro measures of drug efficacy, and extract important determinants of drug efficacy in vivo. The analysis is based on a new quantity-the reproductive capacity-that represents in mathematical terms the in vivo analog of the read-out of a phenotypic assay. Our results suggest a drug-class specific impact of antivirals on the total amount of viral replication. Moreover, we showed that the (drug-)target half life, dominated by immune-system related clearance processes, is a key characteristic that affects both the emergence of resistance as well as the in vitro-in vivo correlation of efficacy measures in HIV treatment. We found that protease- and maturation inhibitors, due to their target half-life, decrease the total amount of viral replication and the emergence of resistance most efficiently.'),
(84561, 2010, 'plos', 'The impact of contact tracing in clustered populations', 'House, Thomas|Keeling, Matt J', 'Warwick Mathematics Institute and Department of Biological Sciences, University of Warwick, Coventry, United Kingdom. T.A.House@warwick.ac.uk|Warwick Mathematics Institute and Department of Biological Sciences, University of Warwick, Coventry, United Kingdom. T.A.House@warwick.ac.uk', 'United Kingdom|United Kingdom', 0, 'Cluster Analysis|Computer Simulation|Contact Tracing|Humans|Models, Biological|Population Dynamics|Prevalence|Sexually Transmitted Diseases', 'Journal Article', '10.1371/journal.pcbi.1000721', '20361048', 'The tracing of potentially infectious contacts has become an important part of the control strategy for many infectious diseases, from early cases of novel infections to endemic sexually transmitted infections. Here, we make use of mathematical models to consider the case of partner notification for sexually transmitted infection, however these models are sufficiently simple to allow more general conclusions to be drawn. We show that, when contact network structure is considered in addition to contact tracing, standard mass action models are generally inadequate. To consider the impact of mutual contacts (specifically clustering) we develop an improvement to existing pairwise network models, which we use to demonstrate that ceteris paribus, clustering improves the efficacy of contact tracing for a large region of parameter space. This result is sometimes reversed, however, for the case of highly effective contact tracing. We also develop stochastic simulations for comparison, using simple re-wiring methods that allow the generation of appropriate comparator networks. In this way we contribute to the general theory of network-based interventions against infectious disease.'),
(84562, 2010, 'plos', 'Investigating homology between proteins using energetic profiles', 'Wrabl, James O|Hilser, Vincent J', 'Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.|Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.', 'United States|United States', 0, 'Amino Acid Sequence|Computer Simulation|Energy Transfer|Models, Chemical|Molecular Sequence Data|Proteins|Sequence Analysis, Protein|Sequence Homology, Amino Acid|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1000722', '20361049', 'Accumulated experimental observations demonstrate that protein stability is often preserved upon conservative point mutation. In contrast, less is known about the effects of large sequence or structure changes on the stability of a particular fold. Almost completely unknown is the degree to which stability of different regions of a protein is generally preserved throughout evolution. In this work, these questions are addressed through thermodynamic analysis of a large representative sample of protein fold space based on remote, yet accepted, homology. More than 3,000 proteins were computationally analyzed using the structural-thermodynamic algorithm COREX/BEST. Estimated position-specific stability (i.e., local Gibbs free energy of folding) and its component enthalpy and entropy were quantitatively compared between all proteins in the sample according to all-vs.-all pairwise structural alignment. It was discovered that the local stabilities of homologous pairs were significantly more correlated than those of non-homologous pairs, indicating that local stability was indeed generally conserved throughout evolution. However, the position-specific enthalpy and entropy underlying stability were less correlated, suggesting that the overall regional stability of a protein was more important than the thermodynamic mechanism utilized to achieve that stability. Finally, two different types of statistically exceptional evolutionary structure-thermodynamic relationships were noted. First, many homologous proteins contained regions of similar thermodynamics despite localized structure change, suggesting a thermodynamic mechanism enabling evolutionary fold change. Second, some homologous proteins with extremely similar structures nonetheless exhibited different local stabilities, a phenomenon previously observed experimentally in this laboratory. These two observations, in conjunction with the principal conclusion that homologous proteins generally conserved local stability, may provide guidance for a future thermodynamically informed classification of protein homology.'),
(84563, 2010, 'plos', 'Temperature control of fimbriation circuit switch in uropathogenic Escherichia coli: quantitative analysis via automated model abstraction', 'Kuwahara, Hiroyuki|Myers, Chris J|Samoilov, Michael S', 'Ray and Stephanie Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|Ray and Stephanie Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|Ray and Stephanie Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.', 'United States|United States|United States', 16, 'Computer Simulation|Escherichia coli|Feedback|Fimbriae Proteins|Fimbriae, Bacterial|Humans|Models, Biological|Signal Transduction|Temperature|Urinary Tract Infections', 'Journal Article', '10.1371/journal.pcbi.1000723', '20361050', 'Uropathogenic Escherichia coli (UPEC) represent the predominant cause of urinary tract infections (UTIs). A key UPEC molecular virulence mechanism is type 1 fimbriae, whose expression is controlled by the orientation of an invertible chromosomal DNA element-the fim switch. Temperature has been shown to act as a major regulator of fim switching behavior and is overall an important indicator as well as functional feature of many urologic diseases, including UPEC host-pathogen interaction dynamics. Given this panoptic physiological role of temperature during UTI progression and notable empirical challenges to its direct in vivo studies, in silico modeling of corresponding biochemical and biophysical mechanisms essential to UPEC pathogenicity may significantly aid our understanding of the underlying disease processes. However, rigorous computational analysis of biological systems, such as fim switch temperature control circuit, has hereto presented a notoriously demanding problem due to both the substantial complexity of the gene regulatory networks involved as well as their often characteristically discrete and stochastic dynamics. To address these issues, we have developed an approach that enables automated multiscale abstraction of biological system descriptions based on reaction kinetics. Implemented as a computational tool, this method has allowed us to efficiently analyze the modular organization and behavior of the E. coli fimbriation switch circuit at different temperature settings, thus facilitating new insights into this mode of UPEC molecular virulence regulation. In particular, our results suggest that, with respect to its role in shutting down fimbriae expression, the primary function of FimB recombinase may be to effect a controlled down-regulation (rather than increase) of the ON-to-OFF fim switching rate via temperature-dependent suppression of competing dynamics mediated by recombinase FimE. Our computational analysis further implies that this down-regulation mechanism could be particularly significant inside the host environment, thus potentially contributing further understanding toward the development of novel therapeutic approaches to UPEC-caused UTIs.'),
(84564, 2010, 'plos', 'Quantifying aggregated uncertainty in Plasmodium falciparum malaria prevalence and populations at risk via efficient space-time geostatistical joint simulation', 'Gething, Peter W|Patil, Anand P|Hay, Simon I', 'Spatial Ecology and Epidemiology Group, Department of Zoology, University of Oxford, Oxford, United Kingdom. peter.gething@zoo.ox.ac.uk|Spatial Ecology and Epidemiology Group, Department of Zoology, University of Oxford, Oxford, United Kingdom. peter.gething@zoo.ox.ac.uk|Spatial Ecology and Epidemiology Group, Department of Zoology, University of Oxford, Oxford, United Kingdom. peter.gething@zoo.ox.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Algorithms|Computational Biology|Computer Simulation|Humans|Malaria, Falciparum|Models, Biological|Plasmodium falciparum|Prevalence|Reproducibility of Results|Risk|Topography, Medical', 'Journal Article', '10.1371/journal.pcbi.1000724', '20369009', 'Risk maps estimating the spatial distribution of infectious diseases are required to guide public health policy from local to global scales. The advent of model-based geostatistics (MBG) has allowed these maps to be generated in a formal statistical framework, providing robust metrics of map uncertainty that enhances their utility for decision-makers. In many settings, decision-makers require spatially aggregated measures over large regions such as the mean prevalence within a country or administrative region, or national populations living under different levels of risk. Existing MBG mapping approaches provide suitable metrics of local uncertainty--the fidelity of predictions at each mapped pixel--but have not been adapted for measuring uncertainty over large areas, due largely to a series of fundamental computational constraints. Here the authors present a new efficient approximating algorithm that can generate for the first time the necessary joint simulation of prevalence values across the very large prediction spaces needed for global scale mapping. This new approach is implemented in conjunction with an established model for P. falciparum allowing robust estimates of mean prevalence at any specified level of spatial aggregation. The model is used to provide estimates of national populations at risk under three policy-relevant prevalence thresholds, along with accompanying model-based measures of uncertainty. By overcoming previously unchallenged computational barriers, this study illustrates how MBG approaches, already at the forefront of infectious disease mapping, can be extended to provide large-scale aggregate measures appropriate for decision-makers.'),
(84565, 2010, 'plos', 'Signatures of arithmetic simplicity in metabolic network architecture', 'Riehl, William J|Krapivsky, Paul L|Redner, Sidney|Segrè, Daniel', 'Program in Bioinformatics and Systems Biology, Boston University, Boston, Massachusetts, United States of America.|Program in Bioinformatics and Systems Biology, Boston University, Boston, Massachusetts, United States of America.|Program in Bioinformatics and Systems Biology, Boston University, Boston, Massachusetts, United States of America.|Program in Bioinformatics and Systems Biology, Boston University, Boston, Massachusetts, United States of America.', 'United States|United States|United States|United States', 0, 'Algorithms|Computational Biology|Computer Simulation|Databases, Genetic|Escherichia coli|Metabolic Networks and Pathways|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1000725', '20369010', 'Metabolic networks perform some of the most fundamental functions in living cells, including energy transduction and building block biosynthesis. While these are the best characterized networks in living systems, understanding their evolutionary history and complex wiring constitutes one of the most fascinating open questions in biology, intimately related to the enigma of lifes origin itself. Is the evolution of metabolism subject to general principles, beyond the unpredictable accumulation of multiple historical accidents? Here we search for such principles by applying to an artificial chemical universe some of the methodologies developed for the study of genome scale models of cellular metabolism. In particular, we use metabolic flux constraint-based models to exhaustively search for artificial chemistry pathways that can optimally perform an array of elementary metabolic functions. Despite the simplicity of the model employed, we find that the ensuing pathways display a surprisingly rich set of properties, including the existence of autocatalytic cycles and hierarchical modules, the appearance of universally preferable metabolites and reactions, and a logarithmic trend of pathway length as a function of input/output molecule size. Some of these properties can be derived analytically, borrowing methods previously used in cryptography. In addition, by mapping biochemical networks onto a simplified carbon atom reaction backbone, we find that properties similar to those predicted for the artificial chemistry hold also for real metabolic networks. These findings suggest that optimality principles and arithmetic simplicity might lie beneath some aspects of biochemical complexity.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84566, 2010, 'plos', 'Accuracy of protein-protein binding sites in high-throughput template-based modeling', 'Kundrotas, Petras J|Vakser, Ilya A', 'Department of Molecular Biosciences, The University of Kansas, Center for Bioinformatics, Lawrence, Kansas, United States of America.|Department of Molecular Biosciences, The University of Kansas, Center for Bioinformatics, Lawrence, Kansas, United States of America.', 'United States|United States', 28, 'Binding Sites|Computational Biology|Databases, Protein|High-Throughput Screening Assays|Models, Biological|Models, Chemical|Models, Molecular|Protein Binding|Protein Conformation|Protein Interaction Mapping|Proteins|Sequence Alignment', 'Journal Article', '10.1371/journal.pcbi.1000727', '20369011', 'The accuracy of protein structures, particularly their binding sites, is essential for the success of modeling protein complexes. Computationally inexpensive methodology is required for genome-wide modeling of such structures. For systematic evaluation of potential accuracy in high-throughput modeling of binding sites, a statistical analysis of target-template sequence alignments was performed for a representative set of protein complexes. For most of the complexes, alignments containing all residues of the interface were found. The full interface alignments were obtained even in the case of poor alignments where a relatively small part of the target sequence (as low as 40%) aligned to the template sequence, with a low overall alignment identity (<30%). Although such poor overall alignments might be considered inadequate for modeling of whole proteins, the alignment of the interfaces was strong enough for docking. In the set of homology models built on these alignments, one third of those ranked 1 by a simple sequence identity criteria had RMSD<5 A, the accuracy suitable for low-resolution template free docking. Such models corresponded to multi-domain target proteins, whereas for single-domain proteins the best models had 5 A<RMSD<10 A, the accuracy suitable for less sensitive structure-alignment methods. Overall, approximately 50% of complexes with the interfaces modeled by high-throughput techniques had accuracy suitable for meaningful docking experiments. This percentage will grow with the increasing availability of co-crystallized protein-protein complexes.'),
(84567, 2010, 'plos', 'The origins of time-delay in template biopolymerization processes', 'Mier-y-Terán-Romero, Luis|Silber, Mary|Hatzimanikatis, Vassily', 'Department of Physics and Astronomy, Northwestern University, Evanston, Illinois, United States of America.|Department of Physics and Astronomy, Northwestern University, Evanston, Illinois, United States of America.|Department of Physics and Astronomy, Northwestern University, Evanston, Illinois, United States of America.', 'United States|United States|United States', 0, 'Algorithms|Computer Simulation|Escherichia coli|Escherichia coli Proteins|Kinetics|Models, Genetic|Nonlinear Dynamics|Protein Biosynthesis|RNA, Messenger|Ribosomes|Transcriptional Activation', 'Journal Article', '10.1371/journal.pcbi.1000726', '20369012', 'Time-delays are common in many physical and biological systems and they give rise to complex dynamic phenomena. The elementary processes involved in template biopolymerization, such as mRNA and protein synthesis, introduce significant time delays. However, there is not currently a systematic mapping between the individual mechanistic parameters and the time delays in these networks. We present here the development of mathematical, time-delay models for protein translation, based on PDE models, which in turn are derived through systematic approximations of first-principles mechanistic models. Theoretical analysis suggests that the key features that determine the time-delays and the agreement between the time-delay and the mechanistic models are ribosome density and distribution, i.e., the number of ribosomes on the mRNA chain relative to their maximum and their distribution along the mRNA chain. Based on analytical considerations and on computational studies, we show that the steady-state and dynamic responses of the time-delay models are in excellent agreement with the detailed mechanistic models, under physiological conditions that correspond to uniform ribosome distribution and for ribosome density up to 70%. The methodology presented here can be used for the development of reduced time-delay models of mRNA synthesis and large genetic networks. The good agreement between the time-delay and the mechanistic models will allow us to use the reduced model and advanced computational methods from nonlinear dynamics in order to perform studies that are not practical using the large-scale mechanistic models.'),
(84568, 2010, 'plos', 'Network modeling identifies molecular functions targeted by miR-204 to suppress head and neck tumor metastasis', 'Lee, Younghee|Yang, Xinan|Huang, Yong|Fan, Hanli|Zhang, Qingbei|Wu, Youngfei|Li, Jianrong|Hasina, Rifat|Cheng, Chao|Lingen, Mark W|Gerstein, Mark B|Weichselbaum, Ralph R|Xing, H Rosie|Lussier, Yves A', 'Section of Genetic Medicine and Center for Biomedical Informatics, Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine and Center for Biomedical Informatics, Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine and Center for Biomedical Informatics, Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine and Center for Biomedical Informatics, Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine and Center for Biomedical Informatics, Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine and Center for Biomedical Informatics, Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine and Center for Biomedical Informatics, Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine and Center for Biomedical Informatics, Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine and Center for Biomedical Informatics, Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine and Center for Biomedical Informatics, Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine and Center for Biomedical Informatics, Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine and Center for Biomedical Informatics, Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine and Center for Biomedical Informatics, Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine and Center for Biomedical Informatics, Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 122, 'Cell Adhesion|Cell Line, Tumor|Cell Movement|Chromosomes, Human, Pair 9|Computational Biology|ErbB Receptors|Gene Expression Profiling|Gene Expression Regulation, Neoplastic|Genetic Predisposition to Disease|Genome, Human|Head and Neck Neoplasms|Humans|Loss of Heterozygosity|MicroRNAs|Neoplasm Metastasis|Protein Interaction Mapping', 'Journal Article', '10.1371/journal.pcbi.1000730', '20369013', 'Due to the large number of putative microRNA gene targets predicted by sequence-alignment databases and the relative low accuracy of such predictions which are conducted independently of biological context by design, systematic experimental identification and validation of every functional microRNA target is currently challenging. Consequently, biological studies have yet to identify, on a genome scale, key regulatory networks perturbed by altered microRNA functions in the context of cancer. In this report, we demonstrate for the first time how phenotypic knowledge of inheritable cancer traits and of risk factor loci can be utilized jointly with gene expression analysis to efficiently prioritize deregulated microRNAs for biological characterization. Using this approach we characterize miR-204 as a tumor suppressor microRNA and uncover previously unknown connections between microRNA regulation, network topology, and expression dynamics. Specifically, we validate 18 gene targets of miR-204 that show elevated mRNA expression and are enriched in biological processes associated with tumor progression in squamous cell carcinoma of the head and neck (HNSCC). We further demonstrate the enrichment of bottleneckness, a key molecular network topology, among miR-204 gene targets. Restoration of miR-204 function in HNSCC cell lines inhibits the expression of its functionally related gene targets, leads to the reduced adhesion, migration and invasion in vitro and attenuates experimental lung metastasis in vivo. As importantly, our investigation also provides experimental evidence linking the function of microRNAs that are located in the cancer-associated genomic regions (CAGRs) to the observed predisposition to human cancers. Specifically, we show miR-204 may serve as a tumor suppressor gene at the 9q21.1-22.3 CAGR locus, a well established risk factor locus in head and neck cancers for which tumor suppressor genes have not been identified. This new strategy that integrates expression profiling, genetics and novel computational biology approaches provides for improved efficiency in characterization and modeling of microRNA functions in cancer as compared to the state of art and is applicable to the investigation of microRNA functions in other biological processes and diseases.'),
(84569, 2010, 'plos', 'Metabolic network topology reveals transcriptional regulatory signatures of type 2 diabetes', 'Zelezniak, Aleksej|Pers, Tune H|Soares, Simão|Patti, Mary Elizabeth|Patil, Kiran Raosaheb', 'Department of Systems Biology, Technical University of Denmark, Center for Microbial Biotechnology, Lyngby, Denmark.|Department of Systems Biology, Technical University of Denmark, Center for Microbial Biotechnology, Lyngby, Denmark.|Department of Systems Biology, Technical University of Denmark, Center for Microbial Biotechnology, Lyngby, Denmark.|Department of Systems Biology, Technical University of Denmark, Center for Microbial Biotechnology, Lyngby, Denmark.|Department of Systems Biology, Technical University of Denmark, Center for Microbial Biotechnology, Lyngby, Denmark.', 'Denmark|Denmark|Denmark|Denmark|Denmark', 65, 'Algorithms|Cluster Analysis|Databases, Genetic|Diabetes Mellitus, Type 2|Gene Expression Profiling|Gene Expression Regulation|Gene Regulatory Networks|Humans|Male|Metabolic Networks and Pathways|Metabolome|Models, Biological|Muscle, Skeletal|Oligonucleotide Array Sequence Analysis|Regulatory Elements, Transcriptional|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000729', '20369014', 'Type 2 diabetes mellitus (T2DM) is a disorder characterized by both insulin resistance and impaired insulin secretion. Recent transcriptomics studies related to T2DM have revealed changes in expression of a large number of metabolic genes in a variety of tissues. Identification of the molecular mechanisms underlying these transcriptional changes and their impact on the cellular metabolic phenotype is a challenging task due to the complexity of transcriptional regulation and the highly interconnected nature of the metabolic network. In this study we integrate skeletal muscle gene expression datasets with human metabolic network reconstructions to identify key metabolic regulatory features of T2DM. These features include reporter metabolites--metabolites with significant collective transcriptional response in the associated enzyme-coding genes, and transcription factors with significant enrichment of binding sites in the promoter regions of these genes. In addition to metabolites from TCA cycle, oxidative phosphorylation, and lipid metabolism (known to be associated with T2DM), we identified several reporter metabolites representing novel biomarker candidates. For example, the highly connected metabolites NAD+/NADH and ATP/ADP were also identified as reporter metabolites that are potentially contributing to the widespread gene expression changes observed in T2DM. An algorithm based on the analysis of the promoter regions of the genes associated with reporter metabolites revealed a transcription factor regulatory network connecting several parts of metabolism. The identified transcription factors include members of the CREB, NRF1 and PPAR family, among others, and represent regulatory targets for further experimental analysis. Overall, our results provide a holistic picture of key metabolic and regulatory nodes potentially involved in the pathogenesis of T2DM.'),
(84570, 2010, 'plos', 'Why genes evolve faster on secondary chromosomes in bacteria', 'Cooper, Vaughn S|Vohr, Samuel H|Wrocklage, Sarah C|Hatcher, Philip J', 'Department of Molecular, University of New Hampshire, Durham, New Hampshire, United States of America. vaughn.cooper@unh.edu|Department of Molecular, University of New Hampshire, Durham, New Hampshire, United States of America. vaughn.cooper@unh.edu|Department of Molecular, University of New Hampshire, Durham, New Hampshire, United States of America. vaughn.cooper@unh.edu|Department of Molecular, University of New Hampshire, Durham, New Hampshire, United States of America. vaughn.cooper@unh.edu', 'United States|United States|United States|United States', 59, 'Burkholderia|Codon|Evolution, Molecular|Genome, Bacterial|Gram-Negative Bacteria|Models, Genetic|Mutation|Phylogeny|RNA, Ribosomal, 16S|Vibrio|Xanthomonas', 'Journal Article', '10.1371/journal.pcbi.1000732', '20369015', 'In bacterial genomes composed of more than one chromosome, one replicon is typically larger, harbors more essential genes than the others, and is considered primary. The greater variability of secondary chromosomes among related taxa has led to the theory that they serve as an accessory genome for specific niches or conditions. By this rationale, purifying selection should be weaker on genes on secondary chromosomes because of their reduced necessity or usage. To test this hypothesis we selected bacterial genomes composed of multiple chromosomes from two genera, Burkholderia and Vibrio, and quantified the evolutionary rates (dN and dS) of all orthologs within each genus. Both evolutionary rate parameters were faster among orthologs found on secondary chromosomes than those on the primary chromosome. Further, in every bacterial genome with multiple chromosomes that we studied, genes on secondary chromosomes exhibited significantly weaker codon usage bias than those on primary chromosomes. Faster evolution and reduced codon bias could in turn result from global effects of chromosome position, as genes on secondary chromosomes experience reduced dosage and expression due to their delayed replication, or selection on specific gene attributes. These alternatives were evaluated using orthologs common to genomes with multiple chromosomes and genomes with single chromosomes. Analysis of these ortholog sets suggested that inherently fast-evolving genes tend to be sorted to secondary chromosomes when they arise, however, prolonged evolution on a secondary chromosome further accelerated substitution rates. In summary, secondary chromosomes in bacteria are evolutionary test beds where genes are weakly preserved and evolve more rapidly, likely because they are used less frequently.'),
(84571, 2010, 'plos', 'Somitogenesis clock-wave initiation requires differential decay and multiple binding sites for clock protein', 'Campanelli, Mark|Gedeon, Tomás', 'Department of Mathematics and Computer Science, Southwest Minnesota State University, Marshall, Minnesota, United States of America.|Department of Mathematics and Computer Science, Southwest Minnesota State University, Marshall, Minnesota, United States of America.', 'United States|United States', 0, 'Animals|Basic Helix-Loop-Helix Transcription Factors|Binding Sites|CLOCK Proteins|DNA-Binding Proteins|Embryonic Development|Gene Expression Regulation, Developmental|Gene Knockdown Techniques|Models, Biological|Protein Binding|Reproducibility of Results|Somites|Transcription Factors|Zebrafish|Zebrafish Proteins', 'Journal Article', '10.1371/journal.pcbi.1000728', '20369016', 'Somitogenesis is a process common to all vertebrate embryos in which repeated blocks of cells arise from the presomitic mesoderm (PSM) to lay a foundational pattern for trunk and tail development. Somites form in the wake of passing waves of periodic gene expression that originate in the tailbud and sweep posteriorly across the PSM. Previous work has suggested that the waves result from a spatiotemporally graded control protein that affects the oscillation rate of clock-gene expression. With a minimally constructed mathematical model, we study the contribution of two control mechanisms to the initial formation of this gene-expression wave. We test four biologically motivated model scenarios with either one or two clock protein transcription binding sites, and with or without differential decay rates for clock protein monomers and dimers. We examine the sensitivity of wave formation with respect to multiple model parameters and robustness to heterogeneity in cell population. We find that only a model with both multiple binding sites and differential decay rates is able to reproduce experimentally observed waveforms. Our results show that the experimentally observed characteristics of somitogenesis wave initiation constrain the underlying genetic control mechanisms.'),
(84572, 2010, 'plos', 'Genome-wide modeling of transcription preinitiation complex disassembly mechanisms using ChIP-chip data', 'Samorodnitsky, Eric|Pugh, B Franklin', 'Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, Pennsylvania, United States of America.', 'United States|United States', 4, 'Chromatin Immunoprecipitation|Fungal Proteins|Genome, Fungal|Models, Genetic|Oligonucleotide Array Sequence Analysis|Regulatory Elements, Transcriptional|Saccharomyces|Transcription Factors|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000733', '20369017', 'Apparent occupancy levels of proteins bound to DNA in vivo can now be routinely measured on a genomic scale. A challenge in relating these occupancy levels to assembly mechanisms that are defined with biochemically isolated components lies in the veracity of assumptions made regarding the in vivo system. Assumptions regarding behavior of molecules in vivo can neither be proven true nor false, and thus is necessarily subjective. Nevertheless, within those confines, connecting in vivo protein-DNA interaction observations with defined biochemical mechanisms is an important step towards fully defining and understanding assembly/disassembly mechanisms in vivo. To this end, we have developed a computational program PathCom that models in vivo protein-DNA occupancy data as biochemical mechanisms under the assumption that occupancy levels can be related to binding duration and explicitly defined assembly/disassembly reactions. We exemplify the process with the assembly of the general transcription factors (TBP, TFIIB, TFIIE, TFIIF, TFIIH, and RNA polymerase II) at the genes of the budding yeast Saccharomyces. Within the assumption inherent in the system our modeling suggests that TBP occupancy at promoters is rather transient compared to other general factors, despite the importance of TBP in nucleating assembly of the preinitiation complex. PathCom is suitable for modeling any assembly/disassembly pathway, given that all the proteins (or species) come together to form a complex.'),
(84573, 2010, 'plos', 'A Stevedores protein knot', 'Bxc3xb6linger, Daniel|Suxc5x82kowska, Joanna I|Hsu, Hsiao-Ping|Mirny, Leonid A|Kardar, Mehran|Onuchic, Josxc3xa9 N|Virnau, Peter', 'Department of Physics, Johannes Gutenberg-Universitxc3xa4t Mainz, Mainz, Germany.|Department of Physics, Johannes Gutenberg-Universitxc3xa4t Mainz, Mainz, Germany.|Department of Physics, Johannes Gutenberg-Universitxc3xa4t Mainz, Mainz, Germany.|Department of Physics, Johannes Gutenberg-Universitxc3xa4t Mainz, Mainz, Germany.|Department of Physics, Johannes Gutenberg-Universitxc3xa4t Mainz, Mainz, Germany.|Department of Physics, Johannes Gutenberg-Universitxc3xa4t Mainz, Mainz, Germany.|Department of Physics, Johannes Gutenberg-Universitxc3xa4t Mainz, Mainz, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany', 106, 'Databases, Protein|Hydrolases|Molecular Dynamics Simulation|Protein Conformation|Protein Folding', 'Journal Article', '10.1371/journal.pcbi.1000731', '20369018', 'Protein knots, mostly regarded as intriguing oddities, are gradually being recognized as significant structural motifs. Seven distinctly knotted folds have already been identified. It is by and large unclear how these exceptional structures actually fold, and only recently, experiments and simulations have begun to shed some light on this issue. In checking the new protein structures submitted to the Protein Data Bank, we encountered the most complex and the smallest knots to date: A recently uncovered alpha-haloacid dehalogenase structure contains a knot with six crossings, a so-called Stevedore knot, in a projection onto a plane. The smallest protein knot is present in an as yet unclassified protein fragment that consists of only 92 amino acids. The topological complexity of the Stevedore knot presents a puzzle as to how it could possibly fold. To unravel this enigma, we performed folding simulations with a structure-based coarse-grained model and uncovered a possible mechanism by which the knot forms in a single loop flip.'),
(84574, 2010, 'plos', 'A human-specific de novo protein-coding gene associated with human brain functions', 'Li, Chuan-Yun|Zhang, Yong|Wang, Zhanbo|Zhang, Yan|Cao, Chunmei|Zhang, Ping-Wu|Lu, Shu-Juan|Li, Xiao-Mo|Yu, Quan|Zheng, Xiaofeng|Du, Quan|Uhl, George R|Liu, Qing-Rong|Wei, Liping', 'Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, China.|Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, China.|Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, China.|Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, China.|Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, China.|Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, China.|Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, China.|Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, China.|Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, China.|Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, China.|Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, China.|Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, China.|Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, China.|Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, China.', 'China|China|China|China|China|China|China|China|China|China|China|China|China|China', 71, 'Alzheimer Disease|Brain|Computer Simulation|Humans|Models, Genetic|Mutation|Nerve Tissue Proteins', 'Journal Article', '10.1371/journal.pcbi.1000734', '20376170', 'To understand whether any human-specific new genes may be associated with human brain functions, we computationally screened the genetic vulnerable factors identified through Genome-Wide Association Studies and linkage analyses of nicotine addiction and found one human-specific de novo protein-coding gene, FLJ33706 (alternative gene symbol C20orf203). Cross-species analysis revealed interesting evolutionary paths of how this gene had originated from noncoding DNA sequences: insertion of repeat elements especially Alu contributed to the formation of the first coding exon and six standard splice junctions on the branch leading to humans and chimpanzees, and two subsequent substitutions in the human lineage escaped two stop codons and created an open reading frame of 194 amino acids. We experimentally verified FLJ33706s mRNA and protein expression in the brain. Real-Time PCR in multiple tissues demonstrated that FLJ33706 was most abundantly expressed in brain. Human polymorphism data suggested that FLJ33706 encodes a protein under purifying selection. A specifically designed antibody detected its protein expression across human cortex, cerebellum and midbrain. Immunohistochemistry study in normal human brain cortex revealed the localization of FLJ33706 protein in neurons. Elevated expressions of FLJ33706 were detected in Alzheimers brain samples, suggesting the role of this novel gene in human-specific pathogenesis of Alzheimers disease. FLJ33706 provided the strongest evidence so far that human-specific de novo genes can have protein-coding potential and differential protein expression, and be involved in human brain functions.'),
(84575, 2010, 'plos', 'Dynamics and control of diseases in networks with community structure', 'Salathé, Marcel|Jones, James H', 'Department of Biology, Stanford University, Stanford, California, United States of America. salathe@stanford.edu|Department of Biology, Stanford University, Stanford, California, United States of America. salathe@stanford.edu', 'United States|United States', 295, 'Algorithms|Community-Acquired Infections|Computational Biology|Computer Simulation|Databases, Factual|Disease Outbreaks|Disease Transmission, Infectious|Host-Pathogen Interactions|Humans|Incidence|Residence Characteristics|Stochastic Processes|Vaccination', 'Journal Article', '10.1371/journal.pcbi.1000736', '20386735', 'The dynamics of infectious diseases spread via direct person-to-person transmission (such as influenza, smallpox, HIV/AIDS, etc.) depends on the underlying host contact network. Human contact networks exhibit strong community structure. Understanding how such community structure affects epidemics may provide insights for preventing the spread of disease between communities by changing the structure of the contact network through pharmaceutical or non-pharmaceutical interventions. We use empirical and simulated networks to investigate the spread of disease in networks with community structure. We find that community structure has a major impact on disease dynamics, and we show that in networks with strong community structure, immunization interventions targeted at individuals bridging communities are more effective than those simply targeting highly connected individuals. Because the structure of relevant contact networks is generally not known, and vaccine supply is often limited, there is great need for efficient vaccination algorithms that do not require full knowledge of the network. We developed an algorithm that acts only on locally available network information and is able to quickly identify targets for successful immunization intervention. The algorithm generally outperforms existing algorithms when vaccine supply is limited, particularly in networks with strong community structure. Understanding the spread of infectious diseases and designing optimal control strategies is a major goal of public health. Social networks show marked patterns of community structure, and our results, based on empirical and simulated data, demonstrate that community structure strongly affects disease dynamics. These results have implications for the design of control strategies.'),
(84576, 2010, 'plos', 'New insights into the genetic control of gene expression using a Bayesian multi-tissue approach', 'Petretto, Enrico|Bottolo, Leonardo|Langley, Sarah R|Heinig, Matthias|McDermott-Roe, Chris|Sarwar, Rizwan|Pravenec, Michal|Hübner, Norbert|Aitman, Timothy J|Cook, Stuart A|Richardson, Sylvia', 'Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, United Kingdom.|Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, United Kingdom.|Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, United Kingdom.|Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, United Kingdom.|Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, United Kingdom.|Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, United Kingdom.|Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, United Kingdom.|Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, United Kingdom.|Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, United Kingdom.|Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, United Kingdom.|Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Adipose Tissue|Adrenal Glands|Algorithms|Animals|Bayes Theorem|Gene Expression Profiling|Gene Expression Regulation|Gene Regulatory Networks|Heart Ventricles|Humans|Kidney|Models, Genetic|Quantitative Trait Loci|Regression Analysis|Reproducibility of Results|Sensitivity and Specificity', 'Journal Article', '10.1371/journal.pcbi.1000737', '20386736', 'The majority of expression quantitative trait locus (eQTL) studies have been carried out in single tissues or cell types, using methods that ignore information shared across tissues. Although global analysis of RNA expression in multiple tissues is now feasible, few integrated statistical frameworks for joint analysis of gene expression across tissues combined with simultaneous analysis of multiple genetic variants have been developed to date. Here, we propose Sparse Bayesian Regression models for mapping eQTLs within individual tissues and simultaneously across tissues. Testing these on a set of 2,000 genes in four tissues, we demonstrate that our methods are more powerful than traditional approaches in revealing the true complexity of the eQTL landscape at the systems-level. Highlighting the power of our method, we identified a two-eQTL model (cis/trans) for the Hopx gene that was experimentally validated and was not detected by conventional approaches. We showed common genetic regulation of gene expression across four tissues for approximately 27% of transcripts, providing >5 fold increase in eQTLs detection when compared with single tissue analyses at 5% FDR level. These findings provide a new opportunity to uncover complex genetic regulatory mechanisms controlling global gene expression while the generality of our modelling approach makes it adaptable to other model systems and humans, with broad application to analysis of multiple intermediate and whole-body phenotypes.'),
(84577, 2010, 'plos', 'Quantitative modeling of Escherichia coli chemotactic motion in environments varying in space and time', 'Jiang, Lili|Ouyang, Qi|Tu, Yuhai', 'Center for Theoretical Biology and School of Physics, Peking University, Beijing, China.|Center for Theoretical Biology and School of Physics, Peking University, Beijing, China.|Center for Theoretical Biology and School of Physics, Peking University, Beijing, China.', 'China|China|China', 0, 'Algorithms|Chemotaxis|Computational Biology|Computer Simulation|Escherichia coli|Models, Biological|Models, Statistical|Signal Transduction|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1000735', '20386737', 'Escherichia coli chemotactic motion in spatiotemporally varying environments is studied by using a computational model based on a coarse-grained description of the intracellular signaling pathway dynamics. We find that the cells chemotaxis drift velocity v(d) is a constant in an exponential attractant concentration gradient [L] proportional, variantexp(Gx). v(d) depends linearly on the exponential gradient G before it saturates when G is larger than a critical value G(C). We find that G(C) is determined by the intracellular adaptation rate k(R) with a simple scaling law: G(C) infinity k(1/2)(R). The linear dependence of v(d) on G = d(ln[L])/dx directly demonstrates E. colis ability in sensing the derivative of the logarithmic attractant concentration. The existence of the limiting gradient G(C) and its scaling with k(R) are explained by the underlying intracellular adaptation dynamics and the flagellar motor response characteristics. For individual cells, we find that the overall average run length in an exponential gradient is longer than that in a homogeneous environment, which is caused by the constant kinase activity shift (decrease). The forward runs (up the gradient) are longer than the backward runs, as expected, and depending on the exact gradient, the (shorter) backward runs can be comparable to runs in a spatially homogeneous environment, consistent with previous experiments. In (spatial) ligand gradients that also vary in time, the chemotaxis motion is damped as the frequency omega of the time-varying spatial gradient becomes faster than a critical value omega(c), which is controlled by the cells chemotaxis adaptation rate k(R). Finally, our model, with no adjustable parameters, agrees quantitatively with the classical capillary assay experiments where the attractant concentration changes both in space and time. Our model can thus be used to study E. coli chemotaxis behavior in arbitrary spatiotemporally varying environments. Further experiments are suggested to test some of the model predictions.'),
(84578, 2010, 'plos', 'On the conservation of the slow conformational dynamics within the amino acid kinase family: NAGK the paradigm', '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', 0, 'Allosteric Regulation|Anisotropy|Catalytic Domain|Computational Biology|Markov Chains|Molecular Dynamics Simulation|Normal Distribution|Phosphotransferases (Carboxyl Group Acceptor)|Signal Transduction|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1000738', '20386738', 'N-acetyl-L-glutamate kinase (NAGK) is the structural paradigm for examining the catalytic mechanisms and dynamics of amino acid kinase family members. Given that the slow conformational dynamics of the NAGK (at the microseconds time scale or slower) may be rate-limiting, it is of importance to assess the mechanisms of the most cooperative modes of motion intrinsically accessible to this enzyme. Here, we present the results from normal mode analysis using an elastic network model representation, which shows that the conformational mechanisms for substrate binding by NAGK strongly correlate with the intrinsic dynamics of the enzyme in the unbound form. We further analyzed the potential mechanisms of allosteric signalling within NAGK using a Markov model for network communication. Comparative analysis of the dynamics of family members strongly suggests that the low-frequency modes of motion and the associated intramolecular couplings that establish signal transduction are highly conserved among family members, in support of the paradigm sequence-->structure-->dynamics-->function.'),
(84579, 2010, 'plos', 'Predicting odor pleasantness with an electronic nose', 'Haddad, Rafi|Medhanie, Abebe|Roth, Yehudah|Harel, David|Sobel, Noam', 'Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. rafihaddad@gmail.com|Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. rafihaddad@gmail.com|Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. rafihaddad@gmail.com|Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. rafihaddad@gmail.com|Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. rafihaddad@gmail.com', 'Israel|Israel|Israel|Israel|Israel', 36, 'Adult|Algorithms|Artificial Intelligence|Culture|Discrimination (Psychology)|Electronics|Environmental Monitoring|Humans|Middle Aged|Models, Biological|Molecular Conformation|Odorants|Oils, Volatile|Olfactory Perception|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000740', '20418961', 'A primary goal for artificial nose (eNose) technology is to report perceptual qualities of novel odors. Currently, however, eNoses primarily detect and discriminate between odorants they previously learned. We tuned an eNose to human odor pleasantness estimates. We then used the eNose to predict the pleasantness of novel odorants, and tested these predictions in naïve subjects who had not participated in the tuning procedure. We found that our apparatus generated odorant pleasantness ratings with above 80% similarity to average human ratings, and with above 90% accuracy at discriminating between categorically pleasant or unpleasant odorants. Similar results were obtained in two cultures, native Israeli and native Ethiopian, without retuning of the apparatus. These findings suggest that unlike in vision and audition, in olfaction there is a systematic predictable link between stimulus structure and stimulus pleasantness. This goes in contrast to the popular notion that odorant pleasantness is completely subjective, and may provide a new method for odor screening and environmental monitoring, as well as a critical building block for digital transmission of smell.'),
(84580, 2010, 'plos', 'Global entrainment of transcriptional systems to periodic inputs', 'Russo, Giovanni|di Bernardo, Mario|Sontag, Eduardo D', 'Department of Systems and Computer Engineering, University of Naples Federico II, Naples, Italy.|Department of Systems and Computer Engineering, University of Naples Federico II, Naples, Italy.|Department of Systems and Computer Engineering, University of Naples Federico II, Naples, Italy.', 'Italy|Italy|Italy', 0, 'Algorithms|Gene Regulatory Networks|Metabolic Networks and Pathways|Models, Biological|Nonlinear Dynamics|Signal Transduction|Systems Biology|Systems Theory|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000739', '20418962', 'This paper addresses the problem of providing mathematical conditions that allow one to ensure that biological networks, such as transcriptional systems, can be globally entrained to external periodic inputs. Despite appearing obvious at first, this is by no means a generic property of nonlinear dynamical systems. Through the use of contraction theory, a powerful tool from dynamical systems theory, it is shown that certain systems driven by external periodic signals have the property that all their solutions converge to a fixed limit cycle. General results are proved, and the properties are verified in the specific cases of models of transcriptional systems as well as constructs of interest in synthetic biology. A self-contained exposition of all needed results is given in the paper.'),
(84581, 2010, 'plos', 'Flow-based cytometric analysis of cell cycle via simulated cell populations', 'Brown, M Rowan|Summers, Huw D|Rees, Paul|Smith, Paul J|Chappell, Sally C|Errington, Rachel J', 'School of Medicine, Cardiff University, Cardiff, United Kingdom. BrownMR@cf.ac.uk|School of Medicine, Cardiff University, Cardiff, United Kingdom. BrownMR@cf.ac.uk|School of Medicine, Cardiff University, Cardiff, United Kingdom. BrownMR@cf.ac.uk|School of Medicine, Cardiff University, Cardiff, United Kingdom. BrownMR@cf.ac.uk|School of Medicine, Cardiff University, Cardiff, United Kingdom. BrownMR@cf.ac.uk|School of Medicine, Cardiff University, Cardiff, United Kingdom. BrownMR@cf.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 8, 'Cell Cycle|Cell Line, Tumor|Computer Simulation|Flow Cytometry|Humans|Models, Biological|Models, Statistical|Osteosarcoma|Piperazines|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000741', '20419143', 'We present a new approach to the handling and interrogating of large flow cytometry data where cell status and function can be described, at the population level, by global descriptors such as distribution mean or co-efficient of variation experimental data. Here we link the real data to initialise a computer simulation of the cell cycle that mimics the evolution of individual cells within a larger population and simulates the associated changes in fluorescence intensity of functional reporters. The model is based on stochastic formulations of cell cycle progression and cell division and uses evolutionary algorithms, allied to further experimental data sets, to optimise the system variables. At the population level, the in-silico cells provide the same statistical distributions of fluorescence as their real counterparts, in addition the model maintains information at the single cell level. The cell model is demonstrated in the analysis of cell cycle perturbation in human osteosarcoma tumour cells, using the topoisomerase II inhibitor, ICRF-193. The simulation gives a continuous temporal description of the pharmacodynamics between discrete experimental analysis points with a 24 hour interval, providing quantitative assessment of inter-mitotic time variation, drug interaction time constants and sub-population fractions within normal and polyploid cell cycles. Repeated simulations indicate a model accuracy of +/-5%. The development of a simulated cell model, initialized and calibrated by reference to experimental data, provides an analysis tool in which biological knowledge can be obtained directly via interrogation of the in-silico cell population. It is envisaged that this approach to the study of cell biology by simulating a virtual cell population pertinent to the data available can be applied to generic cell-based outputs including experimental data from imaging platforms.'),
(84582, 2010, 'plos', 'Simultaneous clustering of multiple gene expression and physical interaction datasets', 'Narayanan, Manikandan|Vetta, Adrian|Schadt, Eric E|Zhu, Jun', 'Department of Genetics, Rosetta Inpharmatics Merck, Seattle, Washington, United States of America. manikandan_narayanan@merck.com|Department of Genetics, Rosetta Inpharmatics Merck, Seattle, Washington, United States of America. manikandan_narayanan@merck.com|Department of Genetics, Rosetta Inpharmatics Merck, Seattle, Washington, United States of America. manikandan_narayanan@merck.com|Department of Genetics, Rosetta Inpharmatics Merck, Seattle, Washington, United States of America. manikandan_narayanan@merck.com', 'United States|United States|United States|United States', 32, 'Algorithms|Computational Biology|Computer Simulation|Databases, Genetic|Ethanol|Gene Expression Profiling|Gene Regulatory Networks|Glucose|Multigene Family|Protein Interaction Mapping|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1000742', '20419151', 'Many genome-wide datasets are routinely generated to study different aspects of biological systems, but integrating them to obtain a coherent view of the underlying biology remains a challenge. We propose simultaneous clustering of multiple networks as a framework to integrate large-scale datasets on the interactions among and activities of cellular components. Specifically, we develop an algorithm JointCluster that finds sets of genes that cluster well in multiple networks of interest, such as coexpression networks summarizing correlations among the expression profiles of genes and physical networks describing protein-protein and protein-DNA interactions among genes or gene-products. Our algorithm provides an efficient solution to a well-defined problem of jointly clustering networks, using techniques that permit certain theoretical guarantees on the quality of the detected clustering relative to the optimal clustering. These guarantees coupled with an effective scaling heuristic and the flexibility to handle multiple heterogeneous networks make our method JointCluster an advance over earlier approaches. Simulation results showed JointCluster to be more robust than alternate methods in recovering clusters implanted in networks with high false positive rates. In systematic evaluation of JointCluster and some earlier approaches for combined analysis of the yeast physical network and two gene expression datasets under glucose and ethanol growth conditions, JointCluster discovers clusters that are more consistently enriched for various reference classes capturing different aspects of yeast biology or yield better coverage of the analysed genes. These robust clusters, which are supported across multiple genomic datasets and diverse reference classes, agree with known biology of yeast under these growth conditions, elucidate the genetic control of coordinated transcription, and enable functional predictions for a number of uncharacterized genes.'),
(84583, 2010, 'plos', 'Prediction of co-receptor usage of HIV-1 from genotype', 'Dybowski, J Nikolaj|Heider, Dominik|Hoffmann, Daniel', 'Department of Bioinformatics, Center for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.|Department of Bioinformatics, Center for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.|Department of Bioinformatics, Center for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.', 'Germany|Germany|Germany', 0, 'Amino Acid Sequence|Artificial Intelligence|CD4 Antigens|Computational Biology|HIV Envelope Protein gp120|HIV-1|Humans|Hydrophobic and Hydrophilic Interactions|Models, Genetic|Peptide Fragments|Protein Interaction Mapping|ROC Curve|Receptors, CCR5|Reproducibility of Results|Static Electricity|Virus Internalization', 'Journal Article', '10.1371/journal.pcbi.1000743', '20419152', 'Human Immunodeficiency Virus 1 uses for entry into host cells a receptor (CD4) and one of two co-receptors (CCR5 or CXCR4). Recently, a new class of antiretroviral drugs has entered clinical practice that specifically bind to the co-receptor CCR5, and thus inhibit virus entry. Accurate prediction of the co-receptor used by the virus in the patient is important as it allows for personalized selection of effective drugs and prognosis of disease progression. We have investigated whether it is possible to predict co-receptor usage accurately by analyzing the amino acid sequence of the main determinant of co-receptor usage, i.e., the third variable loop V3 of the gp120 protein. We developed a two-level machine learning approach that in the first level considers two different properties important for protein-protein binding derived from structural models of V3 and V3 sequences. The second level combines the two predictions of the first level. The two-level method predicts usage of CXCR4 co-receptor for new V3 sequences within seconds, with an area under the ROC curve of 0.937+/-0.004. Moreover, it is relatively robust against insertions and deletions, which frequently occur in V3. The approach could help clinicians to find optimal personalized treatments, and it offers new insights into the molecular basis of co-receptor usage. For instance, it quantifies the importance for co-receptor usage of a pocket that probably is responsible for binding sulfated tyrosine.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84584, 2010, 'plos', 'OptForce: an optimization procedure for identifying all genetic manipulations leading to targeted overproductions', 'Ranganathan, Sridhar|Suthers, Patrick F|Maranas, Costas D', 'Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.', 'United States|United States|United States', 236, 'Algorithms|Computer Simulation|Escherichia coli|Gene Expression Regulation|Genetic Engineering|Metabolic Networks and Pathways|Models, Genetic|Models, Statistical|Succinic Acid|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000744', '20419153', 'Computational procedures for predicting metabolic interventions leading to the overproduction of biochemicals in microbial strains are widely in use. However, these methods rely on surrogate biological objectives (e.g., maximize growth rate or minimize metabolic adjustments) and do not make use of flux measurements often available for the wild-type strain. In this work, we introduce the OptForce procedure that identifies all possible engineering interventions by classifying reactions in the metabolic model depending upon whether their flux values must increase, decrease or become equal to zero to meet a pre-specified overproduction target. We hierarchically apply this classification rule for pairs, triples, quadruples, etc. of reactions. This leads to the identification of a sufficient and non-redundant set of fluxes that must change (i.e., MUST set) to meet a pre-specified overproduction target. Starting with this set we subsequently extract a minimal set of fluxes that must actively be forced through genetic manipulations (i.e., FORCE set) to ensure that all fluxes in the network are consistent with the overproduction objective. We demonstrate our OptForce framework for succinate production in Escherichia coli using the most recent in silico E. coli model, iAF1260. The method not only recapitulates existing engineering strategies but also reveals non-intuitive ones that boost succinate production by performing coordinated changes on pathways distant from the last steps of succinate synthesis.'),
(84585, 2010, 'plos', 'A multi-variant, viral dynamic model of genotype 1 HCV to assess the in vivo evolution of protease-inhibitor resistant variants', 'Adiwijaya, Bambang S|Herrmann, Eva|Hare, Brian|Kieffer, Tara|Lin, Chao|Kwong, Ann D|Garg, Varun|Randle, John C R|Sarrazin, Christoph|Zeuzem, Stefan|Caron, Paul R', 'Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, United States of America. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, United States of America. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, United States of America. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, United States of America. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, United States of America. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, United States of America. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, United States of America. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, United States of America. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, United States of America. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, United States of America. bambang_adiwijaya@vrtx.com|Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, United States of America. bambang_adiwijaya@vrtx.com', 'United States|United States|United States|United States|United States|United States|United States|Un', 66, 'Computer Simulation|Drug Resistance, Viral|Evolution, Molecular|Genetic Fitness|Hepacivirus|Hepatitis C|Humans|Models, Biological|Multivariate Analysis|Mutation|Oligopeptides|Protease Inhibitors|RNA, Viral|Viral Load', 'Journal Article', '10.1371/journal.pcbi.1000745', '20419154', 'Variants resistant to compounds specifically targeting HCV are observed in clinical trials. A multi-variant viral dynamic model was developed to quantify the evolution and in vivo fitness of variants in subjects dosed with monotherapy of an HCV protease inhibitor, telaprevir. Variant fitness was estimated using a model in which variants were selected by competition for shared limited replication space. Fitness was represented in the absence of telaprevir by different variant production rate constants and in the presence of telaprevir by additional antiviral blockage by telaprevir. Model parameters, including rate constants for viral production, clearance, and effective telaprevir concentration, were estimated from 1) plasma HCV RNA levels of subjects before, during, and after dosing, 2) post-dosing prevalence of plasma variants from subjects, and 3) sensitivity of variants to telaprevir in the HCV replicon. The model provided a good fit to plasma HCV RNA levels observed both during and after telaprevir dosing, as well as to variant prevalence observed after telaprevir dosing. After an initial sharp decline in HCV RNA levels during dosing with telaprevir, HCV RNA levels increased in some subjects. The model predicted this increase to be caused by pre-existing variants with sufficient fitness to expand once available replication space increased due to rapid clearance of wild-type (WT) virus. The average replicative fitness estimates in the absence of telaprevir ranged from 1% to 68% of WT fitness. Compared to the relative fitness method, the in vivo estimates from the viral dynamic model corresponded more closely to in vitro replicon data, as well as to qualitative behaviors observed in both on-dosing and long-term post-dosing clinical data. The modeling fitness estimates were robust in sensitivity analyses in which the restoration dynamics of replication space and assumptions of HCV mutation rates were varied.'),
(84586, 2010, 'plos', 'Coordinate dependence of variability analysis', 'Sternad, Dagmar|Park, Se-Woong|Müller, Hermann|Hogan, Neville', 'Department of Biology, Northeastern University, Boston, Massachusetts, United States of America. dagmar@neu.edu|Department of Biology, Northeastern University, Boston, Massachusetts, United States of America. dagmar@neu.edu|Department of Biology, Northeastern University, Boston, Massachusetts, United States of America. dagmar@neu.edu|Department of Biology, Northeastern University, Boston, Massachusetts, United States of America. dagmar@neu.edu', 'United States|United States|United States|United States', 0, 'Analysis of Variance|Anisotropy|Computational Biology|Humans|Neurosciences|Principal Component Analysis|Psychomotor Performance', 'Journal Article', '10.1371/journal.pcbi.1000751', '20421930', 'Analysis of motor performance variability in tasks with redundancy affords insight about synergies underlying central nervous system (CNS) control. Preferential distribution of variability in ways that minimally affect task performance suggests sophisticated neural control. Unfortunately, in the analysis of variability the choice of coordinates used to represent multi-dimensional data may profoundly affect analysis, introducing an arbitrariness which compromises its conclusions. This paper assesses the influence of coordinates. Methods based on analyzing a covariance matrix are fundamentally dependent on an investigators choices. Two reasons are identified: using anisotropy of a covariance matrix as evidence of preferential distribution of variability, and using orthogonality to quantify relevance of variability to task performance. Both are exquisitely sensitive to coordinates. Unless coordinates are known a priori, these methods do not support unambiguous inferences about CNS control. An alternative method uses a two-level approach where variability in task execution (expressed in one coordinate frame) is mapped by a function to its result (expressed in another coordinate frame). An analysis of variability in execution using this function to quantify performance at the level of results offers substantially less sensitivity to coordinates than analysis of a covariance matrix of execution variables. This is an initial step towards developing coordinate-invariant analysis methods for movement neuroscience.'),
(84587, 2010, 'plos', 'Accurate distinction of pathogenic from benign CNVs in mental retardation', 'Hehir-Kwa, Jayne Y|Wieskamp, Nienke|Webber, Caleb|Pfundt, Rolph|Brunner, Han G|Gilissen, Christian|de Vries, Bert B A|Ponting, Chris P|Veltman, Joris A', 'Radboud University Nijmegen Medical Centre, Department of Human Genetics, Nijmegen, The Netherlands.|Radboud University Nijmegen Medical Centre, Department of Human Genetics, Nijmegen, The Netherlands.|Radboud University Nijmegen Medical Centre, Department of Human Genetics, Nijmegen, The Netherlands.|Radboud University Nijmegen Medical Centre, Department of Human Genetics, Nijmegen, The Netherlands.|Radboud University Nijmegen Medical Centre, Department of Human Genetics, Nijmegen, The Netherlands.|Radboud University Nijmegen Medical Centre, Department of Human Genetics, Nijmegen, The Netherlands.|Radboud University Nijmegen Medical Centre, Department of Human Genetics, Nijmegen, The Netherlands.|Radboud University Nijmegen Medical Centre, Department of Human Genetics, Nijmegen, The Netherlands.|Radboud University Nijmegen Medical Centre, Department of Human Genetics, Nijmegen, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Neth', 0, 'Animals|Bayes Theorem|Cohort Studies|DNA Copy Number Variations|Humans|Intellectual Disability|Mice|Mice, Knockout|Models, Genetic|Phenotype|Predictive Value of Tests|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000752', '20421931', 'Copy number variants (CNVs) have recently been recognized as a common form of genomic variation in humans. Hundreds of CNVs can be detected in any individual genome using genomic microarrays or whole genome sequencing technology, but their phenotypic consequences are still poorly understood. Rare CNVs have been reported as a frequent cause of neurological disorders such as mental retardation (MR), schizophrenia and autism, prompting widespread implementation of CNV screening in diagnostics. In previous studies we have shown that, in contrast to benign CNVs, MR-associated CNVs are significantly enriched in genes whose mouse orthologues, when disrupted, result in a nervous system phenotype. In this study we developed and validated a novel computational method for differentiating between benign and MR-associated CNVs using structural and functional genomic features to annotate each CNV. In total 13 genomic features were included in the final version of a Naïve Bayesian Tree classifier, with LINE density and mouse knock-out phenotypes contributing most to the classifiers accuracy. After demonstrating that our method (called GECCO) perfectly classifies CNVs causing known MR-associated syndromes, we show that it achieves high accuracy (94%) and negative predictive value (99%) on a blinded test set of more than 1,200 CNVs from a large cohort of individuals with MR. These results indicate that this classification method will be of value for objectively prioritizing CNVs in clinical research and diagnostics.'),
(84588, 2010, 'plos', 'Ion channel density regulates switches between regular and fast spiking in soma but not in axons', 'Zeberg, Hugo|Blomberg, Clas|Arhem, Peter', 'The Nobel Institute for Neurophysiology, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.|The Nobel Institute for Neurophysiology, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.|The Nobel Institute for Neurophysiology, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.', 'Sweden|Sweden|Sweden', 19, 'Action Potentials|Animals|Axons|Hippocampus|Ion Channels|Loligo|Models, Neurological|Myelin Sheath|Neurons|Patch-Clamp Techniques|Synaptic Membranes|Xenopus laevis', 'Journal Article', '10.1371/journal.pcbi.1000753', '20421932', 'The threshold firing frequency of a neuron is a characterizing feature of its dynamical behaviour, in turn determining its role in the oscillatory activity of the brain. Two main types of dynamics have been identified in brain neurons. Type 1 dynamics (regular spiking) shows a continuous relationship between frequency and stimulation current (f-I(stim)) and, thus, an arbitrarily low frequency at threshold current, Type 2 (fast spiking) shows a discontinuous f-I(stim) relationship and a minimum threshold frequency. In a previous study of a hippocampal neuron model, we demonstrated that its dynamics could be of both Type 1 and Type 2, depending on ion channel density. In the present study we analyse the effect of varying channel density on threshold firing frequency on two well-studied axon membranes, namely the frog myelinated axon and the squid giant axon. Moreover, we analyse the hippocampal neuron model in more detail. The models are all based on voltage-clamp studies, thus comprising experimentally measurable parameters. The choice of analysing effects of channel density modifications is due to their physiological and pharmacological relevance. We show, using bifurcation analysis, that both axon models display exclusively Type 2 dynamics, independently of ion channel density. Nevertheless, both models have a region in the channel-density plane characterized by an N-shaped steady-state current-voltage relationship (a prerequisite for Type 1 dynamics and associated with this type of dynamics in the hippocampal model). In summary, our results suggest that the hippocampal soma and the two axon membranes represent two distinct kinds of membranes, membranes with a channel-density dependent switching between Type 1 and 2 dynamics, and membranes with a channel-density independent dynamics. The difference between the two membrane types suggests functional differences, compatible with a more flexible role of the soma membrane than that of the axon membrane.'),
(84589, 2010, 'plos', 'Simulating microdosimetry in a virtual hepatic lobule', 'Wambaugh, John|Shah, Imran', 'National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America. wambaugh.john@epa.gov|National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America. wambaugh.john@epa.gov', 'United States|United States', 0, 'Animals|Apoptosis|Computational Biology|Computer Simulation|Dose-Response Relationship, Drug|Environmental Exposure|Environmental Pollutants|Hepatic Veins|Humans|Liver|Models, Biological|Tissue Distribution|Toxicity Tests', 'Journal Article', '10.1371/journal.pcbi.1000756', '20421935', 'The liver plays a key role in removing harmful chemicals from the body and is therefore often the first tissue to suffer potentially adverse consequences. To protect public health it is necessary to quantitatively estimate the risk of long-term low dose exposure to environmental pollutants. Animal testing is the primary tool for extrapolating human risk but it is fraught with uncertainty, necessitating novel alternative approaches. Our goal is to integrate in vitro liver experiments with agent-based cellular models to simulate a spatially extended hepatic lobule. Here we describe a graphical model of the sinusoidal network that efficiently simulates portal to centrilobular mass transfer in the hepatic lobule. We analyzed the effects of vascular topology and metabolism on the cell-level distribution following oral exposure to chemicals. The spatial distribution of metabolically inactive chemicals was similar across different vascular networks and a baseline well-mixed compartment. When chemicals were rapidly metabolized, concentration heterogeneity of the parent compound increased across the vascular network. As a result, our spatially extended lobule generated greater variability in dose-dependent cellular responses, in this case apoptosis, than were observed in the classical well-mixed liver or in a parallel tubes model. The mass-balanced graphical approach to modeling the hepatic lobule is computationally efficient for simulating long-term exposure, modular for incorporating complex cellular interactions, and flexible for dealing with evolving tissues.'),
(84590, 2010, 'plos', 'Independent component analysis in spiking neurons', 'Savin, Cristina|Joshi, Prashant|Triesch, Jochen', 'Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany. savin@fias.uni-frankfurt.de|Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany. savin@fias.uni-frankfurt.de|Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany. savin@fias.uni-frankfurt.de', 'Germany|Germany|Germany', 57, 'Action Potentials|Algorithms|Models, Neurological|Neuronal Plasticity|Neurons|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1000757', '20421937', 'Although models based on independent component analysis (ICA) have been successful in explaining various properties of sensory coding in the cortex, it remains unclear how networks of spiking neurons using realistic plasticity rules can realize such computation. Here, we propose a biologically plausible mechanism for ICA-like learning with spiking neurons. Our model combines spike-timing dependent plasticity and synaptic scaling with an intrinsic plasticity rule that regulates neuronal excitability to maximize information transmission. We show that a stochastically spiking neuron learns one independent component for inputs encoded either as rates or using spike-spike correlations. Furthermore, different independent components can be recovered, when the activity of different neurons is decorrelated by adaptive lateral inhibition.'),
(84591, 2010, 'plos', 'Charge as a selection criterion for translocation through the nuclear pore complex', 'Colwell, Lucy J|Brenner, Michael P|Ribbeck, Katharina', 'School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.|School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.|School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States', 56, 'Amino Acid Sequence|Cluster Analysis|Fungal Proteins|Humans|Hydrophobic and Hydrophilic Interactions|Models, Biological|Molecular Sequence Data|Nuclear Pore|Nuclear Pore Complex Proteins|Protein Binding|Protein Transport|Saccharomyces cerevisiae|Static Electricity|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000747', '20421988', 'Nuclear pore complexes (NPCs) are highly selective filters that control the exchange of material between nucleus and cytoplasm. The principles that govern selective filtering by NPCs are not fully understood. Previous studies find that cellular proteins capable of fast translocation through NPCs (transport receptors) are characterized by a high proportion of hydrophobic surface regions. Our analysis finds that transport receptors and their complexes are also highly negatively charged. Moreover, NPC components that constitute the permeability barrier are positively charged. We estimate that electrostatic interactions between a transport receptor and the NPC result in an energy gain of several k(B)T, which would enable significantly increased translocation rates of transport receptors relative to other cellular proteins. We suggest that negative charge is an essential criterion for selective passage through the NPC.'),
(84592, 2010, 'plos', 'A reaction-diffusion model of human brain development', 'Lefèvre, Julien|Mangin, Jean-François', 'LSIS, UMR CNRS 6168, Université Aix-Marseille II, Marseille, France. julien.lefevre@univmed.fr|LSIS, UMR CNRS 6168, Université Aix-Marseille II, Marseille, France. julien.lefevre@univmed.fr', 'France|France', 0, 'Algorithms|Cerebral Cortex|Computer Simulation|Humans|Models, Neurological|Models, Statistical|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000749', '20421989', 'Cortical folding exhibits both reproducibility and variability in the geometry and topology of its patterns. These two properties are obviously the result of the brain development that goes through local cellular and molecular interactions which have important consequences on the global shape of the cortex. Hypotheses to explain the convoluted aspect of the brain are still intensively debated and do not focus necessarily on the variability of folds. Here we propose a phenomenological model based on reaction-diffusion mechanisms involving Turing morphogens that are responsible for the differential growth of two types of areas, sulci (bottom of folds) and gyri (top of folds). We use a finite element approach of our model that is able to compute the evolution of morphogens on any kind of surface and to deform it through an iterative process. Our model mimics the progressive folding of the cortical surface along foetal development. Moreover it reveals patterns of reproducibility when we look at several realizations of the model from a noisy initial condition. However this reproducibility must be tempered by the fact that a same fold engendered by the model can have different topological properties, in one or several parts. These two results on the reproducibility and variability of the model echo the sulcal roots theory that postulates the existence of anatomical entities around which the folding organizes itself. These sulcal roots would correspond to initial conditions in our model. Last but not least, the parameters of our model are able to produce different kinds of patterns that can be linked to developmental pathologies such as polymicrogyria and lissencephaly. The main significance of our model is that it proposes a first approach to the issue of reproducibility and variability of the cortical folding.'),
(84593, 2010, 'plos', 'Efficient physical embedding of topologically complex information processing networks in brains and computer circuits', 'Bassett, Danielle S|Greenfield, Daniel L|Meyer-Lindenberg, Andreas|Weinberger, Daniel R|Moore, Simon W|Bullmore, Edward T', 'Department of Physics, University of California Santa Barbara, Santa Barbara, California, United States of America. dbassett@physics.ucsb.edu|Department of Physics, University of California Santa Barbara, Santa Barbara, California, United States of America. dbassett@physics.ucsb.edu|Department of Physics, University of California Santa Barbara, Santa Barbara, California, United States of America. dbassett@physics.ucsb.edu|Department of Physics, University of California Santa Barbara, Santa Barbara, California, United States of America. dbassett@physics.ucsb.edu|Department of Physics, University of California Santa Barbara, Santa Barbara, California, United States of America. dbassett@physics.ucsb.edu|Department of Physics, University of California Santa Barbara, Santa Barbara, California, United States of America. dbassett@physics.ucsb.edu', 'United States|United States|United States|United States|United States|United States', 236, 'Animals|Brain|Caenorhabditis elegans|Fractals|Humans|Linear Models|Magnetic Resonance Imaging|Mammals|Models, Neurological|Nerve Net|Neural Networks (Computer)', 'Journal Article', '10.1371/journal.pcbi.1000748', '20421990', 'Nervous systems are information processing networks that evolved by natural selection, whereas very large scale integrated (VLSI) computer circuits have evolved by commercially driven technology development. Here we follow historic intuition that all physical information processing systems will share key organizational properties, such as modularity, that generally confer adaptivity of function. It has long been observed that modular VLSI circuits demonstrate an isometric scaling relationship between the number of processing elements and the number of connections, known as Rents rule, which is related to the dimensionality of the circuits interconnect topology and its logical capacity. We show that human brain structural networks, and the nervous system of the nematode C. elegans, also obey Rents rule, and exhibit some degree of hierarchical modularity. We further show that the estimated Rent exponent of human brain networks, derived from MRI data, can explain the allometric scaling relations between gray and white matter volumes across a wide range of mammalian species, again suggesting that these principles of nervous system design are highly conserved. For each of these fractal modular networks, the dimensionality of the interconnect topology was greater than the 2 or 3 Euclidean dimensions of the space in which it was embedded. This relatively high complexity entailed extra cost in physical wiring: although all networks were economically or cost-efficiently wired they did not strictly minimize wiring costs. Artificial and biological information processing systems both may evolve to optimize a trade-off between physical cost and topological complexity, resulting in the emergence of homologous principles of economical, fractal and modular design across many different kinds of nervous and computational networks.'),
(84594, 2010, 'plos', 'Vertical binocular disparity is encoded implicitly within a model neuronal population tuned to horizontal disparity and orientation', 'Read, Jenny C A', 'Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom. j.c.a.read@ncl.ac.uk', 'United Kingdom', 11, 'Action Potentials|Algorithms|Computational Biology|Humans|Models, Neurological|Neurons|Vision Disparity|Visual Fields', 'Journal Article', '10.1371/journal.pcbi.1000754', '20421992', 'Primary visual cortex is often viewed as a cyclopean retina, performing the initial encoding of binocular disparities between left and right images. Because the eyes are set apart horizontally in the head, binocular disparities are predominantly horizontal. Yet, especially in the visual periphery, a range of non-zero vertical disparities do occur and can influence perception. It has therefore been assumed that primary visual cortex must contain neurons tuned to a range of vertical disparities. Here, I show that this is not necessarily the case. Many disparity-selective neurons are most sensitive to changes in disparity orthogonal to their preferred orientation. That is, the disparity tuning surfaces, mapping their response to different two-dimensional (2D) disparities, are elongated along the cells preferred orientation. Because of this, even if a neurons optimal 2D disparity has zero vertical component, the neuron will still respond best to a non-zero vertical disparity when probed with a sub-optimal horizontal disparity. This property can be used to decode 2D disparity, even allowing for realistic levels of neuronal noise. Even if all V1 neurons at a particular retinotopic location are tuned to the expected vertical disparity there (for example, zero at the fovea), the brain could still decode the magnitude and sign of departures from that expected value. This provides an intriguing counter-example to the common wisdom that, in order for a neuronal population to encode a quantity, its members must be tuned to a range of values of that quantity. It demonstrates that populations of disparity-selective neurons encode much richer information than previously appreciated. It suggests a possible strategy for the brain to extract rarely-occurring stimulus values, while concentrating neuronal resources on the most commonly-occurring situations.'),
(84595, 2010, 'plos', 'Structural characteristics of novel protein folds', 'Fernandez-Fuentes, Narcis|Dybas, Joseph M|Fiser, Andras', 'University of Leeds, Leeds Institute of Molecular Medicine Section of Experimental Therapeutics, St. Jamess University Hospital, Leeds, United Kingdom.|University of Leeds, Leeds Institute of Molecular Medicine Section of Experimental Therapeutics, St. Jamess University Hospital, Leeds, United Kingdom.|University of Leeds, Leeds Institute of Molecular Medicine Section of Experimental Therapeutics, St. Jamess University Hospital, Leeds, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Amino Acid Motifs|Genomics|Models, Molecular|Protein Conformation|Protein Folding|Proteins', 'Journal Article', '10.1371/journal.pcbi.1000750', '20421995', 'Folds are the basic building blocks of protein structures. Understanding the emergence of novel protein folds is an important step towards understanding the rules governing the evolution of protein structure and function and for developing tools for protein structure modeling and design. We explored the frequency of occurrences of an exhaustively classified library of supersecondary structural elements (Smotifs), in protein structures, in order to identify features that would define a fold as novel compared to previously known structures. We found that a surprisingly small set of Smotifs is sufficient to describe all known folds. Furthermore, novel folds do not require novel Smotifs, but rather are a new combination of existing ones. Novel folds can be typified by the inclusion of a relatively higher number of rarely occurring Smotifs in their structures and, to a lesser extent, by a novel topological combination of commonly occurring Smotifs. When investigating the structural features of Smotifs, we found that the top 10% of most frequent ones have a higher fraction of internal contacts, while some of the most rare motifs are larger, and contain a longer loop region.'),
(84596, 2010, 'plos', 'PLoS Computational Biology conference postcards from PSB 2010', 'Datta, Ruchira S|Lux, Matthew W|Bourne, Philip E', 'Berkeley Phylogenomics Group, QB3 Institute, University of California Berkeley, Berkeley, California, United States of America.|Berkeley Phylogenomics Group, QB3 Institute, University of California Berkeley, Berkeley, California, United States of America.|Berkeley Phylogenomics Group, QB3 Institute, University of California Berkeley, Berkeley, California, United States of America.', 'United States|United States|United States', 0, 'Computational Biology|Genotype|Phenotype', 'Congress', '10.1371/journal.pcbi.1000746', '20442855', '-'),
(84597, 2010, 'plos', 'Polyglutamine induced misfolding of huntingtin exon1 is modulated by the flanking sequences', 'Lakhani, Vinal V|Ding, Feng|Dokholyan, Nikolay V', 'Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.|Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.|Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.', 'United States|United States|United States', 43, 'Amino Acid Sequence|Cluster Analysis|Exons|Huntingtin Protein|Huntington Disease|Molecular Dynamics Simulation|Molecular Sequence Data|Nerve Tissue Proteins|Nuclear Proteins|Peptides|Protein Folding|Protein Multimerization|Protein Structure, Secondary|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000772', '20442863', 'Polyglutamine (polyQ) expansion in exon1 (XN1) of the huntingtin protein is linked to Huntingtons disease. When the number of glutamines exceeds a threshold of approximately 36-40 repeats, XN1 can readily form amyloid aggregates similar to those associated with disease. Many experiments suggest that misfolding of monomeric XN1 plays an important role in the length-dependent aggregation. Elucidating the misfolding of a XN1 monomer can help determine the molecular mechanism of XN1 aggregation and potentially help develop strategies to inhibit XN1 aggregation. The flanking sequences surrounding the polyQ region can play a critical role in determining the structural rearrangement and aggregation mechanism of XN1. Few experiments have studied XN1 in its entirety, with all flanking regions. To obtain structural insights into the misfolding of XN1 toward amyloid aggregation, we perform molecular dynamics simulations on monomeric XN1 with full flanking regions, a variant missing the polyproline regions, which are hypothesized to prevent aggregation, and an isolated polyQ peptide (Q(n)). For each of these three constructs, we study glutamine repeat lengths of 23, 36, 40 and 47. We find that polyQ peptides have a positive correlation between their probability to form a beta-rich misfolded state and their expansion length. We also find that the flanking regions of XN1 affect its probability to form a beta-rich state compared to the isolated polyQ. Particularly, the polyproline regions form polyproline type II helices and decrease the probability of the polyQ region to form a beta-rich state. Additionally, by lengthening polyQ, the first N-terminal 17 residues are more likely to adopt a beta-sheet conformation rather than an alpha-helix conformation. Therefore, our molecular dynamics study provides a structural insight of XN1 misfolding and elucidates the possible role of the flanking sequences in XN1 aggregation.'),
(84598, 2010, 'plos', 'A quantitative model of transcriptional regulation reveals the influence of binding location on expression', 'MacIsaac, Kenzie D|Lo, Kinyui A|Gordon, William|Motola, Shmulik|Mazor, Tali|Fraenkel, Ernest', 'Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States|United States', 57, '3T3-L1 Cells|Algorithms|Animals|Binding Sites|CREB-Binding Protein|Cerebellum|Conserved Sequence|Gene Expression Regulation|Liver|Male|Mice|Mice, Inbred C57BL|Models, Genetic|Oligonucleotide Array Sequence Analysis|Protein Binding|Regulatory Elements, Transcriptional|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000773', '20442865', 'Understanding the mechanistic basis of transcriptional regulation has been a central focus of molecular biology since its inception. New high-throughput chromatin immunoprecipitation experiments have revealed that most regulatory proteins bind thousands of sites in mammalian genomes. However, the functional significance of these binding sites remains unclear. We present a quantitative model of transcriptional regulation that suggests the contribution of each binding site to tissue-specific gene expression depends strongly on its position relative to the transcription start site. For three cell types, we show that, by considering binding position, it is possible to predict relative expression levels between cell types with an accuracy approaching the level of agreement between different experimental platforms. Our model suggests that, for the transcription factors profiled in these cell types, a regulatory sites influence on expression falls off almost linearly with distance from the transcription start site in a 10 kilobase range. Binding to both evolutionarily conserved and non-conserved sequences contributes significantly to transcriptional regulation. Our approach also reveals the quantitative, tissue-specific role of individual proteins in activating or repressing transcription. These results suggest that regulator binding position plays a previously unappreciated role in influencing expression and blurs the classical distinction between proximal promoter and distal binding events.'),
(84599, 2010, 'plos', 'Neighbor-dependent Ramachandran probability distributions of amino acids developed from a hierarchical Dirichlet process model', 'Ting, Daniel|Wang, Guoli|Shapovalov, Maxim|Mitra, Rajib|Jordan, Michael I|Dunbrack, Roland L', 'Department of Statistics, University of California Berkeley, Berkeley, California, United States of America.|Department of Statistics, University of California Berkeley, Berkeley, California, United States of America.|Department of Statistics, University of California Berkeley, Berkeley, California, United States of America.|Department of Statistics, University of California Berkeley, Berkeley, California, United States of America.|Department of Statistics, University of California Berkeley, Berkeley, California, United States of America.|Department of Statistics, University of California Berkeley, Berkeley, California, United States of America.', 'United States|United States|United States|United States|United States|United States', 0, 'Algorithms|Amino Acid Sequence|Amino Acids|Bayes Theorem|Databases, Protein|Models, Biological|Models, Statistical|Protein Conformation|Proteins', 'Journal Article', '10.1371/journal.pcbi.1000763', '20442867', 'Distributions of the backbone dihedral angles of proteins have been studied for over 40 years. While many statistical analyses have been presented, only a handful of probability densities are publicly available for use in structure validation and structure prediction methods. The available distributions differ in a number of important ways, which determine their usefulness for various purposes. These include: 1) input data size and criteria for structure inclusion (resolution, R-factor, etc.), 2) filtering of suspect conformations and outliers using B-factors or other features, 3) secondary structure of input data (e.g., whether helix and sheet are included, whether beta turns are included), 4) the method used for determining probability densities ranging from simple histograms to modern nonparametric density estimation, and 5) whether they include nearest neighbor effects on the distribution of conformations in different regions of the Ramachandran map. In this work, Ramachandran probability distributions are presented for residues in protein loops from a high-resolution data set with filtering based on calculated electron densities. Distributions for all 20 amino acids (with cis and trans proline treated separately) have been determined, as well as 420 left-neighbor and 420 right-neighbor dependent distributions. The neighbor-independent and neighbor-dependent probability densities have been accurately estimated using Bayesian nonparametric statistical analysis based on the Dirichlet process. In particular, we used hierarchical Dirichlet process priors, which allow sharing of information between densities for a particular residue type and different neighbor residue types. The resulting distributions are tested in a loop modeling benchmark with the program Rosetta, and are shown to improve protein loop conformation prediction significantly. The distributions are available at http://dunbrack.fccc.edu/hdp.'),
(84600, 2010, 'plos', 'The brains router: a cortical network model of serial processing in the primate brain', 'Zylberberg, Ariel|Fernández Slezak, Diego|Roelfsema, Pieter R|Dehaene, Stanislas|Sigman, Mariano', 'Laboratory of Integrative Neuroscience, Physics Department, University of Buenos Aires, Buenos Aires, Argentina. arielz@df.uba.ar|Laboratory of Integrative Neuroscience, Physics Department, University of Buenos Aires, Buenos Aires, Argentina. arielz@df.uba.ar|Laboratory of Integrative Neuroscience, Physics Department, University of Buenos Aires, Buenos Aires, Argentina. arielz@df.uba.ar|Laboratory of Integrative Neuroscience, Physics Department, University of Buenos Aires, Buenos Aires, Argentina. arielz@df.uba.ar|Laboratory of Integrative Neuroscience, Physics Department, University of Buenos Aires, Buenos Aires, Argentina. arielz@df.uba.ar', 'Argentina|Argentina|Argentina|Argentina|Argentina', 85, 'Action Potentials|Analysis of Variance|Attentional Blink|Cerebral Cortex|Cognition|Humans|Models, Neurological|Nerve Net|Reaction Time|Stochastic Processes|Task Performance and Analysis', 'Journal Article', '10.1371/journal.pcbi.1000765', '20442869', 'The human brain efficiently solves certain operations such as object recognition and categorization through a massively parallel network of dedicated processors. However, human cognition also relies on the ability to perform an arbitrarily large set of tasks by flexibly recombining different processors into a novel chain. This flexibility comes at the cost of a severe slowing down and a seriality of operations (100-500 ms per step). A limit on parallel processing is demonstrated in experimental setups such as the psychological refractory period (PRP) and the attentional blink (AB) in which the processing of an element either significantly delays (PRP) or impedes conscious access (AB) of a second, rapidly presented element. Here we present a spiking-neuron implementation of a cognitive architecture where a large number of local parallel processors assemble together to produce goal-driven behavior. The precise mapping of incoming sensory stimuli onto motor representations relies on a router network capable of flexibly interconnecting processors and rapidly changing its configuration from one task to another. Simulations show that, when presented with dual-task stimuli, the network exhibits parallel processing at peripheral sensory levels, a memory buffer capable of keeping the result of sensory processing on hold, and a slow serial performance at the router stage, resulting in a performance bottleneck. The network captures the detailed dynamics of human behavior during dual-task-performance, including both mean RTs and RT distributions, and establishes concrete predictions on neuronal dynamics during dual-task experiments in humans and non-human primates.'),
(84601, 2010, 'plos', 'A critical quantity for noise attenuation in feedback systems', 'Wang, Liming|Xin, Jack|Nie, Qing', 'Center for Mathematical and Computational Biology, Center for Complex Biological Systems, and Department of Mathematics, University of California at Irvine, Irvine, California, United States of America.|Center for Mathematical and Computational Biology, Center for Complex Biological Systems, and Department of Mathematics, University of California at Irvine, Irvine, California, United States of America.|Center for Mathematical and Computational Biology, Center for Complex Biological Systems, and Department of Mathematics, University of California at Irvine, Irvine, California, United States of America.', 'United States|United States|United States', 0, 'Algorithms|Computational Biology|Drug Resistance, Bacterial|Enterobacteriaceae|Feedback, Physiological|Models, Biological|Phosphotransferases|Polymyxin B|Signal Transduction|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1000764', '20442870', 'Feedback modules, which appear ubiquitously in biological regulations, are often subject to disturbances from the input, leading to fluctuations in the output. Thus, the question becomes how a feedback system can produce a faithful response with a noisy input. We employed multiple time scale analysis, Fluctuation Dissipation Theorem, linear stability, and numerical simulations to investigate a module with one positive feedback loop driven by an external stimulus, and we obtained a critical quantity in noise attenuation, termed as signed activation time. We then studied the signed activation time for a system of two positive feedback loops, a system of one positive feedback loop and one negative feedback loop, and six other existing biological models consisting of multiple components along with positive and negative feedback loops. An inverse relationship is found between the noise amplification rate and the signed activation time, defined as the difference between the deactivation and activation time scales of the noise-free system, normalized by the frequency of noises presented in the input. Thus, the combination of fast activation and slow deactivation provides the best noise attenuation, and it can be attained in a single positive feedback loop system. An additional positive feedback loop often leads to a marked decrease in activation time, decrease or slight increase of deactivation time and allows larger kinetic rate variations for slow deactivation and fast activation. On the other hand, a negative feedback loop may increase the activation and deactivation times. The negative relationship between the noise amplification rate and the signed activation time also holds for the six other biological models with multiple components and feedback loops. This principle may be applicable to other feedback systems.'),
(84602, 2010, 'plos', 'Accurately measuring recombination between closely related HIV-1 genomes', 'Schlub, Timothy E|Smyth, Redmond P|Grimm, Andrew J|Mak, Johnson|Davenport, Miles P', 'Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.|Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.|Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.|Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.|Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.', 'Australia|Australia|Australia|Australia|Australia', 38, 'Algorithms|Cell Line|Codon|Genetic Markers|Genome, Viral|HIV-1|Humans|Models, Genetic|Poisson Distribution|Recombination, Genetic|Templates, Genetic', 'Journal Article', '10.1371/journal.pcbi.1000766', '20442872', 'Retroviral recombination is thought to play an important role in the generation of immune escape and multiple drug resistance by shuffling pre-existing mutations in the viral population. Current estimates of HIV-1 recombination rates are derived from measurements within reporter gene sequences or genetically divergent HIV sequences. These measurements do not mimic the recombination occurring in vivo, between closely related genomes. Additionally, the methods used to measure recombination make a variety of assumptions about the underlying process, and often fail to account adequately for issues such as co-infection of cells or the possibility of multiple template switches between recombination sites. We have developed a HIV-1 marker system by making a small number of codon modifications in gag which allow recombination to be measured over various lengths between closely related viral genomes. We have developed statistical tools to measure recombination rates that can compensate for the possibility of multiple template switches. Our results show that when multiple template switches are ignored the error is substantial, particularly when recombination rates are high, or the genomic distance is large. We demonstrate that this system is applicable to other studies to accurately measure the recombination rate and show that recombination does not occur randomly within the HIV genome.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84603, 2010, 'plos', 'A new approach for determining phase response curves reveals that Purkinje cells can act as perfect integrators', 'Phoka, Elena|Cuntz, Hermann|Roth, Arnd|Häusser, Michael', 'Wolfson Institute for Biomedical Research and Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom. e.phoka07@imperial.ac.uk|Wolfson Institute for Biomedical Research and Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom. e.phoka07@imperial.ac.uk|Wolfson Institute for Biomedical Research and Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom. e.phoka07@imperial.ac.uk|Wolfson Institute for Biomedical Research and Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom. e.phoka07@imperial.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 34, 'Action Potentials|Animals|Computational Biology|Electric Stimulation|Electrophysiology|Mice|Models, Neurological|Purkinje Cells|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000768', '20442875', 'Cerebellar Purkinje cells display complex intrinsic dynamics. They fire spontaneously, exhibit bistability, and via mutual network interactions are involved in the generation of high frequency oscillations and travelling waves of activity. To probe the dynamical properties of Purkinje cells we measured their phase response curves (PRCs). PRCs quantify the change in spike phase caused by a stimulus as a function of its temporal position within the interspike interval, and are widely used to predict neuronal responses to more complex stimulus patterns. Significant variability in the interspike interval during spontaneous firing can lead to PRCs with a low signal-to-noise ratio, requiring averaging over thousands of trials. We show using electrophysiological experiments and simulations that the PRC calculated in the traditional way by sampling the interspike interval with brief current pulses is biased. We introduce a corrected approach for calculating PRCs which eliminates this bias. Using our new approach, we show that Purkinje cell PRCs change qualitatively depending on the firing frequency of the cell. At high firing rates, Purkinje cells exhibit single-peaked, or monophasic PRCs. Surprisingly, at low firing rates, Purkinje cell PRCs are largely independent of phase, resembling PRCs of ideal non-leaky integrate-and-fire neurons. These results indicate that Purkinje cells can act as perfect integrators at low firing rates, and that the integration mode of Purkinje cells depends on their firing rate.'),
(84604, 2010, 'plos', 'Evolutionary establishment of moral and double moral standards through spatial interactions', 'Helbing, Dirk|Szolnoki, Attila|Perc, Matjaz|Szabó, György', 'ETH Zurich, Zurich, Switzerland. dhelbing@ethz.ch|ETH Zurich, Zurich, Switzerland. dhelbing@ethz.ch|ETH Zurich, Zurich, Switzerland. dhelbing@ethz.ch|ETH Zurich, Zurich, Switzerland. dhelbing@ethz.ch', 'Switzerland|Switzerland|Switzerland|Switzerland', 207, 'Biological Evolution|Cluster Analysis|Competitive Behavior|Computational Biology|Cooperative Behavior|Game Theory|Humans|Models, Psychological|Morals', 'Journal Article', '10.1371/journal.pcbi.1000758', '20454464', 'Situations where individuals have to contribute to joint efforts or share scarce resources are ubiquitous. Yet, without proper mechanisms to ensure cooperation, the evolutionary pressure to maximize individual success tends to create a tragedy of the commons (such as over-fishing or the destruction of our environment). This contribution addresses a number of related puzzles of human behavior with an evolutionary game theoretical approach as it has been successfully used to explain the behavior of other biological species many times, from bacteria to vertebrates. Our agent-based model distinguishes individuals applying four different behavioral strategies: non-cooperative individuals (defectors), cooperative individuals abstaining from punishment efforts (called cooperators or second-order free-riders), cooperators who punish non-cooperative behavior (moralists), and defectors, who punish other defectors despite being non-cooperative themselves (immoralists). By considering spatial interactions with neighboring individuals, our model reveals several interesting effects: First, moralists can fully eliminate cooperators. This spreading of punishing behavior requires a segregation of behavioral strategies and solves the second-order free-rider problem. Second, the system behavior changes its character significantly even after very long times (who laughs last laughs best effect). Third, the presence of a number of defectors can largely accelerate the victory of moralists over non-punishing cooperators. Fourth, in order to succeed, moralists may profit from immoralists in a way that appears like an unholy collaboration. Our findings suggest that the consideration of punishment strategies allows one to understand the establishment and spreading of moral behavior by means of game-theoretical concepts. This demonstrates that quantitative biological modeling approaches are powerful even in domains that have been addressed with non-mathematical concepts so far. The complex dynamics of certain social behaviors become understandable as the result of an evolutionary competition between different behavioral strategies.'),
(84605, 2010, 'plos', 'Robustness under functional constraint: the genetic network for temporal expression in Drosophila neurogenesis', 'Nakajima, Akihiko|Isshiki, Takako|Kaneko, Kunihiko|Ishihara, Shuji', 'Department of Basic Science, University of Tokyo, Komaba, Tokyo, Japan. nakajima@complex.c.u-tokyo.ac.jp|Department of Basic Science, University of Tokyo, Komaba, Tokyo, Japan. nakajima@complex.c.u-tokyo.ac.jp|Department of Basic Science, University of Tokyo, Komaba, Tokyo, Japan. nakajima@complex.c.u-tokyo.ac.jp|Department of Basic Science, University of Tokyo, Komaba, Tokyo, Japan. nakajima@complex.c.u-tokyo.ac.jp', 'Japan|Japan|Japan|Japan', 13, 'Animals|Body Patterning|Drosophila|Gene Expression Profiling|Gene Expression Regulation|Gene Regulatory Networks|Models, Biological|Models, Statistical|Neurogenesis|Neurons|Regression Analysis|Stem Cells|Systems Biology|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1000760', '20454677', 'Precise temporal coordination of gene expression is crucial for many developmental processes. One central question in developmental biology is how such coordinated expression patterns are robustly controlled. During embryonic development of the Drosophila central nervous system, neural stem cells called neuroblasts express a group of genes in a definite order, which leads to the diversity of cell types. We produced all possible regulatory networks of these genes and examined their expression dynamics numerically. From the analysis, we identified requisite regulations and predicted an unknown factor to reproduce known expression profiles caused by loss-of-function or overexpression of the genes in vivo, as well as in the wild type. Following this, we evaluated the stability of the actual Drosophila network for sequential expression. This network shows the highest robustness against parameter variations and gene expression fluctuations among the possible networks that reproduce the expression profiles. We propose a regulatory module composed of three types of regulations that is responsible for precise sequential expression. This study suggests that the Drosophila network for sequential expression has evolved to generate the robust temporal expression for neuronal specification.'),
(84606, 2010, 'plos', 'How informative are spatial CA3 representations established by the dentate gyrus?', 'Cerasti, Erika|Treves, Alessandro', 'SISSA, Cognitive Neuroscience Sector, Trieste, Italy. cerasti@sissa.it|SISSA, Cognitive Neuroscience Sector, Trieste, Italy. cerasti@sissa.it', 'Italy|Italy', 36, 'Animals|CA3 Region, Hippocampal|Computer Simulation|Dentate Gyrus|Learning|Memory|Models, Neurological|Mossy Fibers, Hippocampal|Neuronal Plasticity|Rats', 'Journal Article', '10.1371/journal.pcbi.1000759', '20454678', 'In the mammalian hippocampus, the dentate gyrus (DG) is characterized by sparse and powerful unidirectional projections to CA3 pyramidal cells, the so-called mossy fibers. Mossy fiber synapses appear to duplicate, in terms of the information they convey, what CA3 cells already receive from entorhinal cortex layer II cells, which project both to the dentate gyrus and to CA3. Computational models of episodic memory have hypothesized that the function of the mossy fibers is to enforce a new, well-separated pattern of activity onto CA3 cells, to represent a new memory, prevailing over the interference produced by the traces of older memories already stored on CA3 recurrent collateral connections. Can this hypothesis apply also to spatial representations, as described by recent neurophysiological recordings in rats? To address this issue quantitatively, we estimate the amount of information DG can impart on a new CA3 pattern of spatial activity, using both mathematical analysis and computer simulations of a simplified model. We confirm that, also in the spatial case, the observed sparse connectivity and level of activity are most appropriate for driving memory storage-and not to initiate retrieval. Surprisingly, the model also indicates that even when DG codes just for space, much of the information it passes on to CA3 acquires a non-spatial and episodic character, akin to that of a random number generator. It is suggested that further hippocampal processing is required to make full spatial use of DG inputs.'),
(84607, 2010, 'plos', 'Learning graph-mer motifs that predict gene expression trajectories in development', 'Li, Xuejing|Panea, Casandra|Wiggins, Chris H|Reinke, Valerie|Leslie, Christina', 'Department of Physics, Columbia University, New York, New York, United States of America.|Department of Physics, Columbia University, New York, New York, United States of America.|Department of Physics, Columbia University, New York, New York, United States of America.|Department of Physics, Columbia University, New York, New York, United States of America.|Department of Physics, Columbia University, New York, New York, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Algorithms|Animals|Caenorhabditis elegans|Gene Expression Profiling|Least-Squares Analysis|Male|Multigene Family|Multivariate Analysis|Oocytes|Principal Component Analysis|Promoter Regions, Genetic|Regression Analysis|Reproducibility of Results|Spermatozoa', 'Journal Article', '10.1371/journal.pcbi.1000761', '20454681', 'A key problem in understanding transcriptional regulatory networks is deciphering what cis regulatory logic is encoded in gene promoter sequences and how this sequence information maps to expression. A typical computational approach to this problem involves clustering genes by their expression profiles and then searching for overrepresented motifs in the promoter sequences of genes in a cluster. However, genes with similar expression profiles may be controlled by distinct regulatory programs. Moreover, if many gene expression profiles in a data set are highly correlated, as in the case of whole organism developmental time series, it may be difficult to resolve fine-grained clusters in the first place. We present a predictive framework for modeling the natural flow of information, from promoter sequence to expression, to learn cis regulatory motifs and characterize gene expression patterns in developmental time courses. We introduce a cluster-free algorithm based on a graph-regularized version of partial least squares (PLS) regression to learn sequence patterns--represented by graphs of k-mers, or graph-mers--that predict gene expression trajectories. Applying the approach to wildtype germline development in Caenorhabditis elegans, we found that the first and second latent PLS factors mapped to expression profiles for oocyte and sperm genes, respectively. We extracted both known and novel motifs from the graph-mers associated to these germline-specific patterns, including novel CG-rich motifs specific to oocyte genes. We found evidence supporting the functional relevance of these putative regulatory elements through analysis of positional bias, motif conservation and in situ gene expression. This study demonstrates that our regression model can learn biologically meaningful latent structure and identify potentially functional motifs from subtle developmental time course expression data.'),
(84608, 2010, 'plos', 'Asymmetric switching in a homodimeric ABC transporter: a simulation study', 'Aittoniemi, Jussi|de Wet, Heidi|Ashcroft, Frances M|Sansom, Mark S P', 'Department of Biochemistry, University of Oxford, Oxford, United Kingdom.|Department of Biochemistry, University of Oxford, Oxford, United Kingdom.|Department of Biochemistry, University of Oxford, Oxford, United Kingdom.|Department of Biochemistry, University of Oxford, Oxford, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'ATP-Binding Cassette Transporters|Adenosine Triphosphate|Amino Acid Sequence|Bacterial Proteins|Binding Sites|Computer Simulation|Drug Resistance, Multiple, Bacterial|Lipid Metabolism|Molecular Dynamics Simulation|Molecular Sequence Data|Sequence Alignment', 'Journal Article', '10.1371/journal.pcbi.1000762', '20454684', 'ABC transporters are a large family of membrane proteins involved in a variety of cellular processes, including multidrug and tumor resistance and ion channel regulation. Advances in the structural and functional understanding of ABC transporters have revealed that hydrolysis at the two canonical nucleotide-binding sites (NBSs) is co-operative and non-simultaneous. A conserved core architecture of bacterial and eukaryotic ABC exporters has been established, as exemplified by the crystal structure of the homodimeric multidrug exporter Sav1866. Currently, it is unclear how sequential ATP hydrolysis arises in a symmetric homodimeric transporter, since it implies at least transient asymmetry at the NBSs. We show by molecular dynamics simulation that the initially symmetric structure of Sav1866 readily undergoes asymmetric transitions at its NBSs in a pre-hydrolytic nucleotide configuration. MgATP-binding residues and a network of charged residues at the dimer interface are shown to form a sequence of putative molecular switches that allow ATP hydrolysis only at one NBS. We extend our findings to eukaryotic ABC exporters which often consist of two non-identical half-transporters, frequently with degeneracy substitutions at one of their two NBSs. Interestingly, many residues involved in asymmetric conformational switching in Sav1866 are substituted in degenerate eukaryotic NBS. This finding strengthens recent suggestions that the interplay of a consensus and a degenerate NBS in eukaroytic ABC proteins pre-determines the sequence of hydrolysis at the two NBSs.'),
(84609, 2010, 'plos', 'Mutation bias favors protein folding stability in the evolution of small populations', 'Mendez, Raul|Fritsche, Miriam|Porto, Markus|Bastolla, Ugo', 'Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, Spain.|Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, Spain.|Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, Spain.|Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, Spain.', 'Spain|Spain|Spain|Spain', 32, 'Bacteria|Bacterial Proteins|Base Composition|Computer Simulation|Evolution, Molecular|Genetic Fitness|Models, Genetic|Mutation|Protein Folding|Protein Stability|Proteins|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.1000767', '20463869', 'Mutation bias in prokaryotes varies from extreme adenine and thymine (AT) in obligatory endosymbiotic or parasitic bacteria to extreme guanine and cytosine (GC), for instance in actinobacteria. GC mutation bias deeply influences the folding stability of proteins, making proteins on the average less hydrophobic and therefore less stable with respect to unfolding but also less susceptible to misfolding and aggregation. We study a model where proteins evolve subject to selection for folding stability under given mutation bias, population size, and neutrality. We find a non-neutral regime where, for any given population size, there is an optimal mutation bias that maximizes fitness. Interestingly, this optimal GC usage is small for small populations, large for intermediate populations and around 50% for large populations. This result is robust with respect to the definition of the fitness function and to the protein structures studied. Our model suggests that small populations evolving with small GC usage eventually accumulate a significant selective advantage over populations evolving without this bias. This provides a possible explanation to the observation that most species adopting obligatory intracellular lifestyles with a consequent reduction of effective population size shifted their mutation spectrum towards AT. The model also predicts that large GC usage is optimal for intermediate population size. To test these predictions we estimated the effective population sizes of bacterial species using the optimal codon usage coefficients computed by dos Reis et al. and the synonymous to non-synonymous substitution ratio computed by Daubin and Moran. We found that the population sizes estimated in these ways are significantly smaller for species with small and large GC usage compared to species with no bias, which supports our prediction.'),
(84610, 2010, 'plos', 'Energy-information trade-offs between movement and sensing', 'MacIver, Malcolm A|Patankar, Neelesh A|Shirgaonkar, Anup A', 'Department of Mechanical Engineering, Northwestern University, Evanston, Illinois, USA.|Department of Mechanical Engineering, Northwestern University, Evanston, Illinois, USA.|Department of Mechanical Engineering, Northwestern University, Evanston, Illinois, USA.', 'United States|United States|United States', 35, 'Animals|Biomechanical Phenomena|Energy Metabolism|Gymnotiformes|Locomotion|Models, Biological|Predatory Behavior|Sensation|Swimming', 'Journal Article', '10.1371/journal.pcbi.1000769', '20463870', 'While there is accumulating evidence for the importance of the metabolic cost of information in sensory systems, how these costs are traded-off with movement when sensing is closely linked to movement is poorly understood. For example, if an animal needs to search a given amount of space beyond the range of its vision system, is it better to evolve a higher acuity visual system, or evolve a body movement system that can more rapidly move the body over that space? How is this trade-off dependent upon the three-dimensional shape of the field of sensory sensitivity (hereafter, sensorium)? How is it dependent upon sensorium mobility, either through rotation of the sensorium via muscles at the base of the sense organ (e.g., eye or pinna muscles) or neck rotation, or by whole body movement through space? Here we show that in an aquatic model system, the electric fish, a choice to swim in a more inefficient manner during prey search results in a higher prey encounter rate due to better sensory performance. The increase in prey encounter rate more than counterbalances the additional energy expended in swimming inefficiently. The reduction of swimming efficiency for improved sensing arises because positioning the sensory receptor surface to scan more space per unit time results in an increase in the area of the body pushing through the fluid, increasing wasteful body drag forces. We show that the improvement in sensory performance that occurs with the costly repositioning of the body depends upon having an elongated sensorium shape. Finally, we show that if the fish was able to reorient their sensorium independent of body movement, as fish with movable eyes can, there would be significant energy savings. This provides insight into the ubiquity of sensory organ mobility in animal design. This study exposes important links between the morphology of the sensorium, sensorium mobility, and behavioral strategy for maximally extracting energy from the environment. An infomechanical approach to complex behavior helps to elucidate how animals distribute functions across sensory systems and movement systems with their diverse energy loads.'),
(84611, 2010, 'plos', 'A Bayesian framework to account for complex non-genetic factors in gene expression levels greatly increases power in eQTL studies', 'Stegle, Oliver|Parts, Leopold|Durbin, Richard|Winn, John', 'Max Planck Institutes Tübingen, Tübingen, Germany. oliver.stegle@tuebingen.mpg.de|Max Planck Institutes Tübingen, Tübingen, Germany. oliver.stegle@tuebingen.mpg.de|Max Planck Institutes Tübingen, Tübingen, Germany. oliver.stegle@tuebingen.mpg.de|Max Planck Institutes Tübingen, Tübingen, Germany. oliver.stegle@tuebingen.mpg.de', 'Germany|Germany|Germany|Germany', 206, 'Animals|Bayes Theorem|Databases, Genetic|Gene Expression|Humans|Internet|Markov Chains|Mice|Models, Genetic|Models, Statistical|Phenotype|Quantitative Trait Loci|Reproducibility of Results|Software|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1000770', '20463871', 'Gene expression measurements are influenced by a wide range of factors, such as the state of the cell, experimental conditions and variants in the sequence of regulatory regions. To understand the effect of a variable of interest, such as the genotype of a locus, it is important to account for variation that is due to confounding causes. Here, we present VBQTL, a probabilistic approach for mapping expression quantitative trait loci (eQTLs) that jointly models contributions from genotype as well as known and hidden confounding factors. VBQTL is implemented within an efficient and flexible inference framework, making it fast and tractable on large-scale problems. We compare the performance of VBQTL with alternative methods for dealing with confounding variability on eQTL mapping datasets from simulations, yeast, mouse, and human. Employing Bayesian complexity control and joint modelling is shown to result in more precise estimates of the contribution of different confounding factors resulting in additional associations to measured transcript levels compared to alternative approaches. We present a threefold larger collection of cis eQTLs than previously found in a whole-genome eQTL scan of an outbred human population. Altogether, 27% of the tested probes show a significant genetic association in cis, and we validate that the additional eQTLs are likely to be real by replicating them in different sets of individuals. Our method is the next step in the analysis of high-dimensional phenotype data, and its application has revealed insights into genetic regulation of gene expression by demonstrating more abundant cis-acting eQTLs in human than previously shown. Our software is freely available online at http://www.sanger.ac.uk/resources/software/peer/.'),
(84612, 2010, 'plos', 'Modeling reveals bistability and low-pass filtering in the network module determining blood stem cell fate', 'Narula, Jatin|Smith, Aileen M|Gottgens, Berthold|Igoshin, Oleg A', 'Department of Bioengineering, Rice University, Houston, Texas, USA.|Department of Bioengineering, Rice University, Houston, Texas, USA.|Department of Bioengineering, Rice University, Houston, Texas, USA.|Department of Bioengineering, Rice University, Houston, Texas, USA.', 'United States|United States|United States|United States', 0, 'Algorithms|Animals|Cell Differentiation|Gene Expression Regulation|Hematopoietic Stem Cells|Mice|Models, Genetic|Nucleosomes|Promoter Regions, Genetic|Thermodynamics|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000771', '20463872', 'Combinatorial regulation of gene expression is ubiquitous in eukaryotes with multiple inputs converging on regulatory control elements. The dynamic properties of these elements determine the functionality of genetic networks regulating differentiation and development. Here we propose a method to quantitatively characterize the regulatory output of distant enhancers with a biophysical approach that recursively determines free energies of protein-protein and protein-DNA interactions from experimental analysis of transcriptional reporter libraries. We apply this method to model the Scl-Gata2-Fli1 triad-a network module important for cell fate specification of hematopoietic stem cells. We show that this triad module is inherently bistable with irreversible transitions in response to physiologically relevant signals such as Notch, Bmp4 and Gata1 and we use the model to predict the sensitivity of the network to mutations. We also show that the triad acts as a low-pass filter by switching between steady states only in response to signals that persist for longer than a minimum duration threshold. We have found that the auto-regulation loops connecting the slow-degrading Scl to Gata2 and Fli1 are crucial for this low-pass filtering property. Taken together our analysis not only reveals new insights into hematopoietic stem cell regulatory network functionality but also provides a novel and widely applicable strategy to incorporate experimental measurements into dynamical network models.'),
(84613, 2010, 'plos', 'Spontaneous quaternary and tertiary T-R transitions of human hemoglobin in molecular dynamics simulation', 'Hub, Jochen S|Kubitzki, Marcus B|de Groot, Bert L', 'Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.|Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.|Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.', 'Sweden|Sweden|Sweden', 36, 'Crystallography, X-Ray|Hemoglobins|Histidine|Humans|Molecular Dynamics Simulation|Principal Component Analysis|Protein Conformation|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000774', '20463873', 'We present molecular dynamics simulations of unliganded human hemoglobin (Hb) A under physiological conditions, starting from the R, R2, and T state. The simulations were carried out with protonated and deprotonated HC3 histidines His(beta)146, and they sum up to a total length of 5.6 micros. We observe spontaneous and reproducible T-->R quaternary transitions of the Hb tetramer and tertiary transitions of the alpha and beta subunits, as detected from principal component projections, from an RMSD measure, and from rigid body rotation analysis. The simulations reveal a marked asymmetry between the alpha and beta subunits. Using the mutual information as correlation measure, we find that the beta subunits are substantially more strongly linked to the quaternary transition than the alpha subunits. In addition, the tertiary populations of the alpha and beta subunits differ substantially, with the beta subunits showing a tendency towards R, and the alpha subunits showing a tendency towards T. Based on the simulation results, we present a transition pathway for coupled quaternary and tertiary transitions between the R and T conformations of Hb.'),
(84614, 2010, 'plos', 'On the zwitterionic nature of gas-phase peptides and protein ions', 'Marchese, Roberto|Grandori, Rita|Carloni, Paolo|Raugei, Simone', 'Statistical and Biological Physics Sector, International School for Advanced Studies (SISSA-ISAS) and DEMOCRITOS, Trieste, Italy.|Statistical and Biological Physics Sector, International School for Advanced Studies (SISSA-ISAS) and DEMOCRITOS, Trieste, Italy.|Statistical and Biological Physics Sector, International School for Advanced Studies (SISSA-ISAS) and DEMOCRITOS, Trieste, Italy.|Statistical and Biological Physics Sector, International School for Advanced Studies (SISSA-ISAS) and DEMOCRITOS, Trieste, Italy.', 'Italy|Italy|Italy|Italy', 41, 'Angiotensin II|Bradykinin|Computational Biology|Gases|Mass Spectrometry|Molecular Dynamics Simulation|Peptides|Protein Conformation|Proteins|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000775', '20463874', 'Determining the total number of charged residues corresponding to a given value of net charge for peptides and proteins in gas phase is crucial for the interpretation of mass-spectrometry data, yet it is far from being understood. Here we show that a novel computational protocol based on force field and massive density functional calculations is able to reproduce the experimental facets of well investigated systems, such as angiotensin II, bradykinin, and tryptophan-cage. The protocol takes into account all of the possible protomers compatible with a given charge state. Our calculations predict that the low charge states are zwitterions, because the stabilization due to intramolecular hydrogen bonding and salt-bridges can compensate for the thermodynamic penalty deriving from deprotonation of acid residues. In contrast, high charge states may or may not be zwitterions because internal solvation might not compensate for the energy cost of charge separation.'),
(84615, 2010, 'plos', 'Assimilating seizure dynamics', 'Ullah, Ghanim|Schiff, Steven J', 'Center for Neural Engineering, Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, Pennsylvania, USA. ghanim@psu.edu|Center for Neural Engineering, Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, Pennsylvania, USA. ghanim@psu.edu', 'United States|United States', 0, 'Animals|CA1 Region, Hippocampal|Intracellular Membranes|Membrane Potentials|Models, Neurological|Neural Networks (Computer)|Patch-Clamp Techniques|Potassium|Rats|Reproducibility of Results|Seizures|Sodium', 'Journal Article', '10.1371/journal.pcbi.1000776', '20463875', 'Observability of a dynamical system requires an understanding of its state-the collective values of its variables. However, existing techniques are too limited to measure all but a small fraction of the physical variables and parameters of neuronal networks. We constructed models of the biophysical properties of neuronal membrane, synaptic, and microenvironment dynamics, and incorporated them into a model-based predictor-controller framework from modern control theory. We demonstrate that it is now possible to meaningfully estimate the dynamics of small neuronal networks using as few as a single measured variable. Specifically, we assimilate noisy membrane potential measurements from individual hippocampal neurons to reconstruct the dynamics of networks of these cells, their extracellular microenvironment, and the activities of different neuronal types during seizures. We use reconstruction to account for unmeasured parts of the neuronal system, relating micro-domain metabolic processes to cellular excitability, and validate the reconstruction of cellular dynamical interactions against actual measurements. Data assimilation, the fusing of measurement with computational models, has significant potential to improve the way we observe and understand brain dynamics.'),
(84616, 2010, 'plos', 'A differentiation-based phylogeny of cancer subtypes', 'Riester, Markus|Stephan-Otto Attolini, Camille|Downey, Robert J|Singer, Samuel|Michor, Franziska', 'Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.|Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.|Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.|Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.|Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.', 'United States|United States|United States|United States|United States', 29, 'Adipogenesis|Algorithms|Analysis of Variance|Cell Differentiation|Cluster Analysis|Computational Biology|Gene Expression Profiling|Gene Expression Regulation, Neoplastic|Humans|Neoplasms|Phylogeny', 'Journal Article', '10.1371/journal.pcbi.1000777', '20463876', 'Histopathological classification of human tumors relies in part on the degree of differentiation of the tumor sample. To date, there is no objective systematic method to categorize tumor subtypes by maturation. In this paper, we introduce a novel computational algorithm to rank tumor subtypes according to the dissimilarity of their gene expression from that of stem cells and fully differentiated tissue, and thereby construct a phylogenetic tree of cancer. We validate our methodology with expression data of leukemia, breast cancer and liposarcoma subtypes and then apply it to a broader group of sarcomas. This ranking of tumor subtypes resulting from the application of our methodology allows the identification of genes correlated with differentiation and may help to identify novel therapeutic targets. Our algorithm represents the first phylogeny-based tool to analyze the differentiation status of human tumors.'),
(84617, 2010, 'plos', 'Identification of key processes that control tumor necrosis factor availability in a tuberculosis granuloma', 'Fallahi-Sichani, Mohammad|Schaller, Matthew A|Kirschner, Denise E|Kunkel, Steven L|Linderman, Jennifer J', 'Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.|Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.|Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.|Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.|Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.', 'United States|United States|United States|United States|United States', 40, 'Algorithms|Animals|Apoptosis|Computer Simulation|Dendritic Cells|Granuloma|Lymphocytes|Macrophages|Mice|Mice, Inbred CBA|Models, Biological|Mycobacterium tuberculosis|Protein Binding|Receptors, Tumor Necrosis Factor|Tuberculin|Tuberculosis|Tumor Necrosis Factor-alpha', 'Journal Article', '10.1371/journal.pcbi.1000778', '20463877', 'Tuberculosis (TB) granulomas are organized collections of immune cells comprised of macrophages, lymphocytes and other cells that form in the lung as a result of immune response to Mycobacterium tuberculosis (Mtb) infection. Formation and maintenance of granulomas are essential for control of Mtb infection and are regulated in part by a pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF). To characterize mechanisms that control TNF availability within a TB granuloma, we developed a multi-scale two compartment partial differential equation model that describes a granuloma as a collection of immune cells forming concentric layers and includes TNF/TNF receptor binding and trafficking processes. We used the results of sensitivity analysis as a tool to identify experiments to measure critical model parameters in an artificial experimental model of a TB granuloma induced in the lungs of mice following injection of mycobacterial antigen-coated beads. Using our model, we then demonstrated that the organization of immune cells within a TB granuloma as well as TNF/TNF receptor binding and intracellular trafficking are two important factors that control TNF availability and may spatially coordinate TNF-induced immunological functions within a granuloma. Further, we showed that the neutralization power of TNF-neutralizing drugs depends on their TNF binding characteristics, including TNF binding kinetics, ability to bind to membrane-bound TNF and TNF binding stoichiometry. To further elucidate the role of TNF in the process of granuloma development, our modeling and experimental findings on TNF-associated molecular scale aspects of the granuloma can be incorporated into larger scale models describing the immune response to TB infection. Ultimately, these modeling and experimental results can help identify new strategies for TB disease control/therapy.'),
(84618, 2010, 'plos', 'Impact of dendritic size and dendritic topology on burst firing in pyramidal cells', 'van Elburg, Ronald A J|van Ooyen, Arjen', 'Department of Artificial Intelligence, Faculty of Mathematics and Natural Sciences, University of Groningen, Groningen, The Netherlands.|Department of Artificial Intelligence, Faculty of Mathematics and Natural Sciences, University of Groningen, Groningen, The Netherlands.', 'Netherlands|Netherlands', 75, 'Action Potentials|Animals|Cats|Computer Simulation|Dendrites|Electric Stimulation|Models, Neurological|Pyramidal Cells|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1000781', '20485556', 'Neurons display a wide range of intrinsic firing patterns. A particularly relevant pattern for neuronal signaling and synaptic plasticity is burst firing, the generation of clusters of action potentials with short interspike intervals. Besides ion-channel composition, dendritic morphology appears to be an important factor modulating firing pattern. However, the underlying mechanisms are poorly understood, and the impact of morphology on burst firing remains insufficiently known. Dendritic morphology is not fixed but can undergo significant changes in many pathological conditions. Using computational models of neocortical pyramidal cells, we here show that not only the total length of the apical dendrite but also the topological structure of its branching pattern markedly influences inter- and intraburst spike intervals and even determines whether or not a cell exhibits burst firing. We found that there is only a range of dendritic sizes that supports burst firing, and that this range is modulated by dendritic topology. Either reducing or enlarging the dendritic tree, or merely modifying its topological structure without changing total dendritic length, can transform a cells firing pattern from bursting to tonic firing. Interestingly, the results are largely independent of whether the cells are stimulated by current injection at the soma or by synapses distributed over the dendritic tree. By means of a novel measure called mean electrotonic path length, we show that the influence of dendritic morphology on burst firing is attributable to the effect both dendritic size and dendritic topology have, not on somatic input conductance, but on the average spatial extent of the dendritic tree and the spatiotemporal dynamics of the dendritic membrane potential. Our results suggest that alterations in size or topology of pyramidal cell morphology, such as observed in Alzheimers disease, mental retardation, epilepsy, and chronic stress, could change neuronal burst firing and thus ultimately affect information processing and cognition.'),
(84619, 2010, 'plos', 'Inductive game theory and the dynamics of animal conflict', 'DeDeo, Simon|Krakauer, David C|Flack, Jessica C', 'Santa Fe Institute, Santa Fe, New Mexico, United States of America.|Santa Fe Institute, Santa Fe, New Mexico, United States of America.|Santa Fe Institute, Santa Fe, New Mexico, United States of America.', 'Mexico|Mexico|Mexico', 29, 'Aggression|Animals|Behavior, Animal|Computer Simulation|Conflict (Psychology)|Female|Game Theory|Macaca nemestrina|Male|Monte Carlo Method|Statistics, Nonparametric', 'Journal Article', '10.1371/journal.pcbi.1000782', '20485557', 'Conflict destabilizes social interactions and impedes cooperation at multiple scales of biological organization. Of fundamental interest are the causes of turbulent periods of conflict. We analyze conflict dynamics in an monkey society model system. We develop a technique, Inductive Game Theory, to extract directly from time-series data the decision-making strategies used by individuals and groups. This technique uses Monte Carlo simulation to test alternative causal models of conflict dynamics. We find individuals base their decision to fight on memory of social factors, not on short timescale ecological resource competition. Furthermore, the social assessments on which these decisions are based are triadic (self in relation to another pair of individuals), not pairwise. We show that this triadic decision making causes long conflict cascades and that there is a high population cost of the large fights associated with these cascades. These results suggest that individual agency has been over-emphasized in the social evolution of complex aggregates, and that pair-wise formalisms are inadequate. An appreciation of the empirical foundations of the collective dynamics of conflict is a crucial step towards its effective management.'),
(84620, 2010, 'plos', 'Mathematical modelling of DNA replication reveals a trade-off between coherence of origin activation and robustness against rereplication', 'Brümmer, Anneke|Salazar, Carlos|Zinzalla, Vittoria|Alberghina, Lilia|Höfer, Thomas', 'Research Group Modelling of Biological Systems (B086), German Cancer Research Center, Heidelberg, Germany.|Research Group Modelling of Biological Systems (B086), German Cancer Research Center, Heidelberg, Germany.|Research Group Modelling of Biological Systems (B086), German Cancer Research Center, Heidelberg, Germany.|Research Group Modelling of Biological Systems (B086), German Cancer Research Center, Heidelberg, Germany.|Research Group Modelling of Biological Systems (B086), German Cancer Research Center, Heidelberg, Germany.', 'Germany|Germany|Germany|Germany|Germany', 30, 'Cyclin-Dependent Kinases|DNA Replication|DNA, Fungal|DNA-Binding Proteins|Models, Genetic|Phosphorylation|Replication Origin|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1000783', '20485558', 'Eukaryotic genomes are duplicated from multiple replication origins exactly once per cell cycle. In Saccharomyces cerevisiae, a complex molecular network has been identified that governs the assembly of the replication machinery. Here we develop a mathematical model that links the dynamics of this network to its performance in terms of rate and coherence of origin activation events, number of activated origins, the resulting distribution of replicon sizes and robustness against DNA rereplication. To parameterize the model, we use measured protein expression data and systematically generate kinetic parameter sets by optimizing the coherence of origin firing. While randomly parameterized networks yield unrealistically slow kinetics of replication initiation, networks with optimized parameters account for the experimentally observed distribution of origin firing times. Efficient inhibition of DNA rereplication emerges as a constraint that limits the rate at which replication can be initiated. In addition to the separation between origin licensing and firing, a time delay between the activation of S phase cyclin-dependent kinase (S-Cdk) and the initiation of DNA replication is required for preventing rereplication. Our analysis suggests that distributive multisite phosphorylation of the S-Cdk targets Sld2 and Sld3 can generate both a robust time delay and contribute to switch-like, coherent activation of replication origins. The proposed catalytic function of the complex formed by Dpb11, Sld3 and Sld2 strongly enhances coherence and robustness of origin firing. The model rationalizes how experimentally observed inefficient replication from fewer origins is caused by premature activation of S-Cdk, while premature activity of the S-Cdk targets Sld2 and Sld3 results in DNA rereplication. Thus the model demonstrates how kinetic deregulation of the molecular network governing DNA replication may result in genomic instability.'),
(84621, 2010, 'plos', 'A model for genetic and epigenetic regulatory networks identifies rare pathways for transcription factor induced pluripotency', 'Artyomov, Maxim N|Meissner, Alexander|Chakraborty, Arup K', 'Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States', 32, 'Animals|Cell Dedifferentiation|Cell Differentiation|Computer Simulation|Embryonic Stem Cells|Epigenesis, Genetic|Gene Regulatory Networks|Mice|Models, Genetic|Pluripotent Stem Cells|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000785', '20485562', 'With relatively low efficiency, differentiated cells can be reprogrammed to a pluripotent state by ectopic expression of a few transcription factors. An understanding of the mechanisms that underlie data emerging from such experiments can help design optimal strategies for creating pluripotent cells for patient-specific regenerative medicine. We have developed a computational model for the architecture of the epigenetic and genetic regulatory networks which describes transformations resulting from expression of reprogramming factors. Importantly, our studies identify the rare temporal pathways that result in induced pluripotent cells. Further experimental tests of predictions emerging from our model should lead to fundamental advances in our understanding of how cellular identity is maintained and transformed.'),
(84622, 2010, 'plos', 'Quantifying the effects of elastic collisions and non-covalent binding on glutamate receptor trafficking in the post-synaptic density', 'Santamaria, Fidel|Gonzalez, Jossina|Augustine, George J|Raghavachari, Sridhar', 'Biology Department, The University of Texas at San Antonio, San Antonio, Texas, United States of America. fidel.santamaria@utsa.edu|Biology Department, The University of Texas at San Antonio, San Antonio, Texas, United States of America. fidel.santamaria@utsa.edu|Biology Department, The University of Texas at San Antonio, San Antonio, Texas, United States of America. fidel.santamaria@utsa.edu|Biology Department, The University of Texas at San Antonio, San Antonio, Texas, United States of America. fidel.santamaria@utsa.edu', 'United States|United States|United States|United States', 32, 'Computer Simulation|Models, Neurological|Monte Carlo Method|Protein Binding|Protein Transport|Receptors, Glutamate|Synaptic Membranes', 'Journal Article', '10.1371/journal.pcbi.1000780', '20485563', 'One mechanism of information storage in neurons is believed to be determined by the strength of synaptic contacts. The strength of an excitatory synapse is partially due to the concentration of a particular type of ionotropic glutamate receptor (AMPAR) in the post-synaptic density (PSD). AMPAR concentration in the PSD has to be plastic, to allow the storage of new memories, but it also has to be stable to preserve important information. Although much is known about the molecular identity of synapses, the biophysical mechanisms by which AMPAR can enter, leave and remain in the synapse are unclear. We used Monte Carlo simulations to determine the influence of PSD structure and activity in maintaining homeostatic concentrations of AMPARs in the synapse. We found that, the high concentration and excluded volume caused by PSD molecules result in molecular crowding. Diffusion of AMPAR in the PSD under such conditions is anomalous. Anomalous diffusion of AMPAR results in retention of these receptors inside the PSD for periods ranging from minutes to several hours in the absence of strong binding of receptors to PSD molecules. Trapping of receptors in the PSD by crowding effects was very sensitive to the concentration of PSD molecules, showing a switch-like behavior for retention of receptors. Non-covalent binding of AMPAR to anchored PSD molecules allowed the synapse to become well-mixed, resulting in normal diffusion of AMPAR. Binding also allowed the exchange of receptors in and out of the PSD. We propose that molecular crowding is an important biophysical mechanism to maintain homeostatic synaptic concentrations of AMPARs in the PSD without the need of energetically expensive biochemical reactions. In this context, binding of AMPAR with PSD molecules could collaborate with crowding to maintain synaptic homeostasis but could also allow synaptic plasticity by increasing the exchange of these receptors with the surrounding extra-synaptic membrane.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84623, 2010, 'plos', 'Analysis and computational dissection of molecular signature multiplicity', 'Statnikov, Alexander|Aliferis, Constantin F', 'Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York, United States of America. Alexander.Statnikov@med.nyu.edu|Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York, United States of America. Alexander.Statnikov@med.nyu.edu', 'United States|United States', 34, 'Algorithms|Area Under Curve|Computational Biology|Computer Simulation|Databases, Genetic|Gene Expression Profiling|Humans|Markov Chains|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1000790', '20502670', 'Molecular signatures are computational or mathematical models created to diagnose disease and other phenotypes and to predict clinical outcomes and response to treatment. It is widely recognized that molecular signatures constitute one of the most important translational and basic science developments enabled by recent high-throughput molecular assays. A perplexing phenomenon that characterizes high-throughput data analysis is the ubiquitous multiplicity of molecular signatures. Multiplicity is a special form of data analysis instability in which different analysis methods used on the same data, or different samples from the same population lead to different but apparently maximally predictive signatures. This phenomenon has far-reaching implications for biological discovery and development of next generation patient diagnostics and personalized treatments. Currently the causes and interpretation of signature multiplicity are unknown, and several, often contradictory, conjectures have been made to explain it. We present a formal characterization of signature multiplicity and a new efficient algorithm that offers theoretical guarantees for extracting the set of maximally predictive and non-redundant signatures independent of distribution. The new algorithm identifies exactly the set of optimal signatures in controlled experiments and yields signatures with significantly better predictivity and reproducibility than previous algorithms in human microarray gene expression datasets. Our results shed light on the causes of signature multiplicity, provide computational tools for studying it empirically and introduce a framework for in silico bioequivalence of this important new class of diagnostic and personalized medicine modalities.'),
(84624, 2010, 'plos', 'Deciphering diseases and biological targets for environmental chemicals using toxicogenomics networks', 'Audouze, Karine|Juncker, Agnieszka Sierakowska|Roque, Francisco J S S A|Krysiak-Baltyn, Konrad|Weinhold, Nils|Taboureau, Olivier|Jensen, Thomas Skøt|Brunak, Søren', 'Department of Systems Biology, Technical University of Denmark, Center for Biological Sequence Analysis, Lyngby, Denmark.|Department of Systems Biology, Technical University of Denmark, Center for Biological Sequence Analysis, Lyngby, Denmark.|Department of Systems Biology, Technical University of Denmark, Center for Biological Sequence Analysis, Lyngby, Denmark.|Department of Systems Biology, Technical University of Denmark, Center for Biological Sequence Analysis, Lyngby, Denmark.|Department of Systems Biology, Technical University of Denmark, Center for Biological Sequence Analysis, Lyngby, Denmark.|Department of Systems Biology, Technical University of Denmark, Center for Biological Sequence Analysis, Lyngby, Denmark.|Department of Systems Biology, Technical University of Denmark, Center for Biological Sequence Analysis, Lyngby, Denmark.|Department of Systems Biology, Technical University of Denmark, Center for Biological Sequence Analysis, Lyngby, Denmark.', 'Denmark|Denmark|Denmark|Denmark|Denmark|Denmark|Denmark|Denmark', 35, 'Cluster Analysis|Databases, Protein|Environmental Pollutants|Gene Expression Regulation|Hazardous Substances|Humans|Neoplasms|Principal Component Analysis|Protein Interaction Domains and Motifs|Protein Interaction Mapping|Reproducibility of Results|Systems Biology|Toxicogenetics', 'Journal Article', '10.1371/journal.pcbi.1000788', '20502671', 'Exposure to environmental chemicals and drugs may have a negative effect on human health. A better understanding of the molecular mechanism of such compounds is needed to determine the risk. We present a high confidence human protein-protein association network built upon the integration of chemical toxicology and systems biology. This computational systems chemical biology model reveals uncharacterized connections between compounds and diseases, thus predicting which compounds may be risk factors for human health. Additionally, the network can be used to identify unexpected potential associations between chemicals and proteins. Examples are shown for chemicals associated with breast cancer, lung cancer and necrosis, and potential protein targets for di-ethylhexyl-phthalate, 2,3,7,8-tetrachlorodibenzo-p-dioxin, pirinixic acid and permethrine. The chemical-protein associations are supported through recent published studies, which illustrate the power of our approach that integrates toxicogenomics data with other data types.'),
(84625, 2010, 'plos', 'Influence of low-level stimulus features, task dependent factors, and spatial biases on overt visual attention', 'Kollmorgen, Sepp|Nortmann, Nora|Schröder, Sylvia|König, Peter', 'Institute of Neurobiopsychology, University of Osnabrück, Osnabrück, Germany.|Institute of Neurobiopsychology, University of Osnabrück, Osnabrück, Germany.|Institute of Neurobiopsychology, University of Osnabrück, Osnabrück, Germany.|Institute of Neurobiopsychology, University of Osnabrück, Osnabrück, Germany.', 'Germany|Germany|Germany|Germany', 37, 'Adolescent|Adult|Algorithms|Attention|Eye Movements|Face|Female|Humans|Linear Models|Male|Models, Biological|Multivariate Analysis|Photic Stimulation|Vision, Ocular', 'Journal Article', '10.1371/journal.pcbi.1000791', '20502672', 'Visual attention is thought to be driven by the interplay between low-level visual features and task dependent information content of local image regions, as well as by spatial viewing biases. Though dependent on experimental paradigms and model assumptions, this idea has given rise to varying claims that either bottom-up or top-down mechanisms dominate visual attention. To contribute toward a resolution of this discussion, here we quantify the influence of these factors and their relative importance in a set of classification tasks. Our stimuli consist of individual image patches (bubbles). For each bubble we derive three measures: a measure of salience based on low-level stimulus features, a measure of salience based on the task dependent information content derived from our subjects classification responses and a measure of salience based on spatial viewing biases. Furthermore, we measure the empirical salience of each bubble based on our subjects measured eye gazes thus characterizing the overt visual attention each bubble receives. A multivariate linear model relates the three salience measures to overt visual attention. It reveals that all three salience measures contribute significantly. The effect of spatial viewing biases is highest and rather constant in different tasks. The contribution of task dependent information is a close runner-up. Specifically, in a standardized task of judging facial expressions it scores highly. The contribution of low-level features is, on average, somewhat lower. However, in a prototypical search task, without an available template, it makes a strong contribution on par with the two other measures. Finally, the contributions of the three factors are only slightly redundant, and the semi-partial correlation coefficients are only slightly lower than the coefficients for full correlations. These data provide evidence that all three measures make significant and independent contributions and that none can be neglected in a model of human overt visual attention.'),
(84626, 2010, 'plos', 'Novel peptide-mediated interactions derived from high-resolution 3-dimensional structures', 'Stein, Amelie|Aloy, Patrick', 'Institute for Research in Biomedicine, Joint IRB-BSC Program in Computational Biology, Barcelona, Spain.|Institute for Research in Biomedicine, Joint IRB-BSC Program in Computational Biology, Barcelona, Spain.', 'Spain|Spain', 48, 'Amino Acid Sequence|Animals|Artificial Intelligence|Computational Biology|Humans|Models, Molecular|Molecular Sequence Data|Peptides|Protein Binding|Protein Conformation|Protein Interaction Domains and Motifs|Protein Interaction Mapping|Proteins|Reproducibility of Results|Sequence Alignment', 'Journal Article', '10.1371/journal.pcbi.1000789', '20502673', 'Many biological responses to intra- and extracellular stimuli are regulated through complex networks of transient protein interactions where a globular domain in one protein recognizes a linear peptide from another, creating a relatively small contact interface. These peptide stretches are often found in unstructured regions of proteins, and contain a consensus motif complementary to the interaction surface displayed by their binding partners. While most current methods for the de novo discovery of such motifs exploit their tendency to occur in disordered regions, our work here focuses on another observation: upon binding to their partner domain, motifs adopt a well-defined structure. Indeed, through the analysis of all peptide-mediated interactions of known high-resolution three-dimensional (3D) structure, we found that the structure of the peptide may be as characteristic as the consensus motif, and help identify target peptides even though they do not match the established patterns. Our analyses of the structural features of known motifs reveal that they tend to have a particular stretched and elongated structure, unlike most other peptides of the same length. Accordingly, we have implemented a strategy based on a Support Vector Machine that uses this features, along with other structure-encoded information about binding interfaces, to search the set of protein interactions of known 3D structure and to identify unnoticed peptide-mediated interactions among them. We have also derived consensus patterns for these interactions, whenever enough information was available, and compared our results with established linear motif patterns and their binding domains. Finally, to cross-validate our identification strategy, we scanned interactome networks from four model organisms with our newly derived patterns to see if any of them occurred more often than expected. Indeed, we found significant over-representations for 64 domain-motif interactions, 46 of which had not been described before, involving over 6,000 interactions in total for which we could suggest the molecular details determining the binding.'),
(84627, 2010, 'plos', 'Chemotactic response and adaptation dynamics in Escherichia coli', 'Clausznitzer, Diana|Oleksiuk, Olga|Løvdok, Linda|Sourjik, Victor|Endres, Robert G', 'Division of Molecular Biosciences, Imperial College London, London, United Kingdom.|Division of Molecular Biosciences, Imperial College London, London, United Kingdom.|Division of Molecular Biosciences, Imperial College London, London, United Kingdom.|Division of Molecular Biosciences, Imperial College London, London, United Kingdom.|Division of Molecular Biosciences, Imperial College London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 38, 'Adaptation, Physiological|Chemotaxis|Chi-Square Distribution|DNA Methylation|Dose-Response Relationship, Drug|Escherichia coli|Models, Biological|Phosphorylation|Signal Transduction|Systems Biology|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000784', '20502674', 'Adaptation of the chemotaxis sensory pathway of the bacterium Escherichia coli is integral for detecting chemicals over a wide range of background concentrations, ultimately allowing cells to swim towards sources of attractant and away from repellents. Its biochemical mechanism based on methylation and demethylation of chemoreceptors has long been known. Despite the importance of adaptation for cell memory and behavior, the dynamics of adaptation are difficult to reconcile with current models of precise adaptation. Here, we follow time courses of signaling in response to concentration step changes of attractant using in vivo fluorescence resonance energy transfer measurements. Specifically, we use a condensed representation of adaptation time courses for efficient evaluation of different adaptation models. To quantitatively explain the data, we finally develop a dynamic model for signaling and adaptation based on the attractant flow in the experiment, signaling by cooperative receptor complexes, and multiple layers of feedback regulation for adaptation. We experimentally confirm the predicted effects of changing the enzyme-expression level and bypassing the negative feedback for demethylation. Our data analysis suggests significant imprecision in adaptation for large additions. Furthermore, our model predicts highly regulated, ultrafast adaptation in response to removal of attractant, which may be useful for fast reorientation of the cell and noise reduction in adaptation.'),
(84628, 2010, 'plos', 'Identifying tightly regulated and variably expressed networks by Differential Rank Conservation (DIRAC)', 'Eddy, James A|Hood, Leroy|Price, Nathan D|Geman, Donald', '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.|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|United States|United States', 57, 'Cluster Analysis|Computational Biology|Databases, Factual|Gene Expression Profiling|Gene Regulatory Networks|Humans|Neoplasms|Phenotype|Reproducibility of Results|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000792', '20523739', 'A powerful way to separate signal from noise in biology is to convert the molecular data from individual genes or proteins into an analysis of comparative biological network behaviors. One of the limitations of previous network analyses is that they do not take into account the combinatorial nature of gene interactions within the network. We report here a new technique, Differential Rank Conservation (DIRAC), which permits one to assess these combinatorial interactions to quantify various biological pathways or networks in a comparative sense, and to determine how they change in different individuals experiencing the same disease process. This approach is based on the relative expression values of participating genes-i.e., the ordering of expression within network profiles. DIRAC provides quantitative measures of how network rankings differ either among networks for a selected phenotype or among phenotypes for a selected network. We examined disease phenotypes including cancer subtypes and neurological disorders and identified networks that are tightly regulated, as defined by high conservation of transcript ordering. Interestingly, we observed a strong trend to looser network regulation in more malignant phenotypes and later stages of disease. At a sample level, DIRAC can detect a change in ranking between phenotypes for any selected network. Variably expressed networks represent statistically robust differences between disease states and serve as signatures for accurate molecular classification, validating the information about expression patterns captured by DIRAC. Importantly, DIRAC can be applied not only to transcriptomic data, but to any ordinal data type.'),
(84629, 2010, 'plos', 'Game theory of social distancing in response to an epidemic', 'Reluga, Timothy C', 'Department of Mathematics, Pennsylvania State University, State College, Pennsylvania, United States of America. timothy@reluga.org', 'United States', 108, 'Algorithms|Computer Simulation|Disease Outbreaks|Game Theory|Humans|Markov Chains|Models, Theoretical|Social Distance|Vaccination', 'Journal Article', '10.1371/journal.pcbi.1000793', '20523740', 'Social distancing practices are changes in behavior that prevent disease transmission by reducing contact rates between susceptible individuals and infected individuals who may transmit the disease. Social distancing practices can reduce the severity of an epidemic, but the benefits of social distancing depend on the extent to which it is used by individuals. Individuals are sometimes reluctant to pay the costs inherent in social distancing, and this can limit its effectiveness as a control measure. This paper formulates a differential-game to identify how individuals would best use social distancing and related self-protective behaviors during an epidemic. The epidemic is described by a simple, well-mixed ordinary differential equation model. We use the differential game to study potential value of social distancing as a mitigation measure by calculating the equilibrium behaviors under a variety of cost-functions. Numerical methods are used to calculate the total costs of an epidemic under equilibrium behaviors as a function of the time to mass vaccination, following epidemic identification. The key parameters in the analysis are the basic reproduction number and the baseline efficiency of social distancing. The results show that social distancing is most beneficial to individuals for basic reproduction numbers around 2. In the absence of vaccination or other intervention measures, optimal social distancing never recovers more than 30% of the cost of infection. We also show how the window of opportunity for vaccine development lengthens as the efficiency of social distancing and detection improve.'),
(84630, 2010, 'plos', 'Weak noise in neurons may powerfully inhibit the generation of repetitive spiking but not its propagation', 'Tuckwell, Henry C|Jost, Jürgen', 'Max Planck Institute for Mathematics in the Sciences, Leipzig, Germany. tuckwell@mis.mpg.de|Max Planck Institute for Mathematics in the Sciences, Leipzig, Germany. tuckwell@mis.mpg.de', 'Germany|Germany', 24, 'Action Potentials|Algorithms|Computer Simulation|Models, Neurological|Neurons', 'Journal Article', '10.1371/journal.pcbi.1000794', '20523741', 'Many neurons have epochs in which they fire action potentials in an approximately periodic fashion. To see what effects noise of relatively small amplitude has on such repetitive activity we recently examined the response of the Hodgkin-Huxley (HH) space-clamped system to such noise as the mean and variance of the applied current vary, near the bifurcation to periodic firing. This article is concerned with a more realistic neuron model which includes spatial extent. Employing the Hodgkin-Huxley partial differential equation system, the deterministic component of the input current is restricted to a small segment whereas the stochastic component extends over a region which may or may not overlap the deterministic component. For mean values below, near and above the critical values for repetitive spiking, the effects of weak noise of increasing strength is ascertained by simulation. As in the point model, small amplitude noise near the critical value dampens the spiking activity and leads to a minimum as noise level increases. This was the case for both additive noise and conductance-based noise. Uniform noise along the whole neuron is only marginally more effective in silencing the cell than noise which occurs near the region of excitation. In fact it is found that if signal and noise overlap in spatial extent, then weak noise may inhibit spiking. If, however, signal and noise are applied on disjoint intervals, then the noise has no effect on the spiking activity, no matter how large its region of application, though the trajectories are naturally altered slightly by noise. Such effects could not be discerned in a point model and are important for real neuron behavior. Interference with the spike train does nevertheless occur when the noise amplitude is larger, even when noise and signal do not overlap, being due to the instigation of secondary noise-induced wave phenomena rather than switching the system from one attractor (firing regularly) to another (a stable point).'),
(84631, 2010, 'plos', 'Analysis of combinatorial regulation: scaling of partnerships between regulators with the number of governed targets', 'Bhardwaj, Nitin|Carson, Matthew B|Abyzov, Alexej|Yan, Koon-Kiu|Lu, Hui|Gerstein, Mark B', 'Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.', 'United States|United States|United States|United States|United States|United States', 20, 'Animals|Computational Biology|Computer Simulation|Escherichia coli|Gene Expression Regulation|Gene Regulatory Networks|Humans|Mice|Models, Genetic|Models, Statistical|Operon|Phosphorylation|Rats|Transcription, Genetic|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1000755', '20523742', 'Through combinatorial regulation, regulators partner with each other to control common targets and this allows a small number of regulators to govern many targets. One interesting question is that given this combinatorial regulation, how does the number of regulators scale with the number of targets? Here, we address this question by building and analyzing co-regulation (co-transcription and co-phosphorylation) networks that describe partnerships between regulators controlling common genes. We carry out analyses across five diverse species: Escherichia coli to human. These reveal many properties of partnership networks, such as the absence of a classical power-law degree distribution despite the existence of nodes with many partners. We also find that the number of co-regulatory partnerships follows an exponential saturation curve in relation to the number of targets. (For E. coli and Bacillus subtilis, only the beginning linear part of this curve is evident due to arrangement of genes into operons.) To gain intuition into the saturation process, we relate the biological regulation to more commonplace social contexts where a small number of individuals can form an intricate web of connections on the internet. Indeed, we find that the size of partnership networks saturates even as the complexity of their output increases. We also present a variety of models to account for the saturation phenomenon. In particular, we develop a simple analytical model to show how new partnerships are acquired with an increasing number of target genes, with certain assumptions, it reproduces the observed saturation. Then, we build a more general simulation of network growth and find agreement with a wide range of real networks. Finally, we perform various down-sampling calculations on the observed data to illustrate the robustness of our conclusions.'),
(84632, 2010, 'plos', 'Making informed choices about microarray data analysis', 'Reimers, Mark', 'Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, United States of America. mreimers@vcu.edu', 'United States', 42, 'Genomics|High-Throughput Screening Assays|Humans|Microarray Analysis|Research Design|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000786', '20523743', '-'),
(84633, 2010, 'plos', 'What do I want from the publisher of the future?', 'Bourne, Philip E', 'Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America. pbourne@ucsd.edu', 'United States', 21, 'Database Management Systems|Humans|Periodicals as Topic|Publishing|Records', 'Journal Article', '10.1371/journal.pcbi.1000787', '20523744', '-'),
(84634, 2010, 'plos', 'A quick guide to large-scale genomic data mining', 'Huttenhower, Curtis|Hofmann, Oliver', 'Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America. chuttenh@hsph.harvard.edu|Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America. chuttenh@hsph.harvard.edu', 'United States|United States', 26, 'Algorithms|Data Mining|Databases, Genetic|Genomics|Humans|Models, Genetic|Oligonucleotide Array Sequence Analysis|Sequence Analysis, DNA|Software', 'Journal Article', '10.1371/journal.pcbi.1000779', '20523745', '-'),
(84635, 2010, 'plos', 'Optimality of mutation and selection in germinal centers', 'Zhang, Jingshan|Shakhnovich, Eugene I', 'Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.', 'United States|United States', 29, 'Algorithms|Animals|Antibody Affinity|B-Lymphocytes|Cell Movement|Databases, Protein|Germinal Center|Humans|Models, Immunological|Models, Statistical|Mutation|Protein Interaction Domains and Motifs|Selection, Genetic|Spleen', 'Journal Article', '10.1371/journal.pcbi.1000800', '20532164', 'The population dynamics theory of B cells in a typical germinal center could play an important role in revealing how affinity maturation is achieved. However, the existing models encountered some conflicts with experiments. To resolve these conflicts, we present a coarse-grained model to calculate the B cell population development in affinity maturation, which allows a comprehensive analysis of its parameter space to look for optimal values of mutation rate, selection strength, and initial antibody-antigen binding level that maximize the affinity improvement. With these optimized parameters, the model is compatible with the experimental observations such as the approximately 100-fold affinity improvements, the number of mutations, the hypermutation rate, and the all or none phenomenon. Moreover, we study the reasons behind the optimal parameters. The optimal mutation rate, in agreement with the hypermutation rate in vivo, results from a tradeoff between accumulating enough beneficial mutations and avoiding too many deleterious or lethal mutations. The optimal selection strength evolves as a balance between the need for affinity improvement and the requirement to pass the population bottleneck. These findings point to the conclusion that germinal centers have been optimized by evolution to generate strong affinity antibodies effectively and rapidly. In addition, we study the enhancement of affinity improvement due to B cell migration between germinal centers. These results could enhance our understanding of the functions of germinal centers.'),
(84636, 2010, 'plos', 'Bistable, irregular firing and population oscillations in a modular attractor memory network', 'Lundqvist, Mikael|Compte, Albert|Lansner, Anders', 'School of Computer Science and Communication, Department of Computational Biology, Royal Institute of Technology (KTH), Stockholm, Sweden.|School of Computer Science and Communication, Department of Computational Biology, Royal Institute of Technology (KTH), Stockholm, Sweden.|School of Computer Science and Communication, Department of Computational Biology, Royal Institute of Technology (KTH), Stockholm, Sweden.', 'Sweden|Sweden|Sweden', 72, 'Animals|Haplorhini|Memory|Models, Neurological|Nerve Net|Poisson Distribution|Pyramidal Cells|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1000803', '20532199', 'Attractor neural networks are thought to underlie working memory functions in the cerebral cortex. Several such models have been proposed that successfully reproduce firing properties of neurons recorded from monkeys performing working memory tasks. However, the regular temporal structure of spike trains in these models is often incompatible with experimental data. Here, we show that the in vivo observations of bistable activity with irregular firing at the single cell level can be achieved in a large-scale network model with a modular structure in terms of several connected hypercolumns. Despite high irregularity of individual spike trains, the model shows population oscillations in the beta and gamma band in ground and active states, respectively. Irregular firing typically emerges in a high-conductance regime of balanced excitation and inhibition. Population oscillations can produce such a regime, but in previous models only a non-coding ground state was oscillatory. Due to the modular structure of our network, the oscillatory and irregular firing was maintained also in the active state without fine-tuning. Our model provides a novel mechanistic view of how irregular firing emerges in cortical populations as they go from beta to gamma oscillations during memory retrieval.'),
(84637, 2010, 'plos', 'Optimal workloop energetics of muscle-actuated systems: an impedance matching view', 'Farahat, Waleed A|Herr, Hugh M', 'Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.', 'United States|United States', 22, 'Animals|Biomechanical Phenomena|Electric Impedance|Energy Metabolism|Models, Biological|Muscle, Skeletal|Rana pipiens', 'Journal Article', '10.1371/journal.pcbi.1000795', '20532203', 'Integrative approaches to studying the coupled dynamics of skeletal muscles with their loads while under neural control have focused largely on questions pertaining to the postural and dynamical stability of animals and humans. Prior studies have focused on how the central nervous system actively modulates muscle mechanical impedance to generate and stabilize motion and posture. However, the question of whether muscle impedance properties can be neurally modulated to create favorable mechanical energetics, particularly in the context of periodic tasks, remains open. Through muscle stiffness tuning, we hypothesize that a pair of antagonist muscles acting against a common load may produce significantly more power synergistically than individually when impedance matching conditions are met between muscle and load. Since neurally modulated muscle stiffness contributes to the coupled muscle-load stiffness, we further anticipate that power-optimal oscillation frequencies will occur at frequencies greater than the natural frequency of the load. These hypotheses were evaluated computationally by applying optimal control methods to a bilinear muscle model, and also evaluated through in vitro measurements on frog Plantaris longus muscles acting individually and in pairs upon a mass-spring-damper load. We find a 7-fold increase in mechanical power when antagonist muscles act synergistically compared to individually at a frequency higher than the load natural frequency. These observed behaviors are interpreted in the context of resonance tuning and the engineering notion of impedance matching. These findings suggest that the central nervous system can adopt strategies to harness inherent muscle impedance in relation to external loads to attain favorable mechanical energetics.'),
(84638, 2010, 'plos', 'Expansion of the protein repertoire in newly explored environments: human gut microbiome specific protein families', 'Ellrott, Kyle|Jaroszewski, Lukasz|Li, Weizhong|Wooley, John C|Godzik, Adam', 'Joint Center for Structural Genomics, Bioinformatics Core, University of California San Diego, La Jolla, California, USA.|Joint Center for Structural Genomics, Bioinformatics Core, University of California San Diego, La Jolla, California, USA.|Joint Center for Structural Genomics, Bioinformatics Core, University of California San Diego, La Jolla, California, USA.|Joint Center for Structural Genomics, Bioinformatics Core, University of California San Diego, La Jolla, California, USA.|Joint Center for Structural Genomics, Bioinformatics Core, University of California San Diego, La Jolla, California, USA.', 'United States|United States|United States|United States|United States', 47, 'Bacterial Proteins|Cluster Analysis|Computational Biology|Databases, Protein|Gastrointestinal Tract|Genome, Bacterial|Humans|Metagenome', 'Journal Article', '10.1371/journal.pcbi.1000798', '20532204', 'The microbes that inhabit particular environments must be able to perform molecular functions that provide them with a competitive advantage to thrive in those environments. As most molecular functions are performed by proteins and are conserved between related proteins, we can expect that organisms successful in a given environmental niche would contain protein families that are specific for functions that are important in that environment. For instance, the human gut is rich in polysaccharides from the diet or secreted by the host, and is dominated by Bacteroides, whose genomes contain highly expanded repertoire of protein families involved in carbohydrate metabolism. To identify other protein families that are specific to this environment, we investigated the distribution of protein families in the currently available human gut genomic and metagenomic data. Using an automated procedure, we identified a group of protein families strongly overrepresented in the human gut. These not only include many families described previously but also, interestingly, a large group of previously unrecognized protein families, which suggests that we still have much to discover about this environment. The identification and analysis of these families could provide us with new information about an environment critical to our health and well being.'),
(84639, 2010, 'plos', 'Achieving optimal growth through product feedback inhibition in metabolism', 'Goyal, Sidhartha|Yuan, Jie|Chen, Thomas|Rabinowitz, Joshua D|Wingreen, Ned S', 'Department of Physics, Princeton University, Princeton, New Jersey, USA.|Department of Physics, Princeton University, Princeton, New Jersey, USA.|Department of Physics, Princeton University, Princeton, New Jersey, USA.|Department of Physics, Princeton University, Princeton, New Jersey, USA.|Department of Physics, Princeton University, Princeton, New Jersey, USA.', 'Jersey|Jersey|Jersey|Jersey|Jersey', 30, 'Biomass|Carbon|Escherichia coli|Feedback, Physiological|Models, Biological|Nitrogen|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000802', '20532205', 'Recent evidence suggests that the metabolism of some organisms, such as Escherichia coli, is remarkably efficient, producing close to the maximum amount of biomass per unit of nutrient consumed. This observation raises the question of what regulatory mechanisms enable such efficiency. Here, we propose that simple product-feedback inhibition by itself is capable of leading to such optimality. We analyze several representative metabolic modules--starting from a linear pathway and advancing to a bidirectional pathway and metabolic cycle, and finally to integration of two different nutrient inputs. In each case, our mathematical analysis shows that product-feedback inhibition is not only homeostatic but also, with appropriate feedback connections, can minimize futile cycling and optimize fluxes. However, the effectiveness of simple product-feedback inhibition comes at the cost of high levels of some metabolite pools, potentially associated with toxicity and osmotic imbalance. These large metabolite pool sizes can be restricted if feedback inhibition is ultrasensitive. Indeed, the multi-layer regulation of metabolism by control of enzyme expression, enzyme covalent modification, and allostery is expected to result in such ultrasensitive feedbacks. To experimentally test whether the qualitative predictions from our analysis of feedback inhibition apply to metabolic modules beyond linear pathways, we examine the case of nitrogen assimilation in E. coli, which involves both nutrient integration and a metabolic cycle. We find that the feedback regulation scheme suggested by our mathematical analysis closely aligns with the actual regulation of the network and is sufficient to explain much of the dynamical behavior of relevant metabolite pool sizes in nutrient-switching experiments.'),
(84640, 2010, 'plos', 'Symmetric allosteric mechanism of hexameric Escherichia coli arginine repressor exploits competition between L-arginine ligands and resident arginine residues', 'Strawn, Rebecca|Melichercik, Milan|Green, Michael|Stockner, Thomas|Carey, Jannette|Ettrich, Rüdiger', 'Chemistry Department, Princeton University, Princeton, New Jersey, USA.|Chemistry Department, Princeton University, Princeton, New Jersey, USA.|Chemistry Department, Princeton University, Princeton, New Jersey, USA.|Chemistry Department, Princeton University, Princeton, New Jersey, USA.|Chemistry Department, Princeton University, Princeton, New Jersey, USA.|Chemistry Department, Princeton University, Princeton, New Jersey, USA.', 'Jersey|Jersey|Jersey|Jersey|Jersey|Jersey', 14, 'Allosteric Regulation|Allosteric Site|Arginine|DNA|Escherichia coli|Escherichia coli Proteins|Molecular Conformation|Molecular Dynamics Simulation|Repressor Proteins|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1000801', '20532206', 'An elegantly simple and probably ancient molecular mechanism of allostery is described for the Escherichia coli arginine repressor ArgR, the master feedback regulator of transcription in L-arginine metabolism. Molecular dynamics simulations with ArgRC, the hexameric domain that binds L-arginine with negative cooperativity, reveal that conserved arginine and aspartate residues in each ligand-binding pocket promote rotational oscillation of apoArgRC trimers by engagement and release of hydrogen-bonded salt bridges. Binding of exogenous L-arginine displaces resident arginine residues and arrests oscillation, shifting the equilibrium quaternary ensemble and promoting motions that maintain the configurational entropy of the system. A single L-arg ligand is necessary and sufficient to arrest oscillation, and enables formation of a cooperative hydrogen-bond network at the subunit interface. The results are used to construct a free-energy reaction coordinate that accounts for the negative cooperativity and distinctive thermodynamic signature of L-arginine binding detected by calorimetry. The symmetry of the hexamer is maintained as each ligand binds, despite the conceptual asymmetry of partially-liganded states. The results thus offer the first opportunity to describe in structural and thermodynamic terms the symmetric relaxed state predicted by the concerted allostery model of Monod, Wyman, and Changeux, revealing that this state is achieved by exploiting the dynamics of the assembly and the distributed nature of its cohesive free energy. The ArgR example reveals that symmetry can be maintained even when binding sites fill sequentially due to negative cooperativity, which was not anticipated by the Monod, Wyman, and Changeux model. The molecular mechanism identified here neither specifies nor requires a pathway for transmission of the allosteric signal through the protein, and it suggests the possibility that binding of free amino acids was an early innovation in the evolution of allostery.'),
(84641, 2010, 'plos', 'Optimal drug synergy in antimicrobial treatments', 'Torella, Joseph Peter|Chait, Remy|Kishony, Roy', 'Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.', 'United States|United States|United States', 93, 'Algorithms|Animals|Anti-Infective Agents|Cluster Analysis|Disease Models, Animal|Drug Resistance, Multiple, Bacterial|Drug Synergism|Humans|Mice|Models, Biological|Pseudomonas Infections|Pseudomonas aeruginosa|Treatment Outcome', 'Journal Article', '10.1371/journal.pcbi.1000796', '20532210', 'The rapid proliferation of antibiotic-resistant pathogens has spurred the use of drug combinations to maintain clinical efficacy and combat the evolution of resistance. Drug pairs can interact synergistically or antagonistically, yielding inhibitory effects larger or smaller than expected from the drugs individual potencies. Clinical strategies often favor synergistic interactions because they maximize the rate at which the infection is cleared from an individual, but it is unclear how such interactions affect the evolution of multi-drug resistance. We used a mathematical model of in vivo infection dynamics to determine the optimal treatment strategy for preventing the evolution of multi-drug resistance. We found that synergy has two conflicting effects: it clears the infection faster and thereby decreases the time during which resistant mutants can arise, but increases the selective advantage of these mutants over wild-type cells. When competition for resources is weak, the former effect is dominant and greater synergy more effectively prevents multi-drug resistance. However, under conditions of strong resource competition, a tradeoff emerges in which greater synergy increases the rate of infection clearance, but also increases the risk of multi-drug resistance. This tradeoff breaks down at a critical level of drug interaction, above which greater synergy has no effect on infection clearance, but still increases the risk of multi-drug resistance. These results suggest that the optimal strategy for suppressing multi-drug resistance is not always to maximize synergy, and that in some cases drug antagonism, despite its weaker efficacy, may better suppress the evolution of multi-drug resistance.'),
(84642, 2010, 'plos', 'Maturation of GABAergic inhibition promotes strengthening of temporally coherent inputs among convergent pathways', 'Kuhlman, Sandra J|Lu, Jiangteng|Lazarus, Matthew S|Huang, Z Josh', 'Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. skuhlman@mednet.ucla.edu|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. skuhlman@mednet.ucla.edu|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. skuhlman@mednet.ucla.edu|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. skuhlman@mednet.ucla.edu', 'United States|United States|United States|United States', 0, 'Animals|Computer Simulation|Electric Stimulation|Mice|Mice, Inbred C57BL|Models, Neurological|Neuronal Plasticity|Pyramidal Cells|Receptors, GABA|Synapses|Time Factors|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1000797', '20532211', 'Spike-timing-dependent plasticity (STDP), a form of Hebbian plasticity, is inherently stabilizing. Whether and how GABAergic inhibition influences STDP is not well understood. Using a model neuron driven by converging inputs modifiable by STDP, we determined that a sufficient level of inhibition was critical to ensure that temporal coherence (correlation among presynaptic spike times) of synaptic inputs, rather than initial strength or number of inputs within a pathway, controlled postsynaptic spike timing. Inhibition exerted this effect by preferentially reducing synaptic efficacy, the ability of inputs to evoke postsynaptic action potentials, of the less coherent inputs. In visual cortical slices, inhibition potently reduced synaptic efficacy at ages during but not before the critical period of ocular dominance (OD) plasticity. Whole-cell recordings revealed that the amplitude of unitary IPSCs from parvalbumin positive (Pv+) interneurons to pyramidal neurons increased during the critical period, while the synaptic decay time-constant decreased. In addition, intrinsic properties of Pv+ interneurons matured, resulting in an increase in instantaneous firing rate. Our results suggest that maturation of inhibition in visual cortex ensures that the temporally coherent inputs (e.g. those from the open eye during monocular deprivation) control postsynaptic spike times of binocular neurons, a prerequisite for Hebbian mechanisms to induce OD plasticity.'),
(84643, 2010, 'plos', 'Characterization of growth and metabolism of the haloalkaliphile Natronomonas pharaonis', 'Gonzalez, Orland|Oberwinkler, Tanja|Mansueto, Locedie|Pfeiffer, Friedhelm|Mendoza, Eduardo|Zimmer, Ralf|Oesterhelt, Dieter', 'Department of Membrane Biochemistry, Max-Planck Institute of Biochemistry, Martinsried, Germany. gonzalez@bio.ifi.lmu.de|Department of Membrane Biochemistry, Max-Planck Institute of Biochemistry, Martinsried, Germany. gonzalez@bio.ifi.lmu.de|Department of Membrane Biochemistry, Max-Planck Institute of Biochemistry, Martinsried, Germany. gonzalez@bio.ifi.lmu.de|Department of Membrane Biochemistry, Max-Planck Institute of Biochemistry, Martinsried, Germany. gonzalez@bio.ifi.lmu.de|Department of Membrane Biochemistry, Max-Planck Institute of Biochemistry, Martinsried, Germany. gonzalez@bio.ifi.lmu.de|Department of Membrane Biochemistry, Max-Planck Institute of Biochemistry, Martinsried, Germany. gonzalez@bio.ifi.lmu.de|Department of Membrane Biochemistry, Max-Planck Institute of Biochemistry, Martinsried, Germany. gonzalez@bio.ifi.lmu.de', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany', 0, 'Acetates|Aerobiosis|Amino Acids|Biomass|Carbon|Computational Biology|Genes, Bacterial|Halobacteriaceae|Linear Models|Metabolic Networks and Pathways|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1000799', '20543878', 'Natronomonas pharaonis is an archaeon adapted to two extreme conditions: high salt concentration and alkaline pH. It has become one of the model organisms for the study of extremophilic life. Here, we present a genome-scale, manually curated metabolic reconstruction for the microorganism. The reconstruction itself represents a knowledge base of the haloalkaliphiles metabolism and, as such, would greatly assist further investigations on archaeal pathways. In addition, we experimentally determined several parameters relevant to growth, including a characterization of the biomass composition and a quantification of carbon and oxygen consumption. Using the metabolic reconstruction and the experimental data, we formulated a constraints-based model which we used to analyze the behavior of the archaeon when grown on a single carbon source. Results of the analysis include the finding that Natronomonas pharaonis, when grown aerobically on acetate, uses a carbon to oxygen consumption ratio that is theoretically near-optimal with respect to growth and energy production. This supports the hypothesis that, under simple conditions, the microorganism optimizes its metabolism with respect to the two objectives. We also found that the archaeon has a very low carbon efficiency of only about 35%. This inefficiency is probably due to a very low P/O ratio as well as to the other difficulties posed by its extreme environment.');
