INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84970, 2011, 'plos', 'Mechanisms of magnetic stimulation of central nervous system neurons', 'Pashut, Tamar|Wolfus, Shuki|Friedman, Alex|Lavidor, Michal|Bar-Gad, Izhar|Yeshurun, Yosef|Korngreen, Alon', 'The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.|The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.|The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.|The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.|The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.|The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.|The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.', 'Israel|Israel|Israel|Israel|Israel|Israel|Israel', 83, 'Action Potentials|Axons|Brain|Central Nervous System|Electromagnetic Fields|Models, Neurological|Neurons|Transcranial Magnetic Stimulation', 'Journal Article', '10.1371/journal.pcbi.1002022', '21455288', 'Transcranial magnetic stimulation (TMS) is a stimulation method in which a magnetic coil generates a magnetic field in an area of interest in the brain. This magnetic field induces an electric field that modulates neuronal activity. The spatial distribution of the induced electric field is determined by the geometry and location of the coil relative to the brain. Although TMS has been used for several decades, the biophysical basis underlying the stimulation of neurons in the central nervous system (CNS) is still unknown. To address this problem we developed a numerical scheme enabling us to combine realistic magnetic stimulation (MS) with compartmental modeling of neurons with arbitrary morphology. The induced electric field for each location in space was combined with standard compartmental modeling software to calculate the membrane current generated by the electromagnetic field for each segment of the neuron. In agreement with previous studies, the simulations suggested that peripheral axons were excited by the spatial gradients of the induced electric field. In both peripheral and central neurons, MS amplitude required for action potential generation was inversely proportional to the square of the diameter of the stimulated compartment. Due to the importance of the fibers diameter, magnetic stimulation of CNS neurons depolarized the soma followed by initiation of an action potential in the initial segment of the axon. Passive dendrites affect this process primarily as current sinks, not sources. The simulations predict that neurons with low current threshold are more susceptible to magnetic stimulation. Moreover, they suggest that MS does not directly trigger dendritic regenerative mechanisms. These insights into the mechanism of MS may be relevant for the design of multi-intensity TMS protocols, may facilitate the construction of magnetic stimulators, and may aid the interpretation of results of TMS of the CNS.'),
(84971, 2011, 'plos', 'Autonomous targeting of infectious superspreaders using engineered transmissible therapies', 'Metzger, Vincent T|Lloyd-Smith, James O|Weinberger, Leor S', 'Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, United States of America.|Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, United States of America.|Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, United States of America.', 'United States|United States|United States', 29, 'Acquired Immunodeficiency Syndrome|Africa|Anti-HIV Agents|Clinical Trials as Topic|Communicable Disease Control|Drug Resistance, Viral|Evolution, Molecular|Genetic Therapy|HIV Infections|Humans|Models, Statistical|Mutation|Pharmaceutical Preparations|Prevalence|Protein Engineering', 'Journal Article', '10.1371/journal.pcbi.1002015', '21483468', 'Infectious disease treatments, both pharmaceutical and vaccine, face three universal challenges: the difficulty of targeting treatments to high-risk superspreader populations who drive the great majority of disease spread, behavioral barriers in the host population (such as poor compliance and risk disinhibition), and the evolution of pathogen resistance. Here, we describe a proposed intervention that would overcome these challenges by capitalizing upon Therapeutic Interfering Particles (TIPs) that are engineered to replicate conditionally in the presence of the pathogen and spread between individuals--analogous to transmissible immunization that occurs with live-attenuated vaccines (but without the potential for reversion to virulence). Building on analyses of HIV field data from sub-Saharan Africa, we construct a multi-scale model, beginning at the single-cell level, to predict the effect of TIPs on individual patient viral loads and ultimately population-level disease prevalence. Our results show that a TIP, engineered with properties based on a recent HIV gene-therapy trial, could stably lower HIV/AIDS prevalence by xe2x88xbc30-fold within 50 years and could complement current therapies. In contrast, optimistic antiretroviral therapy or vaccination campaigns alone could only lower HIV/AIDS prevalence by <2-fold over 50 years. The TIPs efficacy arises from its exploitation of the same risk factors as the pathogen, allowing it to autonomously penetrate superspreader populations, maintain efficacy despite behavioral disinhibition, and limit viral resistance. While demonstrated here for HIV, the TIP concept could apply broadly to many viral infectious diseases and would represent a new paradigm for disease control, away from pathogen eradication but toward robust disease suppression.'),
(84972, 2011, 'plos', 'Inferring visuomotor priors for sensorimotor learning', 'Turnham, Edward J A|Braun, Daniel A|Wolpert, Daniel M', 'Computational and Biological Learning Laboratory, Department of Engineering, University of Cambridge, Cambridge, United Kingdom. ejat3@cam.ac.uk|Computational and Biological Learning Laboratory, Department of Engineering, University of Cambridge, Cambridge, United Kingdom. ejat3@cam.ac.uk|Computational and Biological Learning Laboratory, Department of Engineering, University of Cambridge, Cambridge, United Kingdom. ejat3@cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 20, 'Algorithms|Bayes Theorem|Computers|Feedback, Sensory|Hand|Humans|Informatics|Learning|Models, Theoretical|Motor Skills|Movement|Normal Distribution|Psychomotor Performance|Robotics|Software', 'Journal Article', '10.1371/journal.pcbi.1001112', '21483475', 'Sensorimotor learning has been shown to depend on both prior expectations and sensory evidence in a way that is consistent with Bayesian integration. Thus, prior beliefs play a key role during the learning process, especially when only ambiguous sensory information is available. Here we develop a novel technique to estimate the covariance structure of the prior over visuomotor transformations--the mapping between actual and visual location of the hand--during a learning task. Subjects performed reaching movements under multiple visuomotor transformations in which they received visual feedback of their hand position only at the end of the movement. After experiencing a particular transformation for one reach, subjects have insufficient information to determine the exact transformation, and so their second reach reflects a combination of their prior over visuomotor transformations and the sensory evidence from the first reach. We developed a Bayesian observer model in order to infer the covariance structure of the subjects prior, which was found to give high probability to parameter settings consistent with visuomotor rotations. Therefore, although the set of visuomotor transformations experienced had little structure, the subjects had a strong tendency to interpret ambiguous sensory evidence as arising from rotation-like transformations. We then exposed the same subjects to a highly-structured set of visuomotor transformations, designed to be very different from the set of visuomotor rotations. During this exposure the prior was found to have changed significantly to have a covariance structure that no longer favored rotation-like transformations. In summary, we have developed a technique which can estimate the full covariance structure of a prior in a sensorimotor task and have shown that the prior over visuomotor transformations favor a rotation-like structure. Moreover, through experience of a novel task structure, participants can appropriately alter the covariance structure of their prior.'),
(84973, 2011, 'plos', 'PLoS Computational Biology conference postcard from PSB 2011', 'Eren, A Murat', 'Department of Computer Science, University of New Orleans, New Orleans, Louisiana, United States of America. meren@pardus.org.tr', 'United States', 0, 'Computational Biology|Ecology|Genes, Bacterial|Software', 'Congress', '10.1371/journal.pcbi.1002019', '21483476', '-'),
(84974, 2011, 'plos', 'Consensus-phenotype integration of transcriptomic and metabolomic data implies a role for metabolism in the chemosensitivity of tumour cells', 'Cavill, Rachel|Kamburov, Atanas|Ellis, James K|Athersuch, Toby J|Blagrove, Marcus S C|Herwig, Ralf|Ebbels, Timothy M D|Keun, Hector C', 'Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.|Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.|Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.|Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.|Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.|Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.|Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.|Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 60, 'Antineoplastic Agents|Biomarkers|Carboplatin|Cell Line, Tumor|Cisplatin|Computational Biology|Drug Screening Assays, Antitumor|False Positive Reactions|Humans|Lipoproteins|Metabolomics|Neoplasms|Oligonucleotide Array Sequence Analysis|Organoplatinum Compounds|Phenotype|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1001113', '21483477', 'Using transcriptomic and metabolomic measurements from the NCI60 cell line panel, together with a novel approach to integration of molecular profile data, we show that the biochemical pathways associated with tumour cell chemosensitivity to platinum-based drugs are highly coincident, i.e. they describe a consensus phenotype. Direct integration of metabolome and transcriptome data at the point of pathway analysis improved the detection of consensus pathways by 76%, and revealed associations between platinum sensitivity and several metabolic pathways that were not visible from transcriptome analysis alone. These pathways included the TCA cycle and pyruvate metabolism, lipoprotein uptake and nucleotide synthesis by both salvage and de novo pathways. Extending the approach across a wide panel of chemotherapeutics, we confirmed the specificity of the metabolic pathway associations to platinum sensitivity. We conclude that metabolic phenotyping could play a role in predicting response to platinum chemotherapy and that consensus-phenotype integration of molecular profiling data is a powerful and versatile tool for both biomarker discovery and for exploring the complex relationships between biological pathways and drug response.'),
(84975, 2011, 'plos', 'CAERUS: predicting CAncER oUtcomeS using relationship between protein structural information, protein networks, gene expression data, and mutation data', 'Zhang, Kelvin Xi|Ouellette, B F Francis', 'Graduate Program in Bioinformatics, University of British Columbia, Vancouver, British Columbia, Canada.|Graduate Program in Bioinformatics, University of British Columbia, Vancouver, British Columbia, Canada.', 'Canada|Canada', 20, 'Algorithms|Bayes Theorem|Biomarkers, Tumor|Breast Neoplasms|Cell Line, Tumor|Computational Biology|DNA Mutational Analysis|Female|Gene Expression Profiling|Gene Expression Regulation, Neoplastic|Gene Regulatory Networks|Humans|Mutation|Neoplasm Proteins|Proteomics|Reproducibility of Results|Sensitivity and Specificity', 'Journal Article', '10.1371/journal.pcbi.1001114', '21483478', 'Carcinogenesis is a complex process with multiple genetic and environmental factors contributing to the development of one or more tumors. Understanding the underlying mechanism of this process and identifying related markers to assess the outcome of this process would lead to more directed treatment and thus significantly reduce the mortality rate of cancers. Recently, molecular diagnostics and prognostics based on the identification of patterns within gene expression profiles in the context of protein interaction networks were reported. However, the predictive performances of these approaches were limited. In this study we propose a novel integrated approach, named CAERUS, for the identification of gene signatures to predict cancer outcomes based on the domain interaction network in human proteome. We first developed a model to score each protein by quantifying the domain connections to its interacting partners and the somatic mutations present in the domain. We then defined proteins as gene signatures if their scores were above a preset threshold. Next, for each gene signature, we quantified the correlation of the expression levels between this gene signature and its neighboring proteins. The results of the quantification in each patient were then used to predict cancer outcome by a modified naïve Bayes classifier. In this study we achieved a favorable accuracy of 88.3%, sensitivity of 87.2%, and specificity of 88.9% on a set of well-documented gene expression profiles of 253 consecutive breast cancer patients with different outcomes. We also compiled a list of cancer-associated gene signatures and domains, which provided testable hypotheses for further experimental investigation. Our approach proved successful on different independent breast cancer data sets as well as an ovarian cancer data set. This study constitutes the first predictive method to classify cancer outcomes based on the relationship between the domain organization and protein network.'),
(84976, 2011, 'plos', 'The roots of bioinformatics in theoretical biology', 'Hogeweg, Paulien', 'Theoretical Biology and Bioinformatics Group, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands. P.Hogeweg@uu.nl', 'Netherlands', 116, 'Computational Biology|Computers|Genome|History, 20th Century|History, 21st Century|Humans|Models, Theoretical', 'Historical Article', '10.1371/journal.pcbi.1002021', '21483479', 'From the late 1980s onward, the term bioinformatics mostly has been used to refer to computational methods for comparative analysis of genome data. However, the term was originally more widely defined as the study of informatic processes in biotic systems. In this essay, I will trace this early history (from a personal point of view) and I will argue that the original meaning of the term is re-emerging.'),
(84977, 2011, 'plos', 'Reconciliation of genome-scale metabolic reconstructions for comparative systems analysis', 'Oberhardt, Matthew A|Puchaxc5x82ka, Jacek|Martins dos Santos, Vxc3xadtor A P|Papin, Jason A', 'Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America.|Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America.|Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America.|Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America.', 'United States|United States|United States|United States', 83, 'Algorithms|Biotechnology|Computational Biology|Computer Simulation|Databases, Factual|Gene Expression Regulation, Bacterial|Genome|Genome, Bacterial|Metabolic Networks and Pathways|Phenotype|Pseudomonas|Reproducibility of Results|Software|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.1001116', '21483480', 'In the past decade, over 50 genome-scale metabolic reconstructions have been built for a variety of single- and multi- cellular organisms. These reconstructions have enabled a host of computational methods to be leveraged for systems-analysis of metabolism, leading to greater understanding of observed phenotypes. These methods have been sparsely applied to comparisons between multiple organisms, however, due mainly to the existence of differences between reconstructions that are inherited from the respective reconstruction processes of the organisms to be compared. To circumvent this obstacle, we developed a novel process, termed metabolic network reconciliation, whereby non-biological differences are removed from genome-scale reconstructions while keeping the reconstructions as true as possible to the underlying biological data on which they are based. This process was applied to two organisms of great importance to disease and biotechnological applications, Pseudomonas aeruginosa and Pseudomonas putida, respectively. The result is a pair of revised genome-scale reconstructions for these organisms that can be analyzed at a systems level with confidence that differences are indicative of true biological differences (to the degree that is currently known), rather than artifacts of the reconstruction process. The reconstructions were re-validated with various experimental data after reconciliation. With the reconciled and validated reconstructions, we performed a genome-wide comparison of metabolic flexibility between P. aeruginosa and P. putida that generated significant new insight into the underlying biology of these important organisms. Through this work, we provide a novel methodology for reconciling models, present new genome-scale reconstructions of P. aeruginosa and P. putida that can be directly compared at a network level, and perform a network-wide comparison of the two species. These reconstructions provide fresh insights into the metabolic similarities and differences between these important Pseudomonads, and pave the way towards full comparative analysis of genome-scale metabolic reconstructions of multiple species.'),
(84978, 2011, 'plos', 'Exploring off-targets and off-systems for adverse drug reactions via chemical-protein interactome--clozapine-induced agranulocytosis as a case study', 'Yang, Lun|Wang, Kejian|Chen, Jian|Jegga, Anil G|Luo, Heng|Shi, Leming|Wan, Chunling|Guo, Xizhi|Qin, Shengying|He, Guang|Feng, Guoyin|He, Lin', 'Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. lun.yang@gmail.com|Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. lun.yang@gmail.com|Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. lun.yang@gmail.com|Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. lun.yang@gmail.com|Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. lun.yang@gmail.com|Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. lun.yang@gmail.com|Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. lun.yang@gmail.com|Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. lun.yang@gmail.com|Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. lun.yang@gmail.com|Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. lun.yang@gmail.com|Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. lun.yang@gmail.com|Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. lun.yang@gmail.com', 'China|China|China|China|China|China|China|China|China|China|China|China', 85, 'Agranulocytosis|Benzodiazepines|Biomarkers|Cell Line, Tumor|Clozapine|Computational Biology|Drug-Related Side Effects and Adverse Reactions|GABA Antagonists|HSP70 Heat-Shock Proteins|Humans|Olanzapine|Protein Interaction Mapping|Proteomics|Reactive Oxygen Species|Retrospective Studies|Risk Factors', 'Journal Article', '10.1371/journal.pcbi.1002016', '21483481', 'In the era of personalized medical practice, understanding the genetic basis of patient-specific adverse drug reaction (ADR) is a major challenge. Clozapine provides effective treatments for schizophrenia but its usage is limited because of life-threatening agranulocytosis. A recent high impact study showed the necessity of moving clozapine to a first line drug, thus identifying the biomarkers for drug-induced agranulocytosis has become important. Here we report a methodology termed as antithesis chemical-protein interactome (CPI), which utilizes the docking method to mimic the differences in the drug-protein interactions across a panel of human proteins. Using this method, we identified HSPA1A, a known susceptibility gene for CIA, to be the off-target of clozapine. Furthermore, the mRNA expression of HSPA1A-related genes (off-target associated systems) was also found to be differentially expressed in clozapine treated leukemia cell line. Apart from identifying the CIA causal genes we identified several novel candidate genes which could be responsible for agranulocytosis. Proteins related to reactive oxygen clearance system, such as oxidoreductases and glutathione metabolite enzymes, were significantly enriched in the antithesis CPI. This methodology conducted a multi-dimensional analysis of drugs perturbation to the biological system, investigating both the off-targets and the associated off-systems to explore the molecular basis of an adverse event or the new uses for old drugs.'),
(84979, 2011, 'plos', 'A Bayesian approach to analyse genetic variation within RNA viral populations', 'McKinley, Trevelyan J|Murcia, Pablo R|Gog, Julia R|Varela, Mariana|Wood, James L N', 'Cambridge Infectious Diseases Consortium, Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom. tjm44@cam.ac.uk|Cambridge Infectious Diseases Consortium, Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom. tjm44@cam.ac.uk|Cambridge Infectious Diseases Consortium, Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom. tjm44@cam.ac.uk|Cambridge Infectious Diseases Consortium, Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom. tjm44@cam.ac.uk|Cambridge Infectious Diseases Consortium, Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom. tjm44@cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'AIDS Vaccines|Animals|Bayes Theorem|Computational Biology|Databases, Genetic|Evolution, Molecular|Genetic Variation|Horses|Macaca mulatta|Models, Statistical|Nucleotides|RNA Viruses|RNA, Viral|Reverse Transcriptase Polymerase Chain Reaction', 'Journal Article', '10.1371/journal.pcbi.1002027', '21483482', 'The development of modern and affordable sequencing technologies has allowed the study of viral populations to an unprecedented depth. This is of particular interest for the study of within-host RNA viral populations, where variation due to error-prone polymerases can lead to immune escape, antiviral resistance and adaptation to new host species. Methods to sequence RNA virus genomes include reverse transcription (RT) and polymerase chain reaction (PCR). RT-PCR is a molecular biology technique widely used to amplify DNA from an RNA template. The method itself relies on the in vitro synthesis of copy DNA from RNA followed by multiple cycles of DNA amplification. However, this method introduces artefactual errors that can act as confounding factors when the sequence data are analysed. Although there are a growing number of published studies exploring the intra- and inter-host evolutionary dynamics of RNA viruses, the complexity of the methods used to generate sequences makes it difficult to produce probabilistic statements about the likely sources of observed sequence variants. This complexity is further compounded as both the depth of sequencing and the length of the genome segment of interest increase. Here we develop a bayesian method to characterise and differentiate between likely structures for the background viral population. This approach can then be used to identify nucleotide sites that show evidence of change in the within-host viral population structure, either over time or relative to a reference sequence (e.g. an inoculum or another source of infection), or both, without having to build complex evolutionary models. Identification of these sites can help to inform the design of more focussed experiments using molecular biology tools, such as site-directed mutagenesis, to assess the function of specific amino acids. We illustrate the method by applying to datasets from experimental transmission of equine influenza, and a pre-clinical vaccine trial for HIV-1.'),
(84980, 2011, 'plos', 'Reactive oxygen species production by forward and reverse electron fluxes in the mitochondrial respiratory chain', 'Selivanov, Vitaly A|Votyakova, Tatyana V|Pivtoraiko, Violetta N|Zeak, Jennifer|Sukhomlin, Tatiana|Trucco, Massimo|Roca, Josep|Cascante, Marta', 'Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and IBUB, Barcelona, Spain.|Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and IBUB, Barcelona, Spain.|Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and IBUB, Barcelona, Spain.|Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and IBUB, Barcelona, Spain.|Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and IBUB, Barcelona, Spain.|Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and IBUB, Barcelona, Spain.|Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and IBUB, Barcelona, Spain.|Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and IBUB, Barcelona, Spain.', 'Spain|Spain|Spain|Spain|Spain|Spain|Spain|Spain', 92, 'ATP Synthetase Complexes|Algorithms|Animals|Brain|Citric Acid Cycle|Computational Biology|Computer Simulation|Electron Transport|Electrons|Membrane Potential, Mitochondrial|Mitochondria|Rats|Rats, Wistar|Reactive Oxygen Species|Spectrometry, Fluorescence', 'Journal Article', '10.1371/journal.pcbi.1001115', '21483483', 'Reactive oxygen species (ROS) produced in the mitochondrial respiratory chain (RC) are primary signals that modulate cellular adaptation to environment, and are also destructive factors that damage cells under the conditions of hypoxia/reoxygenation relevant for various systemic diseases or transplantation. The important role of ROS in cell survival requires detailed investigation of mechanism and determinants of ROS production. To perform such an investigation we extended our rule-based model of complex III in order to account for electron transport in the whole RC coupled to proton translocation, transmembrane electrochemical potential generation, TCA cycle reactions, and substrate transport to mitochondria. It fits respiratory electron fluxes measured in rat brain mitochondria fueled by succinate or pyruvate and malate, and the dynamics of NAD(+) reduction by reverse electron transport from succinate through complex I. The fitting of measured characteristics gave an insight into the mechanism of underlying processes governing the formation of free radicals that can transfer an unpaired electron to oxygen-producing superoxide and thus can initiate the generation of ROS. Our analysis revealed an association of ROS production with levels of specific radicals of individual electron transporters and their combinations in species of complexes I and III. It was found that the phenomenon of bistability, revealed previously as a property of complex III, remains valid for the whole RC. The conditions for switching to a state with a high content of free radicals in complex III were predicted based on theoretical analysis and were confirmed experimentally. These findings provide a new insight into the mechanisms of ROS production in RC.'),
(84981, 2011, 'plos', 'Modification of gene duplicability during the evolution of protein interaction network', 'DAntonio, Matteo|Ciccarelli, Francesca D', 'Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.|Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.', 'Italy|Italy', 0, 'Animals|Biological Evolution|Computational Biology|Drosophila melanogaster|Escherichia coli|Evolution, Molecular|Gene Duplication|Genes, Duplicate|Genetic Diseases, Inborn|Humans|MicroRNAs|Models, Biological|Models, Genetic|Protein Interaction Mapping|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.1002029', '21490719', 'Duplications of genes encoding highly connected and essential proteins are selected against in several species but not in human, where duplicated genes encode highly connected proteins. To understand when and how gene duplicability changed in evolution, we compare gene and network properties in four species (Escherichia coli, yeast, fly, and human) that are representative of the increase in evolutionary complexity, defined as progressive growth in the number of genes, cells, and cell types. We find that the origin and conservation of a gene significantly correlates with the properties of the encoded protein in the protein-protein interaction network. All four species preserve a core of singleton and central hubs that originated early in evolution, are highly conserved, and accomplish basic biological functions. Another group of hubs appeared in metazoans and duplicated in vertebrates, mostly through vertebrate-specific whole genome duplication. Such recent and duplicated hubs are frequently targets of microRNAs and show tissue-selective expression, suggesting that these are alternative mechanisms to control their dosage. Our study shows how networks modified during evolution and contributes to explaining the occurrence of somatic genetic diseases, such as cancer, in terms of network perturbations.'),
(84982, 2011, 'plos', 'Multi-scaled explorations of binding-induced folding of intrinsically disordered protein inhibitor IA3 to its target enzyme', 'Wang, Jin|Wang, Yong|Chu, Xiakun|Hagen, Stephen J|Han, Wei|Wang, Erkang', 'State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, Peoples Republic of China. jin.wang.1@stonybrook.edu|State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, Peoples Republic of China. jin.wang.1@stonybrook.edu|State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, Peoples Republic of China. jin.wang.1@stonybrook.edu|State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, Peoples Republic of China. jin.wang.1@stonybrook.edu|State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, Peoples Republic of China. jin.wang.1@stonybrook.edu|State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, Peoples Republic of China. jin.wang.1@stonybrook.edu', 'China|China|China|China|China|China', 60, 'Algorithms|Aspartic Acid Proteases|Computational Biology|Computer Simulation|Kinetics|Pepsin A|Protein Binding|Protein Conformation|Protein Folding|Protein Structure, Tertiary|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Stochastic Processes|Surface Properties|Temperature|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1001118', '21490720', 'Biomolecular function is realized by recognition, and increasing evidence shows that recognition is determined not only by structure but also by flexibility and dynamics. We explored a biomolecular recognition process that involves a major conformational change - protein folding. In particular, we explore the binding-induced folding of IA3, an intrinsically disordered protein that blocks the active site cleft of the yeast aspartic proteinase saccharopepsin (YPrA) by folding its own N-terminal residues into an amphipathic alpha helix. We developed a multi-scaled approach that explores the underlying mechanism by combining structure-based molecular dynamics simulations at the residue level with a stochastic path method at the atomic level. Both the free energy profile and the associated kinetic paths reveal a common scheme whereby IA3 binds to its target enzyme prior to folding itself into a helix. This theoretical result is consistent with recent time-resolved experiments. Furthermore, exploration of the detailed trajectories reveals the important roles of non-native interactions in the initial binding that occurs prior to IA3 folding. In contrast to the common view that non-native interactions contribute only to the roughness of landscapes and impede binding, the non-native interactions here facilitate binding by reducing significantly the entropic search space in the landscape. The information gained from multi-scaled simulations of the folding of this intrinsically disordered protein in the presence of its binding target may prove useful in the design of novel inhibitors of aspartic proteinases.'),
(84983, 2011, 'plos', 'A third measure-metastable state in the dynamics of spontaneous shape change in healthy humans white cells', 'Selz, Karen A', 'Fetzer Franklin Laboratory of the Cielo Institute, Asheville, North Carolina, USA. selz@cieloinstitute.org', 'United States', 0, 'Adult|Aged|Algorithms|Apoptosis|Cell Shape|Computational Biology|Humans|Inflammation|Leukocyte Count|Leukocytes|Macrophages|Middle Aged|Models, Statistical|Neoplasms|Neovascularization, Pathologic|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1001117', '21490721', 'Human polymorphonuclear leucocytes, PMN, are highly motile cells with average 12-15 µm diameters and prominent, loboid nuclei. They are produced in the bone marrow, are essential for host defense, and are the most populous of white blood cell types. PMN also participate in acute and chronic inflammatory processes, in the regulation of the immune response, in angiogenesis, and interact with tumors. To accommodate these varied functions, their behavior is adaptive, but still definable in terms of a set of behavioral states. PMN morphodynamics have generally involved a non-equilibrium stationary, spheroid Idling state that transitions to an activated, ellipsoid translocating state in response to chemical signals. These two behavioral shape-states, spheroid and ellipsoid, are generally recognized as making up the vocabulary of a healthy PMN. A third, random state has occasionally been reported as associated with disease states. I have observed this third, Treadmilling state, in PMN from healthy subjects, the cells demonstrating metastable dynamical behaviors known to anticipate phase transitions in mathematical, physical, and biological systems. For this study, human PMN were microscopically imaged and analyzed as single living cells. I used a microscope with a novel high aperture, cardioid annular condenser with better than 100 nanometer resolution of simultaneous, mixed dark field and intrinsic fluorescent images to record shape changes in 189 living PMNs. Relative radial roundness, R(t), served as a computable order parameter. Comparison of R(t) series of 10 cells in the Idling and 10 in the Treadmilling state reveals the robustness of the random appearing Treadmilling state, and the emergence of behaviors observed in the neighborhood of global state transitions, including increased correlation length and variance (divergence), sudden jumps, mixed phases, bimodality, power spectral scaling and temporal slowing. Wavelet transformation of an R(t) series of an Idling to Treadmilling state change, demonstrated behaviors concomitant with the observed transition.'),
(84984, 2011, 'plos', 'MDCK cystogenesis driven by cell stabilization within computational analogues', 'Engelberg, Jesse A|Datta, Anirban|Mostov, Keith E|Hunt, C Anthony', 'UCSF/UC Berkeley Joint Graduate Group in Bioengineering, University of California, San Francisco, California, USA.|UCSF/UC Berkeley Joint Graduate Group in Bioengineering, University of California, San Francisco, California, USA.|UCSF/UC Berkeley Joint Graduate Group in Bioengineering, University of California, San Francisco, California, USA.|UCSF/UC Berkeley Joint Graduate Group in Bioengineering, University of California, San Francisco, California, USA.', 'United States|United States|United States|United States', 0, 'Animals|Apoptosis|Cell Adhesion|Cell Culture Techniques|Cell Death|Cell Line|Cell Nucleus|Computational Biology|Computer Simulation|Cysts|Dogs|Models, Biological|Software|Tight Junctions', 'Journal Article', '10.1371/journal.pcbi.1002030', '21490722', 'The study of epithelial morphogenesis is fundamental to increasing our understanding of organ function and disease. Great progress has been made through study of culture systems such as Madin-Darby canine kidney (MDCK) cells, but many aspects of even simple morphogenesis remain unclear. For example, are specific cell actions tightly coupled to the characteristics of the cells environment or are they more often cell state dependent? How does the single lumen, single cell layer cyst consistently emerge from a variety of cell actions? To improve insight, we instantiated in silico analogues that used hypothesized cell behavior mechanisms to mimic MDCK cystogenesis. We tested them through in vitro experimentation and quantitative validation. We observed novel growth patterns, including a cell behavior shift that began around day five of growth. We created agent-oriented analogues that used the cellular Potts model along with an Iterative Refinement protocol. Following several refinements, we achieved a degree of validation for two separate mechanisms. Both survived falsification and achieved prespecified measures of similarity to cell culture properties. In silico components and mechanisms mapped to in vitro counterparts. In silico, the axis of cell division significantly affects lumen number without changing cell number or cyst size. Reducing the amount of in silico luminal cell death had limited effect on cystogenesis. Simulations provide an observable theory for cystogenesis based on hypothesized, cell-level operating principles.'),
(84985, 2011, 'plos', 'The morphology of the rat vibrissal array: a model for quantifying spatiotemporal patterns of whisker-object contact', 'Towal, R Blythe|Quist, Brian W|Gopal, Venkatesh|Solomon, Joseph H|Hartmann, Mitra J Z', 'Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, USA.|Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, USA.|Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, USA.|Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, USA.|Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, USA.', 'United States|United States|United States|United States|United States', 0, 'Algorithms|Animals|Biomechanical Phenomena|Brain Mapping|Computational Biology|Female|Imaging, Three-Dimensional|Rats|Rats, Sprague-Dawley|Reproducibility of Results|Somatosensory Cortex|Stress, Mechanical|Time Factors|Touch|Trigeminal Ganglion|Vibrissae', 'Journal Article', '10.1371/journal.pcbi.1001120', '21490724', 'In all sensory modalities, the data acquired by the nervous system is shaped by the biomechanics, material properties, and the morphology of the peripheral sensory organs. The rat vibrissal (whisker) system is one of the premier models in neuroscience to study the relationship between physical embodiment of the sensor array and the neural circuits underlying perception. To date, however, the three-dimensional morphology of the vibrissal array has not been characterized. Quantifying array morphology is important because it directly constrains the mechanosensory inputs that will be generated during behavior. These inputs in turn shape all subsequent neural processing in the vibrissal-trigeminal system, from the trigeminal ganglion to primary somatosensory (barrel) cortex. Here we develop a set of equations for the morphology of the vibrissal array that accurately describes the location of every point on every whisker to within ±5% of the whisker length. Given only a whiskers identity (row and column location within the array), the equations establish the whiskers two-dimensional (2D) shape as well as three-dimensional (3D) position and orientation. The equations were developed via parameterization of 2D and 3D scans of six rat vibrissal arrays, and the parameters were specifically chosen to be consistent with those commonly measured in behavioral studies. The final morphological model was used to simulate the contact patterns that would be generated as a rat uses its whiskers to tactually explore objects with varying curvatures. The simulations demonstrate that altering the morphology of the array changes the relationship between the sensory signals acquired and the curvature of the object. The morphology of the vibrissal array thus directly constrains the nature of the neural computations that can be associated with extraction of a particular object feature. These results illustrate the key role that the physical embodiment of the sensor array plays in the sensing process.'),
(84986, 2011, 'plos', 'Cell-sorting at the A/P boundary in the Drosophila wing primordium: a computational model to consolidate observed non-local effects of Hh signaling', 'Schilling, Sabine|Willecke, Maria|Aegerter-Wilmsen, Tinri|Cirpka, Olaf A|Basler, Konrad|von Mering, Christian', 'Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.|Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.|Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.|Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.|Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.|Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 21, 'Animals|Cell Communication|Cloning, Molecular|Computational Biology|Computer Simulation|Crosses, Genetic|Drosophila melanogaster|Hedgehog Proteins|Homozygote|Mitosis|Models, Biological|Models, Statistical|Signal Transduction|Stress, Mechanical|Wings, Animal', 'Journal Article', '10.1371/journal.pcbi.1002025', '21490725', 'Non-intermingling, adjacent populations of cells define compartment boundaries, such boundaries are often essential for the positioning and the maintenance of tissue-organizers during growth. In the developing wing primordium of Drosophila melanogaster, signaling by the secreted protein Hedgehog (Hh) is required for compartment boundary maintenance. However, the precise mechanism of Hh input remains poorly understood. Here, we combine experimental observations of perturbed Hh signaling with computer simulations of cellular behavior, and connect physical properties of cells to their Hh signaling status. We find that experimental disruption of Hh signaling has observable effects on cell sorting surprisingly far from the compartment boundary, which is in contrast to a previous model that confines Hh influence to the compartment boundary itself. We have recapitulated our experimental observations by simulations of Hh diffusion and transduction coupled to mechanical tension along cell-to-cell contact surfaces. Intriguingly, the best results were obtained under the assumption that Hh signaling cannot alter the overall tension force of the cell, but will merely re-distribute it locally inside the cell, relative to the signaling status of neighboring cells. Our results suggest a scenario in which homotypic interactions of a putative Hh target molecule at the cell surface are converted into a mechanical force. Such a scenario could explain why the mechanical output of Hh signaling appears to be confined to the compartment boundary, despite the longer range of the Hh molecule itself. Our study is the first to couple a cellular vertex model describing mechanical properties of cells in a growing tissue, to an explicit model of an entire signaling pathway, including a freely diffusible component. We discuss potential applications and challenges of such an approach.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(84987, 2011, 'plos', 'Quantifying the relative contributions of divisive and subtractive feedback to rhythm generation', 'Tabak, Joël|Rinzel, John|Bertram, Richard', 'Department of Biological Sciences, Florida State University, Tallahassee, Florida, USA. joel@neuro.fsu.edu|Department of Biological Sciences, Florida State University, Tallahassee, Florida, USA. joel@neuro.fsu.edu|Department of Biological Sciences, Florida State University, Tallahassee, Florida, USA. joel@neuro.fsu.edu', 'United States|United States|United States', 0, 'Action Potentials|Animals|Computational Biology|Computer Simulation|Humans|Models, Biological|Models, Neurological|Models, Statistical|Models, Theoretical|Neural Networks (Computer)|Neurons|Oscillometry|Software', 'Journal Article', '10.1371/journal.pcbi.1001124', '21533065', 'Biological systems are characterized by a high number of interacting components. Determining the role of each component is difficult, addressed here in the context of biological oscillations. Rhythmic behavior can result from the interplay of positive feedback that promotes bistability between high and low activity, and slow negative feedback that switches the system between the high and low activity states. Many biological oscillators include two types of negative feedback processes: divisive (decreases the gain of the positive feedback loop) and subtractive (increases the input threshold) that both contribute to slowly move the system between the high- and low-activity states. Can we determine the relative contribution of each type of negative feedback process to the rhythmic activity? Does one dominate? Do they control the active and silent phase equally? To answer these questions we use a neural network model with excitatory coupling, regulated by synaptic depression (divisive) and cellular adaptation (subtractive feedback). We first attempt to apply standard experimental methodologies: either passive observation to correlate the variations of a variable of interest to system behavior, or deletion of a component to establish whether a component is critical for the system. We find that these two strategies can lead to contradictory conclusions, and at best their interpretive power is limited. We instead develop a computational measure of the contribution of a process, by evaluating the sensitivity of the active (high activity) and silent (low activity) phase durations to the time constant of the process. The measure shows that both processes control the active phase, in proportion to their speed and relative weight. However, only the subtractive process plays a major role in setting the duration of the silent phase. This computational method can be used to analyze the role of negative feedback processes in a wide range of biological rhythms.'),
(84988, 2011, 'plos', 'In silico elucidation of the recognition dynamics of ubiquitin', 'Long, Dong|Brüschweiler, Rafael', 'Chemical Sciences Laboratory, Department of Chemistry and Biochemistry and National High Magnetic Field Laboratory, Florida State University, Tallahassee, Florida, USA.|Chemical Sciences Laboratory, Department of Chemistry and Biochemistry and National High Magnetic Field Laboratory, Florida State University, Tallahassee, Florida, USA.', 'United States|United States', 0, 'Computational Biology|Crystallography, X-Ray|Humans|Kinetics|Ligands|Magnetic Resonance Spectroscopy|Models, Statistical|Molecular Dynamics Simulation|Protein Binding|Protein Conformation|Protein Structure, Tertiary|Reproducibility of Results|Temperature|Thermodynamics|Ubiquitin', 'Journal Article', '10.1371/journal.pcbi.1002035', '21533067', 'Elucidation of the mechanism of biomacromolecular recognition events has been a topic of intense interest over the past century. The inherent dynamic nature of both protein and ligand molecules along with the continuous reshaping of the energy landscape during the binding process renders it difficult to characterize this process at atomic detail. Here, we investigate the recognition dynamics of ubiquitin via microsecond all-atom molecular dynamics simulation providing both thermodynamic and kinetic information. The high-level of consistency found with respect to experimental NMR data lends support to the accuracy of the in silico representation of the conformational substates and their interconversions of free ubiquitin. Using an energy-based reweighting approach, the statistical distribution of conformational states of ubiquitin is monitored as a function of the distance between ubiquitin and its binding partner Hrs-UIM. It is found that extensive and dense sampling of conformational space afforded by the µs MD trajectory is essential for the elucidation of the binding mechanism as is Boltzmann sampling, overcoming inherent limitations of sparsely sampled empirical ensembles. The results reveal a population redistribution mechanism that takes effect when the ligand is at intermediate range of 1-2 nm from ubiquitin. This mechanism, which may be depicted as a superposition of the conformational selection and induced fit mechanisms, also applies to other binding partners of ubiquitin, such as the GGA3 GAT domain.'),
(84989, 2011, 'plos', 'Accessing a hidden conformation of the maltose binding protein using accelerated molecular dynamics', 'Bucher, Denis|Grant, Barry J|Markwick, Phineus R|McCammon, J Andrew', 'Department of Chemistry and Biochemistry and Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California, USA. bucher.denis@gmail.com|Department of Chemistry and Biochemistry and Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California, USA. bucher.denis@gmail.com|Department of Chemistry and Biochemistry and Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California, USA. bucher.denis@gmail.com|Department of Chemistry and Biochemistry and Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California, USA. bucher.denis@gmail.com', 'United States|United States|United States|United States', 0, 'Allosteric Site|Binding Sites|Computational Biology|Computer Simulation|Crystallography, X-Ray|Escherichia coli|Ligands|Magnetic Resonance Spectroscopy|Maltose-Binding Proteins|Models, Biological|Models, Statistical|Oscillometry|Protein Conformation|Static Electricity', 'Journal Article', '10.1371/journal.pcbi.1002034', '21533070', 'Periplasmic binding proteins (PBPs) are a large family of molecular transporters that play a key role in nutrient uptake and chemotaxis in Gram-negative bacteria. All PBPs have characteristic two-domain architecture with a central interdomain ligand-binding cleft. Upon binding to their respective ligands, PBPs undergo a large conformational change that effectively closes the binding cleft. This conformational change is traditionally viewed as a ligand induced-fit process, however, the intrinsic dynamics of the protein may also be crucial for ligand recognition. Recent NMR paramagnetic relaxation enhancement (PRE) experiments have shown that the maltose binding protein (MBP) - a prototypical member of the PBP superfamily - exists in a rapidly exchanging (ns to µs regime) mixture comprising an open state (approx 95%), and a minor partially closed state (approx 5%). Here we describe accelerated MD simulations that provide a detailed picture of the transition between the open and partially closed states, and confirm the existence of a dynamical equilibrium between these two states in apo MBP. We find that a flexible part of the protein called the balancing interface motif (residues 175-184) is displaced during the transformation. Continuum electrostatic calculations indicate that the repacking of non-polar residues near the hinge region plays an important role in driving the conformational change. Oscillations between open and partially closed states create variations in the shape and size of the binding site. The study provides a detailed description of the conformational space available to ligand-free MBP, and has implications for understanding ligand recognition and allostery in related proteins.'),
(84990, 2011, 'plos', 'Linking microscopic spatial patterns of tissue destruction in emphysema to macroscopic decline in stiffness using a 3D computational model', 'Parameswaran, Harikrishnan|Majumdar, Arnab|Suki, Béla', 'Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA.|Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA.|Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA.', 'United States|United States|United States', 0, 'Algorithms|Computational Biology|Computer Simulation|Elasticity|Emphysema|Humans|Imaging, Three-Dimensional|Lung|Models, Biological|Models, Statistical|Models, Theoretical|Principal Component Analysis|Pulmonary Alveoli|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1001125', '21533072', 'Pulmonary emphysema is a connective tissue disease characterized by the progressive destruction of alveolar walls leading to airspace enlargement and decreased elastic recoil of the lung. However, the relationship between microscopic tissue structure and decline in stiffness of the lung is not well understood. In this study, we developed a 3D computational model of lung tissue in which a pre-strained cuboidal block of tissue was represented by a tessellation of space filling polyhedra, with each polyhedral unit-cell representing an alveolus. Destruction of alveolar walls was mimicked by eliminating faces that separate two polyhedral either randomly or in a spatially correlated manner, in which the highest force bearing walls were removed at each step. Simulations were carried out to establish a link between the geometries that emerged and the rate of decline in bulk modulus of the tissue block. The spatially correlated process set up by the force-based destruction lead to a significantly faster rate of decline in bulk modulus accompanied by highly heterogeneous structures than the random destruction pattern. Using the Karhunen-Loève transformation, an estimator of the change in bulk modulus from the first four moments of airspace cell volumes was setup. Simulations were then obtained for tissue destruction with different idealized alveolar geometry, levels of pre-strain, linear and nonlinear elasticity assumptions for alveolar walls and also mixed destruction patterns where both random and force-based destruction occurs simultaneously. In all these cases, the change in bulk modulus from cell volumes was accurately estimated. We conclude that microscopic structural changes in emphysema and the associated decline in tissue stiffness are linked by the spatial pattern of the destruction process.'),
(84991, 2011, 'plos', 'Discovering biological progression underlying microarray samples', 'Qiu, Peng|Gentles, Andrew J|Plevritis, Sylvia K', 'Department of Radiology, Stanford University, Stanford, California, USA. pqiu@mdanderson.org|Department of Radiology, Stanford University, Stanford, California, USA. pqiu@mdanderson.org|Department of Radiology, Stanford University, Stanford, California, USA. pqiu@mdanderson.org', 'United States|United States|United States', 0, 'Algorithms|Animals|B-Lymphocytes|Cell Differentiation|Cell Lineage|Cluster Analysis|Computational Biology|Databases, Factual|Embryonic Stem Cells|Gene Expression Profiling|Humans|Male|Mice|Oligonucleotide Array Sequence Analysis|Prostatic Neoplasms|Software', 'Journal Article', '10.1371/journal.pcbi.1001123', '21533210', 'In biological systems that undergo processes such as differentiation, a clear concept of progression exists. We present a novel computational approach, called Sample Progression Discovery (SPD), to discover patterns of biological progression underlying microarray gene expression data. SPD assumes that individual samples of a microarray dataset are related by an unknown biological process (i.e., differentiation, development, cell cycle, disease progression), and that each sample represents one unknown point along the progression of that process. SPD aims to organize the samples in a manner that reveals the underlying progression and to simultaneously identify subsets of genes that are responsible for that progression. We demonstrate the performance of SPD on a variety of microarray datasets that were generated by sampling a biological process at different points along its progression, without providing SPD any information of the underlying process. When applied to a cell cycle time series microarray dataset, SPD was not provided any prior knowledge of samples time order or of which genes are cell-cycle regulated, yet SPD recovered the correct time order and identified many genes that have been associated with the cell cycle. When applied to B-cell differentiation data, SPD recovered the correct order of stages of normal B-cell differentiation and the linkage between preB-ALL tumor cells with their cell origin preB. When applied to mouse embryonic stem cell differentiation data, SPD uncovered a landscape of ESC differentiation into various lineages and genes that represent both generic and lineage specific processes. When applied to a prostate cancer microarray dataset, SPD identified gene modules that reflect a progression consistent with disease stages. SPD may be best viewed as a novel tool for synthesizing biological hypotheses because it provides a likely biological progression underlying a microarray dataset and, perhaps more importantly, the candidate genes that regulate that progression.'),
(84992, 2011, 'plos', 'Network archaeology: uncovering ancient networks from present-day interactions', 'Navlakha, Saket|Kingsford, Carl', 'Department of Computer Science and Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, USA.|Department of Computer Science and Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, USA.', 'United States|United States', 0, 'Algorithms|Animals|Cluster Analysis|Computational Biology|Computer Simulation|Evolution, Molecular|Fungal Proteins|Gene Deletion|Genes, Fungal|Models, Theoretical|Probability|Protein Interaction Mapping|Reproducibility of Results|Saccharomyces cerevisiae|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1001119', '21533211', 'What proteins interacted in a long-extinct ancestor of yeast? How have different members of a protein complex assembled together over time? Our ability to answer such questions has been limited by the unavailability of ancestral protein-protein interaction (PPI) networks. To overcome this limitation, we propose several novel algorithms to reconstruct the growth history of a present-day network. Our likelihood-based method finds a probable previous state of the graph by applying an assumed growth model backwards in time. This approach retains node identities so that the history of individual nodes can be tracked. Using this methodology, we estimate protein ages in the yeast PPI network that are in good agreement with sequence-based estimates of age and with structural features of protein complexes. Further, by comparing the quality of the inferred histories for several different growth models (duplication-mutation with complementarity, forest fire, and preferential attachment), we provide additional evidence that a duplication-based model captures many features of PPI network growth better than models designed to mimic social network growth. From the reconstructed history, we model the arrival time of extant and ancestral interactions and predict that complexes have significantly re-wired over time and that new edges tend to form within existing complexes. We also hypothesize a distribution of per-protein duplication rates, track the change of the networks clustering coefficient, and predict paralogous relationships between extant proteins that are likely to be complementary to the relationships inferred using sequence alone. Finally, we infer plausible parameters for the model, thereby predicting the relative probability of various evolutionary events. The success of these algorithms indicates that parts of the history of the yeast PPI are encoded in its present-day form.'),
(84993, 2011, 'plos', 'A stochastic model of latently infected cell reactivation and viral blip generation in treated HIV patients', 'Conway, Jessica M|Coombs, Daniel', 'Department of Mathematics and Institute of Applied Mathematics, University of British Columbia, Vancouver, British Columbia, Canada. coombs@math.ubc.ca|Department of Mathematics and Institute of Applied Mathematics, University of British Columbia, Vancouver, British Columbia, Canada. coombs@math.ubc.ca', 'Canada|Canada', 53, 'Computer Simulation|HIV|HIV Infections|Humans|Models, Biological|Stochastic Processes|Viral Load|Virus Activation', 'Journal Article', '10.1371/journal.pcbi.1002033', '21552334', 'Motivated by viral persistence in HIV+ patients on long-term anti-retroviral treatment (ART), we present a stochastic model of HIV viral dynamics in the blood stream. We consider the hypothesis that the residual viremia in patients on ART can be explained principally by the activation of cells latently infected by HIV before the initiation of ART and that viral blips (clinically-observed short periods of detectable viral load) represent large deviations from the mean. We model the system as a continuous-time, multi-type branching process. Deriving equations for the probability generating function we use a novel numerical approach to extract the probability distributions for latent reservoir sizes and viral loads. We find that latent reservoir extinction-time distributions underscore the importance of considering reservoir dynamics beyond simply the half-life. We calculate blip amplitudes and frequencies by computing complete viral load probability distributions, and study the duration of viral blips via direct numerical simulation. We find that our model qualitatively reproduces short small-amplitude blips detected in clinical studies of treated HIV infection. Stochastic models of this type provide insight into treatment-outcome variability that cannot be found from deterministic models.'),
(84994, 2011, 'plos', 'A mathematical framework for estimating pathogen transmission fitness and inoculum size using data from a competitive mixtures animal model', 'McCaw, James M|Arinaminpathy, Nimalan|Hurt, Aeron C|McVernon, Jodie|McLean, Angela R', 'Vaccine and Immunisation Research Group, Murdoch Childrens Research Institute, Royal Childrens Hospital, Parkville, Victoria, Australia. jamesm@unimelb.edu.au|Vaccine and Immunisation Research Group, Murdoch Childrens Research Institute, Royal Childrens Hospital, Parkville, Victoria, Australia. jamesm@unimelb.edu.au|Vaccine and Immunisation Research Group, Murdoch Childrens Research Institute, Royal Childrens Hospital, Parkville, Victoria, Australia. jamesm@unimelb.edu.au|Vaccine and Immunisation Research Group, Murdoch Childrens Research Institute, Royal Childrens Hospital, Parkville, Victoria, Australia. jamesm@unimelb.edu.au|Vaccine and Immunisation Research Group, Murdoch Childrens Research Institute, Royal Childrens Hospital, Parkville, Victoria, Australia. jamesm@unimelb.edu.au', 'Australia|Australia|Australia|Australia|Australia', 0, 'Algorithms|Computational Biology|Computer Simulation|Drug Resistance, Viral|Genetic Fitness|Humans|Influenza, Human|Models, Biological|Orthomyxoviridae', 'Journal Article', '10.1371/journal.pcbi.1002026', '21552544', 'We present a method to measure the relative transmissibility (transmission fitness) of one strain of a pathogen compared to another. The model is applied to data from competitive mixtures experiments in which animals are co-infected with a mixture of two strains. We observe the mixture in each animal over time and over multiple generations of transmission. We use data from influenza experiments in ferrets to demonstrate the approach. Assessment of the relative transmissibility between two strains of influenza is important in at least three contexts: 1) Within the human population antigenically novel strains of influenza arise and compete for susceptible hosts. 2) During a pandemic event, a novel sub-type of influenza competes with the existing seasonal strain(s). The unfolding epidemiological dynamics are dependent upon both the populations susceptibility profile and the inherent transmissibility of the novel strain compared to the existing strain(s). 3) Neuraminidase inhibitors (NAIs), while providing significant potential to reduce transmission of influenza, exert selective pressure on the virus and so promote the emergence of drug-resistant strains. Any adverse outcome due to selection and subsequent spread of an NAI-resistant strain is exquisitely dependent upon the transmission fitness of that strain. Measurement of the transmission fitness of two competing strains of influenza is thus of critical importance in determining the likely time-course and epidemiology of an influenza outbreak, or the potential impact of an intervention measure such as NAI distribution. The mathematical framework introduced here also provides an estimate for the size of the transmitted inoculum. We demonstrate the frameworks behaviour using data from ferret transmission studies, and through simulation suggest how to optimise experimental design for assessment of transmissibility. The method introduced here for assessment of mixed transmission events has applicability beyond influenza, to other viral and bacterial pathogens.'),
(84995, 2011, 'plos', 'Minimum Information About a Simulation Experiment (MIASE)', 'Waltemath, Dagmar|Adams, Richard|Beard, Daniel A|Bergmann, Frank T|Bhalla, Upinder S|Britten, Randall|Chelliah, Vijayalakshmi|Cooling, Michael T|Cooper, Jonathan|Crampin, Edmund J|Garny, Alan|Hoops, Stefan|Hucka, Michael|Hunter, Peter|Klipp, Edda|Laibe, Camille|Miller, Andrew K|Moraru, Ion|Nickerson, David|Nielsen, Poul|Nikolski, Macha|Sahle, Sven|Sauro, Herbert M|Schmidt, Henning|Snoep, Jacky L|Tolle, Dominic|Wolkenhauer, Olaf|Le Novère, Nicolas', 'Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.|Database and Information Systems, Graduate Research School dIEM oSiRiS, Rostock University, Rostock, Mecklenburg-Vorpommern, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germ', 79, 'Computer Simulation|Reproducibility of Results|Research Design', 'Journal Article', '10.1371/journal.pcbi.1001122', '21552546', '-'),
(84996, 2011, 'plos', 'Drug discovery using chemical systems biology: weak inhibition of multiple kinases may contribute to the anti-cancer effect of nelfinavir', 'Xie, Li|Evangelidis, Thomas|Xie, Lei|Bourne, Philip E', 'Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, United States of America. lxie@ucsd.edu|Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, United States of America. lxie@ucsd.edu|Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, United States of America. lxie@ucsd.edu|Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, United States of America. lxie@ucsd.edu', 'United States|United States|United States|United States', 127, 'Antineoplastic Agents|Binding Sites|Drug Discovery|Drug Interactions|Humans|Molecular Dynamics Simulation|Nelfinavir|Protein Binding|Protein Kinase Inhibitors|Protein Kinases|Systems Biology|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002037', '21552547', 'Nelfinavir is a potent HIV-protease inhibitor with pleiotropic effects in cancer cells. Experimental studies connect its anti-cancer effects to the suppression of the Akt signaling pathway, but the actual molecular targets remain unknown. Using a structural proteome-wide off-target pipeline, which integrates molecular dynamics simulation and MM/GBSA free energy calculations with ligand binding site comparison and biological network analysis, we identified putative human off-targets of Nelfinavir and analyzed the impact on the associated biological processes. Our results suggest that Nelfinavir is able to inhibit multiple members of the protein kinase-like superfamily, which are involved in the regulation of cellular processes vital for carcinogenesis and metastasis. The computational predictions are supported by kinase activity assays and are consistent with existing experimental and clinical evidence. This finding provides a molecular basis to explain the broad-spectrum anti-cancer effect of Nelfinavir and presents opportunities to optimize the drug as a targeted polypharmacology agent.'),
(84997, 2011, 'plos', 'A comparison of mathematical models for polarization of single eukaryotic cells in response to guided cues', 'Jilkine, Alexandra|Edelstein-Keshet, Leah', 'Green Comprehensive Center for Computational and Systems Biology, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. Alexandra.Jilkine@UTSouthwestern.edu|Green Comprehensive Center for Computational and Systems Biology, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. Alexandra.Jilkine@UTSouthwestern.edu', 'United States|United States', 0, 'Animals|Cell Polarity|Eukaryotic Cells|Humans|Models, Biological|Systems Biology', 'Comparative Study', '10.1371/journal.pcbi.1001121', '21552548', 'Polarization, a primary step in the response of an individual eukaryotic cell to a spatial stimulus, has attracted numerous theoretical treatments complementing experimental studies in a variety of cell types. While the phenomenon itself is universal, details differ across cell types, and across classes of models that have been proposed. Most models address how symmetry breaking leads to polarization, some in abstract settings, others based on specific biochemistry. Here, we compare polarization in response to a stimulus (e.g., a chemoattractant) in cells typically used in experiments (yeast, amoebae, leukocytes, keratocytes, fibroblasts, and neurons), and, in parallel, responses of several prototypical models to typical stimulation protocols. We find that the diversity of cell behaviors is reflected by a diversity of models, and that some, but not all models, can account for amplification of stimulus, maintenance of polarity, adaptation, sensitivity to new signals, and robustness.'),
(84998, 2011, 'plos', 'Disentangling the roles of approach, activation and valence in instrumental and pavlovian responding', 'Huys, Quentin J M|Cools, Roshan|Gölzer, Martin|Friedel, Eva|Heinz, Andreas|Dolan, Raymond J|Dayan, Peter', 'Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. qhuys@cantab.net|Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. qhuys@cantab.net|Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. qhuys@cantab.net|Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. qhuys@cantab.net|Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. qhuys@cantab.net|Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. qhuys@cantab.net|Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom. qhuys@cantab.net', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 159, 'Adult|Analysis of Variance|Choice Behavior|Computational Biology|Conditioning, Classical|Female|Humans|Learning|Male|Models, Psychological|Punishment|Reflex|Reward', 'Journal Article', '10.1371/journal.pcbi.1002028', '21556131', 'Hard-wired, Pavlovian, responses elicited by predictions of rewards and punishments exert significant benevolent and malevolent influences over instrumentally-appropriate actions. These influences come in two main groups, defined along anatomical, pharmacological, behavioural and functional lines. Investigations of the influences have so far concentrated on the groups as a whole, here we take the critical step of looking inside each group, using a detailed reinforcement learning model to distinguish effects to do with value, specific actions, and general activation or inhibition. We show a high degree of sophistication in Pavlovian influences, with appetitive Pavlovian stimuli specifically promoting approach and inhibiting withdrawal, and aversive Pavlovian stimuli promoting withdrawal and inhibiting approach. These influences account for differences in the instrumental performance of approach and withdrawal behaviours. Finally, although losses are as informative as gains, we find that subjects neglect losses in their instrumental learning. Our findings argue for a view of the Pavlovian system as a constraint or prior, facilitating learning by alleviating computational costs that come with increased flexibility.'),
(84999, 2011, 'plos', 'Simulating the mammalian blastocyst--molecular and mechanical interactions pattern the embryo', 'Krupinski, Pawel|Chickarmane, Vijay|Peterson, Carsten', 'Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden.|Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden.|Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden.', 'Sweden|Sweden|Sweden', 0, 'Animals|Blastocyst|Cell Adhesion|Cell Division|Computational Biology|Computer Simulation|Dictyostelium|Embryo, Mammalian|Embryonic Development|Gene Expression Regulation, Developmental|Germ Layers|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1001128', '21573197', 'Mammalian embryogenesis is a dynamic process involving gene expression and mechanical forces between proliferating cells. The exact nature of these interactions, which determine the lineage patterning of the trophectoderm and endoderm tissues occurring in a highly regulated manner at precise periods during the embryonic development, is an area of debate. We have developed a computational modeling framework for studying this process, by which the combined effects of mechanical and genetic interactions are analyzed within the context of proliferating cells. At a purely mechanical level, we demonstrate that the perpendicular alignment of the animal-vegetal (a-v) and embryonic-abembryonic (eb-ab) axes is a result of minimizing the total elastic conformational energy of the entire collection of cells, which are constrained by the zona pellucida. The coupling of gene expression with the mechanics of cell movement is important for formation of both the trophectoderm and the endoderm. In studying the formation of the trophectoderm, we contrast and compare quantitatively two hypotheses: (1) The position determines gene expression, and (2) the gene expression determines the position. Our model, which couples gene expression with mechanics, suggests that differential adhesion between different cell types is a critical determinant in the robust endoderm formation. In addition to differential adhesion, two different testable hypotheses emerge when considering endoderm formation: (1) A directional force acts on certain cells and moves them into forming the endoderm layer, which separates the blastocoel and the cells of the inner cell mass (ICM). In this case the blastocoel simply acts as a static boundary. (2) The blastocoel dynamically applies pressure upon the cells in contact with it, such that cell segregation in the presence of differential adhesion leads to the endoderm formation. To our knowledge, this is the first attempt to combine cell-based spatial mechanical simulations with genetic networks to explain mammalian embryogenesis. Such a framework provides the means to test hypotheses in a controlled in silico environment.'),
(85000, 2011, 'plos', 'Modeling evolutionary dynamics of epigenetic mutations in hierarchically organized tumors', 'Sottoriva, Andrea|Vermeulen, Louis|Tavaré, Simon', 'Computational Biology Group, University of Cambridge, CRUK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom. as949@cam.ac.uk|Computational Biology Group, University of Cambridge, CRUK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom. as949@cam.ac.uk|Computational Biology Group, University of Cambridge, CRUK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom. as949@cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 44, 'Cell Physiological Phenomena|Computer Simulation|DNA Methylation|Epigenesis, Genetic|Evolution, Molecular|Genetic Fitness|Humans|Models, Genetic|Monte Carlo Method|Mutation|Neoplasms|Neoplastic Stem Cells|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1001132', '21573198', 'The cancer stem cell (CSC) concept is a highly debated topic in cancer research. While experimental evidence in favor of the cancer stem cell theory is apparently abundant, the results are often criticized as being difficult to interpret. An important reason for this is that most experimental data that support this model rely on transplantation studies. In this study we use a novel cellular Potts model to elucidate the dynamics of established malignancies that are driven by a small subset of CSCs. Our results demonstrate that epigenetic mutations that occur during mitosis display highly altered dynamics in CSC-driven malignancies compared to a classical, non-hierarchical model of growth. In particular, the heterogeneity observed in CSC-driven tumors is considerably higher. We speculate that this feature could be used in combination with epigenetic (methylation) sequencing studies of human malignancies to prove or refute the CSC hypothesis in established tumors without the need for transplantation. Moreover our tumor growth simulations indicate that CSC-driven tumors display evolutionary features that can be considered beneficial during tumor progression. Besides an increased heterogeneity they also exhibit properties that allow the escape of clones from local fitness peaks. This leads to more aggressive phenotypes in the long run and makes the neoplasm more adaptable to stringent selective forces such as cancer treatment. Indeed when therapy is applied the clone landscape of the regrown tumor is more aggressive with respect to the primary tumor, whereas the classical model demonstrated similar patterns before and after therapy. Understanding these often counter-intuitive fundamental properties of (non-)hierarchically organized malignancies is a crucial step in validating the CSC concept as well as providing insight into the therapeutical consequences of this model.'),
(85001, 2011, 'plos', 'Feedback control architecture and the bacterial chemotaxis network', 'Hamadeh, Abdullah|Roberts, Mark A J|August, Elias|McSharry, Patrick E|Maini, Philip K|Armitage, Judith P|Papachristodoulou, Antonis', 'Department of Engineering Science, University of Oxford, Oxford, United Kingdom.|Department of Engineering Science, University of Oxford, Oxford, United Kingdom.|Department of Engineering Science, University of Oxford, Oxford, United Kingdom.|Department of Engineering Science, University of Oxford, Oxford, United Kingdom.|Department of Engineering Science, University of Oxford, Oxford, United Kingdom.|Department of Engineering Science, University of Oxford, Oxford, United Kingdom.|Department of Engineering Science, University of Oxford, Oxford, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Bacterial Physiological Phenomena|Bacterial Proteins|Chemotactic Factors|Chemotaxis|Feedback, Physiological|Linear Models|Models, Biological|Reproducibility of Results|Rhodobacter sphaeroides|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1001130', '21573199', 'Bacteria move towards favourable and away from toxic environments by changing their swimming pattern. This response is regulated by the chemotaxis signalling pathway, which has an important feature: it uses feedback to reset (adapt) the bacterial sensing ability, which allows the bacteria to sense a range of background environmental changes. The role of this feedback has been studied extensively in the simple chemotaxis pathway of Escherichia coli. However it has been recently found that the majority of bacteria have multiple chemotaxis homologues of the E. coli proteins, resulting in more complex pathways. In this paper we investigate the configuration and role of feedback in Rhodobacter sphaeroides, a bacterium containing multiple homologues of the chemotaxis proteins found in E. coli. Multiple proteins could produce different possible feedback configurations, each having different chemotactic performance qualities and levels of robustness to variations and uncertainties in biological parameters and to intracellular noise. We develop four models corresponding to different feedback configurations. Using a series of carefully designed experiments we discriminate between these models and invalidate three of them. When these models are examined in terms of robustness to noise and parametric uncertainties, we find that the non-invalidated model is superior to the others. Moreover, it has a cascade control feedback architecture which is used extensively in engineering to improve system performance, including robustness. Given that the majority of bacteria are known to have multiple chemotaxis pathways, in this paper we show that some feedback architectures allow them to have better performance than others. In particular, cascade control may be an important feature in achieving robust functionality in more complex signalling pathways and in improving their performance.'),
(85002, 2011, 'plos', 'Impact of fast sodium channel inactivation on spike threshold dynamics and synaptic integration', 'Platkiewicz, Jonathan|Brette, Romain', 'Laboratoire Psychologie de la Perception, CNRS and Université Paris Descartes, Paris, France.|Laboratoire Psychologie de la Perception, CNRS and Université Paris Descartes, Paris, France.', 'France|France', 0, 'Action Potentials|Animals|Cats|Cerebral Cortex|Databases, Factual|Models, Neurological|Neurons|Patch-Clamp Techniques|Sodium Channels|Synapses', 'Journal Article', '10.1371/journal.pcbi.1001129', '21573200', 'Neurons spike when their membrane potential exceeds a threshold value. In central neurons, the spike threshold is not constant but depends on the stimulation. Thus, input-output properties of neurons depend both on the effect of presynaptic spikes on the membrane potential and on the dynamics of the spike threshold. Among the possible mechanisms that may modulate the threshold, one strong candidate is Na channel inactivation, because it specifically impacts spike initiation without affecting the membrane potential. We collected voltage-clamp data from the literature and we found, based on a theoretical criterion, that the properties of Na inactivation could indeed cause substantial threshold variability by itself. By analyzing simple neuron models with fast Na inactivation (one channel subtype), we found that the spike threshold is correlated with the mean membrane potential and negatively correlated with the preceding depolarization slope, consistent with experiments. We then analyzed the impact of threshold dynamics on synaptic integration. The difference between the postsynaptic potential (PSP) and the dynamic threshold in response to a presynaptic spike defines an effective PSP. When the neuron is sufficiently depolarized, this effective PSP is briefer than the PSP. This mechanism regulates the temporal window of synaptic integration in an adaptive way. Finally, we discuss the role of other potential mechanisms. Distal spike initiation, channel noise and Na activation dynamics cannot account for the observed negative slope-threshold relationship, while adaptive conductances (e.g. K+) and Na inactivation can. We conclude that Na inactivation is a metabolically efficient mechanism to control the temporal resolution of synaptic integration.'),
(85003, 2011, 'plos', 'Theoretical model for cellular shapes driven by protrusive and adhesive forces', 'Kabaso, Doron|Shlomovitz, Roie|Schloen, Kathrin|Stradal, Theresia|Gov, Nir S', 'Department of Chemical Physics, The Weizmann Institute of Science, Rehovot, Israel.|Department of Chemical Physics, The Weizmann Institute of Science, Rehovot, Israel.|Department of Chemical Physics, The Weizmann Institute of Science, Rehovot, Israel.|Department of Chemical Physics, The Weizmann Institute of Science, Rehovot, Israel.|Department of Chemical Physics, The Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel|Israel|Israel|Israel', 44, 'Actins|Animals|Biomechanical Phenomena|Cell Adhesion|Cell Shape|Cells, Cultured|Cytoskeleton|Extracellular Matrix|Fibroblasts|Mice|Models, Biological|Pseudopodia', 'Journal Article', '10.1371/journal.pcbi.1001127', '21573201', 'The forces that arise from the actin cytoskeleton play a crucial role in determining the cell shape. These include protrusive forces due to actin polymerization and adhesion to the external matrix. We present here a theoretical model for the cellular shapes resulting from the feedback between the membrane shape and the forces acting on the membrane, mediated by curvature-sensitive membrane complexes of a convex shape. In previous theoretical studies we have investigated the regimes of linear instability where spontaneous formation of cellular protrusions is initiated. Here we calculate the evolution of a two dimensional cell contour beyond the linear regime and determine the final steady-state shapes arising within the model. We find that shapes driven by adhesion or by actin polymerization (lamellipodia) have very different morphologies, as observed in cells. Furthermore, we find that as the strength of the protrusive forces diminish, the system approaches a stabilization of a periodic pattern of protrusions. This result can provide an explanation for a number of puzzling experimental observations regarding cellular shape dependence on the properties of the extra-cellular matrix.'),
(85004, 2011, 'plos', 'Detecting network communities: an application to phylogenetic analysis', 'Andrade, Roberto F S|Rocha-Neto, Ivan C|Santos, Leonardo B L|de Santana, Charles N|Diniz, Marcelo V C|Lobão, Thierry Petit|Goés-Neto, Aristóteles|Pinho, Suani T R|El-Hani, Charbel N', 'Institute of Physics, Federal University of Bahia, Campus Universitário de Ondina, Salvador, Bahia, Brazil.|Institute of Physics, Federal University of Bahia, Campus Universitário de Ondina, Salvador, Bahia, Brazil.|Institute of Physics, Federal University of Bahia, Campus Universitário de Ondina, Salvador, Bahia, Brazil.|Institute of Physics, Federal University of Bahia, Campus Universitário de Ondina, Salvador, Bahia, Brazil.|Institute of Physics, Federal University of Bahia, Campus Universitário de Ondina, Salvador, Bahia, Brazil.|Institute of Physics, Federal University of Bahia, Campus Universitário de Ondina, Salvador, Bahia, Brazil.|Institute of Physics, Federal University of Bahia, Campus Universitário de Ondina, Salvador, Bahia, Brazil.|Institute of Physics, Federal University of Bahia, Campus Universitário de Ondina, Salvador, Bahia, Brazil.|Institute of Physics, Federal University of Bahia, Campus Universitário de Ondina, Salvador, Bahia, Brazil.', 'Brazil|Brazil|Brazil|Brazil|Brazil|Brazil|Brazil|Brazil|Brazil', 0, 'Algorithms|Amino Acid Sequence|Archaea|Bacteria|Bacterial Physiological Phenomena|Bayes Theorem|Chitin|Chitin Synthase|Computational Biology|Databases, Genetic|Enzymes|Eukaryotic Cells|Metabolic Networks and Pathways|Models, Biological|Phylogeny|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1001131', '21573202', 'This paper proposes a new method to identify communities in generally weighted complex networks and apply it to phylogenetic analysis. In this case, weights correspond to the similarity indexes among protein sequences, which can be used for network construction so that the network structure can be analyzed to recover phylogenetically useful information from its properties. The analyses discussed here are mainly based on the modular character of protein similarity networks, explored through the Newman-Girvan algorithm, with the help of the neighborhood matrix . The most relevant networks are found when the network topology changes abruptly revealing distinct modules related to the sets of organisms to which the proteins belong. Sound biological information can be retrieved by the computational routines used in the network approach, without using biological assumptions other than those incorporated by BLAST. Usually, all the main bacterial phyla and, in some cases, also some bacterial classes corresponded totally (100%) or to a great extent (>70%) to the modules. We checked for internal consistency in the obtained results, and we scored close to 84% of matches for community pertinence when comparisons between the results were performed. To illustrate how to use the network-based method, we employed data for enzymes involved in the chitin metabolic pathway that are present in more than 100 organisms from an original data set containing 1,695 organisms, downloaded from GenBank on May 19, 2007. A preliminary comparison between the outcomes of the network-based method and the results of methods based on Bayesian, distance, likelihood, and parsimony criteria suggests that the former is as reliable as these commonly used methods. We conclude that the network-based method can be used as a powerful tool for retrieving modularity information from weighted networks, which is useful for phylogenetic analysis.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85005, 2011, 'plos', 'Distributions of transposable elements reveal hazardous zones in mammalian introns', 'Zhang, Ying|Romanish, Mark T|Mager, Dixie L', 'Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.|Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.|Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.', 'Canada|Canada|Canada', 0, 'Animals|Computational Biology|Computer Simulation|DNA Transposable Elements|Databases, Genetic|Ether-A-Go-Go Potassium Channels|Expressed Sequence Tags|Humans|Introns|Male|Mice|Mice, Inbred C57BL|Models, Genetic|Mutagenesis, Insertional|Mutation|RNA Splicing|TRPC Cation Channels|Terminal Repeat Sequences|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002046', '21573203', 'Comprising nearly half of the human and mouse genomes, transposable elements (TEs) are found within most genes. Although the vast majority of TEs in introns are fixed in the species and presumably exert no significant effects on the enclosing gene, some markedly perturb transcription and result in disease or a mutated phenotype. Factors determining the likelihood that an intronic TE will affect transcription are not clear. In this study, we examined intronic TE distributions in both human and mouse and found several factors that likely contribute to whether a particular TE can influence gene transcription. Specifically, we observed that TEs near exons are greatly underrepresented compared to random distributions, but the size of these underrepresentation zones differs between TE classes. Compared to elsewhere in introns, TEs within these zones are shorter on average and show stronger orientation biases. Moreover, TEs in extremely close proximity (<20 bp) to exons show a strong bias to be near splice-donor sites. Interestingly, disease-causing intronic TE insertions show the opposite distributional trends, and by examining expressed sequence tag (EST) databases, we found that the proportion of TEs contributing to chimeric TE-gene transcripts is significantly higher within their underrepresentation zones. In addition, an analysis of predicted splice sites within human long terminal repeat (LTR) elements showed a significantly lower total number and weaker strength for intronic LTRs near exons. Based on these factors, we selectively examined a list of polymorphic mouse LTR elements in introns and showed clear evidence of transcriptional disruption by LTR element insertions in the Trpc6 and Kcnh6 genes. Taken together, these studies lend insight into the potential selective forces that have shaped intronic TE distributions and enable identification of TEs most likely to exert transcriptional effects on genes.'),
(85006, 2011, 'plos', 'How molecular motors are arranged on a cargo is important for vesicular transport', 'Erickson, Robert P|Jia, Zhiyuan|Gross, Steven P|Yu, Clare C', 'Department of Physics and Astronomy, University of California, Irvine, Irvine, California, United States of America.|Department of Physics and Astronomy, University of California, Irvine, Irvine, California, United States of America.|Department of Physics and Astronomy, University of California, Irvine, Irvine, California, United States of America.|Department of Physics and Astronomy, University of California, Irvine, Irvine, California, United States of America.', 'United States|United States|United States|United States', 53, 'Biological Transport|Computational Biology|Computer Simulation|Kinesin|Microtubules|Models, Biological|Models, Molecular|Monte Carlo Method|Particle Size|Protein Binding|Transport Vesicles|Viscosity', 'Journal Article', '10.1371/journal.pcbi.1002032', '21573204', 'The spatial organization of the cell depends upon intracellular trafficking of cargos hauled along microtubules and actin filaments by the molecular motor proteins kinesin, dynein, and myosin. Although much is known about how single motors function, there is significant evidence that cargos in vivo are carried by multiple motors. While some aspects of multiple motor function have received attention, how the cargo itself--and motor organization on the cargo--affects transport has not been considered. To address this, we have developed a three-dimensional Monte Carlo simulation of motors transporting a spherical cargo, subject to thermal fluctuations that produce both rotational and translational diffusion. We found that these fluctuations could exert a load on the motor(s), significantly decreasing the mean travel distance and velocity of large cargos, especially at large viscosities. In addition, the presence of the cargo could dramatically help the motor to bind productively to the microtubule: the relatively slow translational and rotational diffusion of moderately sized cargos gave the motors ample opportunity to bind to a microtubule before the motor/cargo ensemble diffuses out of range of that microtubule. For rapidly diffusing cargos, the probability of their binding to a microtubule was high if there were nearby microtubules that they could easily reach by translational diffusion. Our simulations found that one reason why motors may be approximately 100 nm long is to improve their on rates when attached to comparably sized cargos. Finally, our results suggested that to efficiently regulate the number of active motors, motors should be clustered together rather than spread randomly over the surface of the cargo. While our simulation uses the specific parameters for kinesin, these effects result from generic properties of the motors, cargos, and filaments, so they should apply to other motors as well.'),
(85007, 2011, 'plos', 'Combinations of protein-chemical complex structures reveal new targets for established drugs', 'Kalinina, Olga V|Wichmann, Oliver|Apic, Gordana|Russell, Robert B', 'Cell Networks, University of Heidelberg, Heidelberg, Germany.|Cell Networks, University of Heidelberg, Heidelberg, Germany.|Cell Networks, University of Heidelberg, Heidelberg, Germany.|Cell Networks, University of Heidelberg, Heidelberg, Germany.', 'Germany|Germany|Germany|Germany', 0, 'Animals|Binding Sites|Computational Biology|Computer Simulation|Databases, Protein|Drug Discovery|Humans|Mice|Models, Molecular|Pharmaceutical Preparations|Protein Binding|Protein Interaction Domains and Motifs|Protein Kinase Inhibitors|Protein Kinases|Proteins', 'Journal Article', '10.1371/journal.pcbi.1002043', '21573205', 'Biological networks are powerful tools for predicting undocumented relationships between molecules. The underlying principle is that existing interactions between molecules can be used to predict new interactions. Here we use this principle to suggest new protein-chemical interactions via the network derived from three-dimensional structures. For pairs of proteins sharing a common ligand, we use protein and chemical superimpositions combined with fast structural compatibility screens to predict whether additional compounds bound by one protein would bind the other. The method reproduces 84% of complexes in a benchmark, and we make many predictions that would not be possible using conventional modeling techniques. Within 19,578 novel predicted interactions are 7,793 involving 718 drugs, including filaminast, coumarin, alitretonin and erlotinib. The growth rate of confident predictions is twice that of experimental complexes, meaning that a complete structural drug-protein repertoire will be available at least ten years earlier than by X-ray and NMR techniques alone.'),
(85008, 2011, 'plos', 'Temporal encoding in a nervous system', 'Aldworth, Zane N|Dimitrov, Alexander G|Cummins, Graham I|Gedeon, Tomáš|Miller, John P', 'Center for Computational Biology, Montana State University, Bozeman, Montana, United States of America. zane.aldworth@nih.gov|Center for Computational Biology, Montana State University, Bozeman, Montana, United States of America. zane.aldworth@nih.gov|Center for Computational Biology, Montana State University, Bozeman, Montana, United States of America. zane.aldworth@nih.gov|Center for Computational Biology, Montana State University, Bozeman, Montana, United States of America. zane.aldworth@nih.gov|Center for Computational Biology, Montana State University, Bozeman, Montana, United States of America. zane.aldworth@nih.gov', 'United States|United States|United States|United States|United States', 0, 'Action Potentials|Animals|Computational Biology|Computer Simulation|Female|Gryllidae|Information Theory|Linear Models|Models, Neurological|Nervous System Physiological Phenomena|Neurons|Nonlinear Dynamics|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1002041', '21573206', 'We examined the extent to which temporal encoding may be implemented by single neurons in the cercal sensory system of the house cricket Acheta domesticus. We found that these neurons exhibit a greater-than-expected coding capacity, due in part to an increased precision in brief patterns of action potentials. We developed linear and non-linear models for decoding the activity of these neurons. We found that the stimuli associated with short-interval patterns of spikes (ISIs of 8 ms or less) could be predicted better by second-order models as compared to linear models. Finally, we characterized the difference between these linear and second-order models in a low-dimensional subspace, and showed that modification of the linear models along only a few dimensions improved their predictive power to parity with the second order models. Together these results show that single neurons are capable of using temporal patterns of spikes as fundamental symbols in their neural code, and that they communicate specific stimulus distributions to subsequent neural structures.'),
(85009, 2011, 'plos', 'Identification of hammerhead ribozymes in all domains of life reveals novel structural variations', 'Perreault, Jonathan|Weinberg, Zasha|Roth, Adam|Popescu, Olivia|Chartrand, Pascal|Ferbeyre, Gerardo|Breaker, Ronald R', 'Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, United States of America.|Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, United States of America.|Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, United States of America.|Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, United States of America.|Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, United States of America.|Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, United States of America.|Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 76, 'Agrobacterium tumefaciens|Animals|Azorhizobium caulinodans|Base Sequence|Clostridium|Computational Biology|Genome|Humans|Magnesium|Models, Molecular|Molecular Sequence Data|Mutation|Nucleic Acid Conformation|Phylogeny|RNA, Bacterial|RNA, Catalytic|Swine', 'Journal Article', '10.1371/journal.pcbi.1002031', '21573207', 'Hammerhead ribozymes are small self-cleaving RNAs that promote strand scission by internal phosphoester transfer. Comparative sequence analysis was used to identify numerous additional representatives of this ribozyme class than were previously known, including the first representatives in fungi and archaea. Moreover, we have uncovered the first natural examples of type II hammerheads, and our findings reveal that this permuted form occurs in bacteria as frequently as type I and III architectures. We also identified a commonly occurring pseudoknot that forms a tertiary interaction critical for high-speed ribozyme activity. Genomic contexts of many hammerhead ribozymes indicate that they perform biological functions different from their known role in generating unit-length RNA transcripts of multimeric viroid and satellite virus genomes. In rare instances, nucleotide variation occurs at positions within the catalytic core that are otherwise strictly conserved, suggesting that core mutations are occasionally tolerated or preferred.'),
(85010, 2011, 'plos', 'Gene expression in the rodent brain is associated with its regional connectivity', 'Wolf, Lior|Goldberg, Chen|Manor, Nathan|Sharan, Roded|Ruppin, Eytan', 'Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel. wolf@cs.tau.ac.i|Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel. wolf@cs.tau.ac.i|Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel. wolf@cs.tau.ac.i|Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel. wolf@cs.tau.ac.i|Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel. wolf@cs.tau.ac.i', 'Israel|Israel|Israel|Israel|Israel', 0, 'Algorithms|Animals|Artificial Intelligence|Brain|Caenorhabditis elegans|Computational Biology|Databases, Factual|Gene Expression|Mice|Models, Neurological|Neural Pathways|Rats', 'Journal Article', '10.1371/journal.pcbi.1002040', '21573208', 'The putative link between gene expression of brain regions and their neural connectivity patterns is a fundamental question in neuroscience. Here this question is addressed in the first large scale study of a prototypical mammalian rodent brain, using a combination of rat brain regional connectivity data with gene expression of the mouse brain. Remarkably, even though this study uses data from two different rodent species (due to the data limitations), we still find that the connectivity of the majority of brain regions is highly predictable from their gene expression levels-the outgoing (incoming) connectivity is successfully predicted for 73% (56%) of brain regions, with an overall fairly marked accuracy level of 0.79 (0.83). Many genes are found to play a part in predicting both the incoming and outgoing connectivity (241 out of the 500 top selected genes, p-value<1e-5). Reassuringly, the genes previously known from the literature to be involved in axon guidance do carry significant information about regional brain connectivity. Surveying the genes known to be associated with the pathogenesis of several brain disorders, we find that those associated with schizophrenia, autism and attention deficit disorder are the most highly enriched in the connectivity-related genes identified here. Finally, we find that the profile of functional annotation groups that are associated with regional connectivity in the rodent is significantly correlated with the annotation profile of genes previously found to determine neural connectivity in C. elegans (Pearson correlation of 0.24, p<1e-6 for the outgoing connections and 0.27, p<1e-5 for the incoming). Overall, the association between connectivity and gene expression in a specific extant rodent species brain is likely to be even stronger than found here, given the limitations of current data.'),
(85011, 2011, 'plos', 'Emergence of switch-like behavior in a large family of simple biochemical networks', 'Siegal-Gaskins, Dan|Mejia-Guerra, Maria Katherine|Smith, Gregory D|Grotewold, Erich', 'Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio, United States of America. dsg@mbi.osu.edu|Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio, United States of America. dsg@mbi.osu.edu|Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio, United States of America. dsg@mbi.osu.edu|Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio, United States of America. dsg@mbi.osu.edu', 'United States|United States|United States|United States', 0, 'Computer Simulation|Gene Regulatory Networks|Genes, Fungal|Genomics|Models, Chemical|Models, Genetic|Protein Interaction Mapping|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins', 'Journal Article', '10.1371/journal.pcbi.1002039', '21589886', 'Bistability plays a central role in the gene regulatory networks (GRNs) controlling many essential biological functions, including cellular differentiation and cell cycle control. However, establishing the network topologies that can exhibit bistability remains a challenge, in part due to the exceedingly large variety of GRNs that exist for even a small number of components. We begin to address this problem by employing chemical reaction network theory in a comprehensive in silico survey to determine the capacity for bistability of more than 40,000 simple networks that can be formed by two transcription factor-coding genes and their associated proteins (assuming only the most elementary biochemical processes). We find that there exist reaction rate constants leading to bistability in xe2x88xbc90% of these GRN models, including several circuits that do not contain any of the TF cooperativity commonly associated with bistable systems, and the majority of which could only be identified as bistable through an original subnetwork-based analysis. A topological sorting of the two-gene family of networks based on the presence or absence of biochemical reactions reveals eleven minimal bistable networks (i.e., bistable networks that do not contain within them a smaller bistable subnetwork). The large number of previously unknown bistable network topologies suggests that the capacity for switch-like behavior in GRNs arises with relative ease and is not easily lost through network evolution. To highlight the relevance of the systematic application of CRNT to bistable network identification in real biological systems, we integrated publicly available protein-protein interaction, protein-DNA interaction, and gene expression data from Saccharomyces cerevisiae, and identified several GRNs predicted to behave in a bistable fashion.'),
(85012, 2011, 'plos', 'Transcriptional regulation: effects of promoter proximal pausing on speed, synchrony and reliability', 'Boettiger, Alistair N|Ralph, Peter L|Evans, Steven N', 'Biophysics Graduate Group and Department of Molecular and Cellular Biology, University of California, Berkeley, California, United States of America. alistair@berkeley.edu|Biophysics Graduate Group and Department of Molecular and Cellular Biology, University of California, Berkeley, California, United States of America. alistair@berkeley.edu|Biophysics Graduate Group and Department of Molecular and Cellular Biology, University of California, Berkeley, California, United States of America. alistair@berkeley.edu', 'United States|United States|United States', 0, 'Animals|Drosophila|Embryo, Nonmammalian|Enhancer Elements, Genetic|Markov Chains|Models, Genetic|Promoter Regions, Genetic|RNA Polymerase II|RNA, Messenger|Transcription Initiation Site|Transcription, Genetic|Transcriptional Activation', 'Journal Article', '10.1371/journal.pcbi.1001136', '21589887', 'Recent whole genome polymerase binding assays in the Drosophila embryo have shown that a substantial proportion of uninduced genes have pre-assembled RNA polymerase-II transcription initiation complex (PIC) bound to their promoters. These constitute a subset of promoter proximally paused genes for which mRNA elongation instead of promoter access is regulated. This difference can be described as a rearrangement of the regulatory topology to control the downstream transcriptional process of elongation rather than the upstream transcriptional initiation event. It has been shown experimentally that genes with the former mode of regulation tend to induce faster and more synchronously, and that promoter-proximal pausing is observed mainly in metazoans, in accord with a posited impact on synchrony. However, it has not been shown whether or not it is the change in the regulated step per se that is causal. We investigate this question by proposing and analyzing a continuous-time Markov chain model of PIC assembly regulated at one of two steps: initial polymerase association with DNA, or release from a paused, transcribing state. Our analysis demonstrates that, over a wide range of physical parameters, increased speed and synchrony are functional consequences of elongation control. Further, we make new predictions about the effect of elongation regulation on the consistent control of total transcript number between cells. We also identify which elements in the transcription induction pathway are most sensitive to molecular noise and thus possibly the most evolutionarily constrained. Our methods produce symbolic expressions for quantities of interest with reasonable computational effort and they can be used to explore the interplay between interaction topology and molecular noise in a broader class of biochemical networks. We provide general-purpose code implementing these methods.'),
(85013, 2011, 'plos', 'An imperfect dopaminergic error signal can drive temporal-difference learning', 'Potjans, Wiebke|Diesmann, Markus|Morrison, Abigail', 'Institute of Neuroscience and Medicine (INM-6), Computational and Systems Neuroscience, Research Center Jülich, Jülich, Germany. w.potjans@fz-juelich.de|Institute of Neuroscience and Medicine (INM-6), Computational and Systems Neuroscience, Research Center Jülich, Jülich, Germany. w.potjans@fz-juelich.de|Institute of Neuroscience and Medicine (INM-6), Computational and Systems Neuroscience, Research Center Jülich, Jülich, Germany. w.potjans@fz-juelich.de', 'Germany|Germany|Germany', 26, 'Action Potentials|Algorithms|Animals|Dopamine|Humans|Learning|Models, Neurological|Nerve Net|Neuronal Plasticity|Rats|Reward', 'Journal Article', '10.1371/journal.pcbi.1001133', '21589888', 'An open problem in the field of computational neuroscience is how to link synaptic plasticity to system-level learning. A promising framework in this context is temporal-difference (TD) learning. Experimental evidence that supports the hypothesis that the mammalian brain performs temporal-difference learning includes the resemblance of the phasic activity of the midbrain dopaminergic neurons to the TD error and the discovery that cortico-striatal synaptic plasticity is modulated by dopamine. However, as the phasic dopaminergic signal does not reproduce all the properties of the theoretical TD error, it is unclear whether it is capable of driving behavior adaptation in complex tasks. Here, we present a spiking temporal-difference learning model based on the actor-critic architecture. The model dynamically generates a dopaminergic signal with realistic firing rates and exploits this signal to modulate the plasticity of synapses as a third factor. The predictions of our proposed plasticity dynamics are in good agreement with experimental results with respect to dopamine, pre- and post-synaptic activity. An analytical mapping from the parameters of our proposed plasticity dynamics to those of the classical discrete-time TD algorithm reveals that the biological constraints of the dopaminergic signal entail a modified TD algorithm with self-adapting learning parameters and an adapting offset. We show that the neuronal network is able to learn a task with sparse positive rewards as fast as the corresponding classical discrete-time TD algorithm. However, the performance of the neuronal network is impaired with respect to the traditional algorithm on a task with both positive and negative rewards and breaks down entirely on a task with purely negative rewards. Our model demonstrates that the asymmetry of a realistic dopaminergic signal enables TD learning when learning is driven by positive rewards but not when driven by negative rewards.'),
(85014, 2011, 'plos', 'Epistasis in a model of molecular signal transduction', 'Pumir, Alain|Shraiman, Boris', 'Laboratoire de Physique, Ecole Normale Supérieure de Lyon, Lyon, France.|Laboratoire de Physique, Ecole Normale Supérieure de Lyon, Lyon, France.', 'France|France', 11, 'Animals|Epistasis, Genetic|Genetic Loci|Light Signal Transduction|Models, Genetic|Models, Statistical|Polymorphism, Genetic|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1001134', '21589889', 'Biological functions typically involve complex interacting molecular networks, with numerous feedback and regulation loops. How the properties of the system are affected when one, or several of its parts are modified is a question of fundamental interest, with numerous implications for the way we study and understand biological processes and treat diseases. This question can be rephrased in terms of relating genotypes to phenotypes: to what extent does the effect of a genetic variation at one locus depend on genetic variation at all other loci? Systematic quantitative measurements of epistasis--the deviation from additivity in the effect of alleles at different loci--on a given quantitative trait remain a major challenge. Here, we take a complementary approach of studying theoretically the effect of varying multiple parameters in a validated model of molecular signal transduction. To connect with the genotype/phenotype mapping we interpret parameters of the model as different loci with discrete choices of these parameters as alleles, which allows us to systematically examine the dependence of the signaling output--a quantitative trait--on the set of possible allelic combinations. We show quite generally that quantitative traits behave approximately additively (weak epistasis) when alleles correspond to small changes of parameters, epistasis appears as a result of large differences between alleles. When epistasis is relatively strong, it is concentrated in a sparse subset of loci and in low order (e.g. pair-wise) interactions. We find that focusing on interaction between loci that exhibit strong additive effects is an efficient way of identifying most of the epistasis. Our model study defines a theoretical framework for interpretation of experimental data and provides statistical predictions for the structure of genetic interaction expected for moderately complex biological circuits.'),
(85015, 2011, 'plos', 'Quantitative epistasis analysis and pathway inference from genetic interaction data', 'Phenix, Hilary|Morin, Katy|Batenchuk, Cory|Parker, Jacob|Abedi, Vida|Yang, Liu|Tepliakova, Lioudmila|Perkins, Theodore J|Kærn, Mads', 'Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada.|Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada.|Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada.|Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada.|Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada.|Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada.|Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada.|Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada.|Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada.', 'Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada', 0, 'Computational Biology|Epistasis, Genetic|Galactose|Gene Deletion|Gene Expression Regulation, Fungal|Gene Regulatory Networks|Genes, Fungal|Metabolic Networks and Pathways|Models, Genetic|Phenotype|Saccharomyces cerevisiae|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002048', '21589890', 'Inferring regulatory and metabolic network models from quantitative genetic interaction data remains a major challenge in systems biology. Here, we present a novel quantitative model for interpreting epistasis within pathways responding to an external signal. The model provides the basis of an experimental method to determine the architecture of such pathways, and establishes a new set of rules to infer the order of genes within them. The method also allows the extraction of quantitative parameters enabling a new level of information to be added to genetic network models. It is applicable to any system where the impact of combinatorial loss-of-function mutations can be quantified with sufficient accuracy. We test the method by conducting a systematic analysis of a thoroughly characterized eukaryotic gene network, the galactose utilization pathway in Saccharomyces cerevisiae. For this purpose, we quantify the effects of single and double gene deletions on two phenotypic traits, fitness and reporter gene expression. We show that applying our method to fitness traits reveals the order of metabolic enzymes and the effects of accumulating metabolic intermediates. Conversely, the analysis of expression traits reveals the order of transcriptional regulatory genes, secondary regulatory signals and their relative strength. Strikingly, when the analyses of the two traits are combined, the method correctly infers ~80% of the known relationships without any false positives.'),
(85016, 2011, 'plos', 'Exhaustive sampling of docking poses reveals binding hypotheses for propafenone type inhibitors of P-glycoprotein', 'Klepsch, Freya|Chiba, Peter|Ecker, Gerhard F', 'Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.|Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.|Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.', 'Austria|Austria|Austria', 63, 'ATP Binding Cassette Transporter, Subfamily B, Member 1|Amino Acid Sequence|Animals|Binding Sites|Cluster Analysis|Drug Discovery|Humans|Mice|Models, Molecular|Propafenone|Protein Binding|Structural Homology, Protein|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1002036', '21589945', 'Overexpression of the xenotoxin transporter P-glycoprotein (P-gp) represents one major reason for the development of multidrug resistance (MDR), leading to the failure of antibiotic and cancer therapies. Inhibitors of P-gp have thus been advocated as promising candidates for overcoming the problem of MDR. However, due to lack of a high-resolution structure the concrete mode of interaction of both substrates and inhibitors is still not known. Therefore, structure-based design studies have to rely on protein homology models. In order to identify binding hypotheses for propafenone-type P-gp inhibitors, five different propafenone derivatives with known structure-activity relationship (SAR) pattern were docked into homology models of the apo and the nucleotide-bound conformation of the transporter. To circumvent the uncertainty of scoring functions, we exhaustively sampled the pose space and analyzed the poses by combining information retrieved from SAR studies with common scaffold clustering. The results suggest propafenone binding at the transmembrane helices 5, 6, 7 and 8 in both models, with the amino acid residue Y307 playing a crucial role. The identified binding site in the non-energized state is overlapping with, but not identical to, known binding areas of cyclic P-gp inhibitors and verapamil. These findings support the idea of several small binding sites forming one large binding cavity. Furthermore, the binding hypotheses for both catalytic states were analyzed and showed only small differences in their protein-ligand interaction fingerprints, which indicates only small movements of the ligand during the catalytic cycle.'),
(85017, 2011, 'plos', 'deFuse: an algorithm for gene fusion discovery in tumor RNA-Seq data', 'McPherson, Andrew|Hormozdiari, Fereydoun|Zayed, Abdalnasser|Giuliany, Ryan|Ha, Gavin|Sun, Mark G F|Griffith, Malachi|Heravi Moussavi, Alireza|Senz, Janine|Melnyk, Nataliya|Pacheco, Marina|Marra, Marco A|Hirst, Martin|Nielsen, Torsten O|Sahinalp, S Cenk|Huntsman, David|Shah, Sohrab P', 'Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada.', 'Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Canada|Ca', 342, 'Algorithms|Base Sequence|Carcinoma|Cell Line, Tumor|Female|Gene Expression Regulation, Neoplastic|Humans|Male|Melanoma|Molecular Sequence Data|Mutation|Oncogene Fusion|Ovarian Neoplasms|Prostatic Neoplasms|Sarcoma|Sequence Analysis, RNA|Skin Neoplasms', 'Journal Article', '10.1371/journal.pcbi.1001138', '21625565', 'Gene fusions created by somatic genomic rearrangements are known to play an important role in the onset and development of some cancers, such as lymphomas and sarcomas. RNA-Seq (whole transcriptome shotgun sequencing) is proving to be a useful tool for the discovery of novel gene fusions in cancer transcriptomes. However, algorithmic methods for the discovery of gene fusions using RNA-Seq data remain underdeveloped. We have developed deFuse, a novel computational method for fusion discovery in tumor RNA-Seq data. Unlike existing methods that use only unique best-hit alignments and consider only fusion boundaries at the ends of known exons, deFuse considers all alignments and all possible locations for fusion boundaries. As a result, deFuse is able to identify fusion sequences with demonstrably better sensitivity than previous approaches. To increase the specificity of our approach, we curated a list of 60 true positive and 61 true negative fusion sequences (as confirmed by RT-PCR), and have trained an adaboost classifier on 11 novel features of the sequence data. The resulting classifier has an estimated value of 0.91 for the area under the ROC curve. We have used deFuse to discover gene fusions in 40 ovarian tumor samples, one ovarian cancer cell line, and three sarcoma samples. We report herein the first gene fusions discovered in ovarian cancer. We conclude that gene fusions are not infrequent events in ovarian cancer and that these events have the potential to substantially alter the expression patterns of the genes involved, gene fusions should therefore be considered in efforts to comprehensively characterize the mutational profiles of ovarian cancer transcriptomes.'),
(85018, 2011, 'plos', 'A toolbox model of evolution of metabolic pathways on networks of arbitrary topology', 'Pang, Tin Yau|Maslov, Sergei', 'Department of Condensed Matter Physics and Materials Science, Brookhaven National Laboratory, Upton, New York, United States of America.|Department of Condensed Matter Physics and Materials Science, Brookhaven National Laboratory, Upton, New York, United States of America.', 'United States|United States', 0, 'Computer Simulation|Evolution, Molecular|Metabolic Networks and Pathways|Models, Biological|Prokaryotic Cells|Regulon', 'Journal Article', '10.1371/journal.pcbi.1001137', '21625566', 'In prokaryotic genomes the number of transcriptional regulators is known to be proportional to the square of the total number of protein-coding genes. A toolbox model of evolution was recently proposed to explain this empirical scaling for metabolic enzymes and their regulators. According to its rules, the metabolic network of an organism evolves by horizontal transfer of pathways from other species. These pathways are part of a larger universal network formed by the union of all species-specific networks. It remained to be understood, however, how the topological properties of this universal network influence the scaling law of functional content of genomes in the toolbox model. Here we answer this question by first analyzing the scaling properties of the toolbox model on arbitrary tree-like universal networks. We prove that critical branching topology, in which the average number of upstream neighbors of a node is equal to one, is both necessary and sufficient for quadratic scaling. We further generalize the rules of the model to incorporate reactions with multiple substrates/products as well as branched and cyclic metabolic pathways. To achieve its metabolic tasks, the new model employs evolutionary optimized pathways with minimal number of reactions. Numerical simulations of this realistic model on the universal network of all reactions in the KEGG database produced approximately quadratic scaling between the number of regulated pathways and the size of the metabolic network. To quantify the geometrical structure of individual pathways, we investigated the relationship between their number of reactions, byproducts, intermediate, and feedback metabolites. Our results validate and explain the ubiquitous appearance of the quadratic scaling for a broad spectrum of topologies of underlying universal metabolic networks. They also demonstrate why, in spite of small-world topology, real-life metabolic networks are characterized by a broad distribution of pathway lengths and sizes of metabolic regulons in regulatory networks.'),
(85019, 2011, 'plos', 'Spatial learning and action planning in a prefrontal cortical network model', 'Martinet, Louis-Emmanuel|Sheynikhovich, Denis|Benchenane, Karim|Arleo, Angelo', 'Laboratory of Neurobiology of Adaptive Processes, UMR 7102, CNRS-UPMC Univ P6, Paris, France.|Laboratory of Neurobiology of Adaptive Processes, UMR 7102, CNRS-UPMC Univ P6, Paris, France.|Laboratory of Neurobiology of Adaptive Processes, UMR 7102, CNRS-UPMC Univ P6, Paris, France.|Laboratory of Neurobiology of Adaptive Processes, UMR 7102, CNRS-UPMC Univ P6, Paris, France.', 'France|France|France|France', 46, 'Animals|Cognition|Hippocampus|Learning|Models, Neurological|Nerve Net|Prefrontal Cortex|Rats|Spatial Behavior', 'Journal Article', '10.1371/journal.pcbi.1002045', '21625569', 'The interplay between hippocampus and prefrontal cortex (PFC) is fundamental to spatial cognition. Complementing hippocampal place coding, prefrontal representations provide more abstract and hierarchically organized memories suitable for decision making. We model a prefrontal network mediating distributed information processing for spatial learning and action planning. Specific connectivity and synaptic adaptation principles shape the recurrent dynamics of the network arranged in cortical minicolumns. We show how the PFC columnar organization is suitable for learning sparse topological-metrical representations from redundant hippocampal inputs. The recurrent nature of the network supports multilevel spatial processing, allowing structural features of the environment to be encoded. An activation diffusion mechanism spreads the neural activity through the column population leading to trajectory planning. The model provides a functional framework for interpreting the activity of PFC neurons recorded during navigation tasks. We illustrate the link from single unit activity to behavioral responses. The results suggest plausible neural mechanisms subserving the cognitive insight capability originally attributed to rodents by Tolman & Honzik. Our time course analysis of neural responses shows how the interaction between hippocampus and PFC can yield the encoding of manifold information pertinent to spatial planning, including prospective coding and distance-to-goal correlates.'),
(85020, 2011, 'plos', 'Cellularly-driven differences in network synchronization propensity are differentially modulated by firing frequency', 'Fink, Christian G|Booth, Victoria|Zochowski, Michal', 'Department of Physics, University of Michigan, Ann Arbor, Michigan, United States of America. tcgfink@umich.edu|Department of Physics, University of Michigan, Ann Arbor, Michigan, United States of America. tcgfink@umich.edu|Department of Physics, University of Michigan, Ann Arbor, Michigan, United States of America. tcgfink@umich.edu', 'United States|United States|United States', 0, 'Action Potentials|Cerebral Cortex|Computer Simulation|Cortical Synchronization|Humans|Models, Neurological|Nerve Net|Neurons|Pyramidal Cells', 'Journal Article', '10.1371/journal.pcbi.1002062', '21625571', 'Spatiotemporal pattern formation in neuronal networks depends on the interplay between cellular and network synchronization properties. The neuronal phase response curve (PRC) is an experimentally obtainable measure that characterizes the cellular response to small perturbations, and can serve as an indicator of cellular propensity for synchronization. Two broad classes of PRCs have been identified for neurons: Type I, in which small excitatory perturbations induce only advances in firing, and Type II, in which small excitatory perturbations can induce both advances and delays in firing. Interestingly, neuronal PRCs are usually attenuated with increased spiking frequency, and Type II PRCs typically exhibit a greater attenuation of the phase delay region than of the phase advance region. We found that this phenomenon arises from an interplay between the time constants of active ionic currents and the interspike interval. As a result, excitatory networks consisting of neurons with Type I PRCs responded very differently to frequency modulation compared to excitatory networks composed of neurons with Type II PRCs. Specifically, increased frequency induced a sharp decrease in synchrony of networks of Type II neurons, while frequency increases only minimally affected synchrony in networks of Type I neurons. These results are demonstrated in networks in which both types of neurons were modeled generically with the Morris-Lecar model, as well as in networks consisting of Hodgkin-Huxley-based model cortical pyramidal cells in which simulated effects of acetylcholine changed PRC type. These results are robust to different network structures, synaptic strengths and modes of driving neuronal activity, and they indicate that Type I and Type II excitatory networks may display two distinct modes of processing information.'),
(85021, 2011, 'plos', 'A multiscale approach to characterize the early aggregation steps of the amyloid-forming peptide GNNQQNY from the yeast prion sup-35', 'Nasica-Labouze, Jessica|Meli, Massimiliano|Derreumaux, Philippe|Colombo, Giorgio|Mousseau, Normand', 'Département de Physique and GEPROM, Université de Montréal, Montréal, Québec, Canada.|Département de Physique and GEPROM, Université de Montréal, Montréal, Québec, Canada.|Département de Physique and GEPROM, Université de Montréal, Montréal, Québec, Canada.|Département de Physique and GEPROM, Université de Montréal, Montréal, Québec, Canada.|Département de Physique and GEPROM, Université de Montréal, Montréal, Québec, Canada.', 'Canada|Canada|Canada|Canada|Canada', 61, 'Amyloid|Molecular Dynamics Simulation|Oligopeptides|Peptide Termination Factors|Prions|Protein Conformation|Saccharomyces cerevisiae Proteins', 'Journal Article', '10.1371/journal.pcbi.1002051', '21625573', 'The self-organization of peptides into amyloidogenic oligomers is one of the key events for a wide range of molecular and degenerative diseases. Atomic-resolution characterization of the mechanisms responsible for the aggregation process and the resulting structures is thus a necessary step to improve our understanding of the determinants of these pathologies. To address this issue, we combine the accelerated sampling properties of replica exchange molecular dynamics simulations based on the OPEP coarse-grained potential with the atomic resolution description of interactions provided by all-atom MD simulations, and investigate the oligomerization process of the GNNQQNY for three system sizes: 3-mers, 12-mers and 20-mers. Results for our integrated simulations show a rich variety of structural arrangements for aggregates of all sizes. Elongated fibril-like structures can form transiently in the 20-mer case, but they are not stable and easily interconvert in more globular and disordered forms. Our extensive characterization of the intermediate structures and their physico-chemical determinants points to a high degree of polymorphism for the GNNQQNY sequence that can be reflected at the macroscopic scale. Detailed mechanisms and structures that underlie amyloid aggregation are also provided.'),
(85022, 2011, 'plos', 'Attracting dynamics of frontal cortex ensembles during memory-guided decision-making', 'Balaguer-Ballester, Emili|Lapish, Christopher C|Seamans, Jeremy K|Durstewitz, Daniel', 'Bernstein-Center for Computational Neuroscience Heidelberg-Mannheim, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. emili.balaguer@zi-mannheim.de|Bernstein-Center for Computational Neuroscience Heidelberg-Mannheim, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. emili.balaguer@zi-mannheim.de|Bernstein-Center for Computational Neuroscience Heidelberg-Mannheim, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. emili.balaguer@zi-mannheim.de|Bernstein-Center for Computational Neuroscience Heidelberg-Mannheim, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. emili.balaguer@zi-mannheim.de', 'Germany|Germany|Germany|Germany', 41, 'Animals|Decision Making|Frontal Lobe|Gyrus Cinguli|Maze Learning|Memory|Nerve Net|Neurons|Rats', 'Journal Article', '10.1371/journal.pcbi.1002057', '21625577', 'A common theoretical view is that attractor-like properties of neuronal dynamics underlie cognitive processing. However, although often proposed theoretically, direct experimental support for the convergence of neural activity to stable population patterns as a signature of attracting states has been sparse so far, especially in higher cortical areas. Combining state space reconstruction theorems and statistical learning techniques, we were able to resolve details of anterior cingulate cortex (ACC) multiple single-unit activity (MSUA) ensemble dynamics during a higher cognitive task which were not accessible previously. The approach worked by constructing high-dimensional state spaces from delays of the original single-unit firing rate variables and the interactions among them, which were then statistically analyzed using kernel methods. We observed cognitive-epoch-specific neural ensemble states in ACC which were stable across many trials (in the sense of being predictive) and depended on behavioral performance. More interestingly, attracting properties of these cognitively defined ensemble states became apparent in high-dimensional expansions of the MSUA spaces due to a proper unfolding of the neural activity flow, with properties common across different animals. These results therefore suggest that ACC networks may process different subcomponents of higher cognitive tasks by transiting among different attracting states.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85023, 2011, 'plos', 'Topological cluster analysis reveals the systemic organization of the Caenorhabditis elegans connectome', 'Sohn, Yunkyu|Choi, Myung-Kyu|Ahn, Yong-Yeol|Lee, Junho|Jeong, Jaeseung', 'Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.|Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.|Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.|Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.|Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.', '-|-|-|-|-', 37, 'Animals|Caenorhabditis elegans|Cluster Analysis|Models, Neurological|Nerve Net|Neurons|Synapses', 'Journal Article', '10.1371/journal.pcbi.1001139', '21625578', 'The modular organization of networks of individual neurons interwoven through synapses has not been fully explored due to the incredible complexity of the connectivity architecture. Here we use the modularity-based community detection method for directed, weighted networks to examine hierarchically organized modules in the complete wiring diagram (connectome) of Caenorhabditis elegans (C. elegans) and to investigate their topological properties. Incorporating bilateral symmetry of the network as an important cue for proper cluster assignment, we identified anatomical clusters in the C. elegans connectome, including a body-spanning cluster, which correspond to experimentally identified functional circuits. Moreover, the hierarchical organization of the five clusters explains the systemic cooperation (e.g., mechanosensation, chemosensation, and navigation) that occurs among the structurally segregated biological circuits to produce higher-order complex behaviors.'),
(85024, 2011, 'plos', 'Integrative analysis of transgenic alfalfa (Medicago sativa L) suggests new metabolic control mechanisms for monolignol biosynthesis', 'Lee, Yun|Chen, Fang|Gallego-Giraldo, Lina|Dixon, Richard A|Voit, Eberhard O', 'Integrative BioSystems Institute and The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, United States of America.|Integrative BioSystems Institute and The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, United States of America.|Integrative BioSystems Institute and The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, United States of America.|Integrative BioSystems Institute and The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, United States of America.|Integrative BioSystems Institute and The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, United States of America.', 'Georgia|Georgia|Georgia|Georgia|Georgia', 46, 'Alcohols|Computer Simulation|Lignin|Medicago sativa|Metabolomics|Monte Carlo Method|Plants, Genetically Modified|Salicylic Acid', 'Journal Article', '10.1371/journal.pcbi.1002047', '21625579', 'The entanglement of lignin polymers with cellulose and hemicellulose in plant cell walls is a major biological barrier to the economically viable production of biofuels from woody biomass. Recent efforts of reducing this recalcitrance with transgenic techniques have been showing promise for ameliorating or even obviating the need for costly pretreatments that are otherwise required to remove lignin from cellulose and hemicelluloses. At the same time, genetic manipulations of lignin biosynthetic enzymes have sometimes yielded unforeseen consequences on lignin composition, thus raising the question of whether the current understanding of the pathway is indeed correct. To address this question systemically, we developed and applied a novel modeling approach that, instead of analyzing the pathway within a single target context, permits a comprehensive, simultaneous investigation of different datasets in wild type and transgenic plants. Specifically, the proposed approach combines static flux-based analysis with a Monte Carlo simulation in which very many randomly chosen sets of parameter values are evaluated against kinetic models of lignin biosynthesis in different stem internodes of wild type and lignin-modified alfalfa plants. In addition to four new postulates that address the reversibility of some key reactions, the modeling effort led to two novel postulates regarding the control of the lignin biosynthetic pathway. The first posits functionally independent pathways toward the synthesis of different lignin monomers, while the second postulate proposes a novel feedforward regulatory mechanism. Subsequent laboratory experiments have identified the signaling molecule salicylic acid as a potential mediator of the postulated control mechanism. Overall, the results demonstrate that mathematical modeling can be a valuable complement to conventional transgenic approaches and that it can provide biological insights that are otherwise difficult to obtain.'),
(85025, 2011, 'plos', 'How structure determines correlations in neuronal networks', 'Pernice, Volker|Staude, Benjamin|Cardanobile, Stefano|Rotter, Stefan', 'Bernstein Center Freiburg, Freiburg, Germany. pernice@bcf.uni-freiburg.de|Bernstein Center Freiburg, Freiburg, Germany. pernice@bcf.uni-freiburg.de|Bernstein Center Freiburg, Freiburg, Germany. pernice@bcf.uni-freiburg.de|Bernstein Center Freiburg, Freiburg, Germany. pernice@bcf.uni-freiburg.de', 'Germany|Germany|Germany|Germany', 128, 'Algorithms|Animals|Computer Simulation|Mice|Models, Neurological|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.1002059', '21625580', 'Networks are becoming a ubiquitous metaphor for the understanding of complex biological systems, spanning the range between molecular signalling pathways, neural networks in the brain, and interacting species in a food web. In many models, we face an intricate interplay between the topology of the network and the dynamics of the system, which is generally very hard to disentangle. A dynamical feature that has been subject of intense research in various fields are correlations between the noisy activity of nodes in a network. We consider a class of systems, where discrete signals are sent along the links of the network. Such systems are of particular relevance in neuroscience, because they provide models for networks of neurons that use action potentials for communication. We study correlations in dynamic networks with arbitrary topology, assuming linear pulse coupling. With our novel approach, we are able to understand in detail how specific structural motifs affect pairwise correlations. Based on a power series decomposition of the covariance matrix, we describe the conditions under which very indirect interactions will have a pronounced effect on correlations and population dynamics. In random networks, we find that indirect interactions may lead to a broad distribution of activation levels with low average but highly variable correlations. This phenomenon is even more pronounced in networks with distance dependent connectivity. In contrast, networks with highly connected hubs or patchy connections often exhibit strong average correlations. Our results are particularly relevant in view of new experimental techniques that enable the parallel recording of spiking activity from a large number of neurons, an appropriate interpretation of which is hampered by the currently limited understanding of structure-dynamics relations in complex networks.'),
(85026, 2011, 'plos', 'Speed/accuracy trade-off between the habitual and the goal-directed processes', 'Keramati, Mehdi|Dezfouli, Amir|Piray, Payam', 'School of Management and Economics, Sharif University of Technology, Tehran, Iran. mohammadmahdi.keramati@ens.fr|School of Management and Economics, Sharif University of Technology, Tehran, Iran. mohammadmahdi.keramati@ens.fr|School of Management and Economics, Sharif University of Technology, Tehran, Iran. mohammadmahdi.keramati@ens.fr', '-|-|-', 160, 'Algorithms|Animals|Behavior, Animal|Choice Behavior|Computer Simulation|Decision Making|Dopamine|Goals|Humans|Learning|Markov Chains|Maze Learning|Models, Neurological|Neurons|Rats|Reinforcement (Psychology)|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1002055', '21637741', 'Instrumental responses are hypothesized to be of two kinds: habitual and goal-directed, mediated by the sensorimotor and the associative cortico-basal ganglia circuits, respectively. The existence of the two heterogeneous associative learning mechanisms can be hypothesized to arise from the comparative advantages that they have at different stages of learning. In this paper, we assume that the goal-directed system is behaviourally flexible, but slow in choice selection. The habitual system, in contrast, is fast in responding, but inflexible in adapting its behavioural strategy to new conditions. Based on these assumptions and using the computational theory of reinforcement learning, we propose a normative model for arbitration between the two processes that makes an approximately optimal balance between search-time and accuracy in decision making. Behaviourally, the model can explain experimental evidence on behavioural sensitivity to outcome at the early stages of learning, but insensitivity at the later stages. It also explains that when two choices with equal incentive values are available concurrently, the behaviour remains outcome-sensitive, even after extensive training. Moreover, the model can explain choice reaction time variations during the course of learning, as well as the experimental observation that as the number of choices increases, the reaction time also increases. Neurobiologically, by assuming that phasic and tonic activities of midbrain dopamine neurons carry the reward prediction error and the average reward signals used by the model, respectively, the model predicts that whereas phasic dopamine indirectly affects behaviour through reinforcing stimulus-response associations, tonic dopamine can directly affect behaviour through manipulating the competition between the habitual and the goal-directed systems and thus, affect reaction time.'),
(85027, 2011, 'plos', 'How modeling can reconcile apparently discrepant experimental results: the case of pacemaking in dopaminergic neurons', 'Drion, Guillaume|Massotte, Laurent|Sepulchre, Rodolphe|Seutin, Vincent', 'Laboratory of Pharmacology and GIGA Neurosciences, University of Liège, Liège, Belgium.|Laboratory of Pharmacology and GIGA Neurosciences, University of Liège, Liège, Belgium.|Laboratory of Pharmacology and GIGA Neurosciences, University of Liège, Liège, Belgium.|Laboratory of Pharmacology and GIGA Neurosciences, University of Liège, Liège, Belgium.', 'Belgium|Belgium|Belgium|Belgium', 51, 'Action Potentials|Analysis of Variance|Animals|Calcium Channels|Computational Biology|Dopamine|Dopamine Agents|Male|Mesencephalon|Models, Biological|Neurons|Rats|Rats, Wistar|Sodium Channels', 'Journal Article', '10.1371/journal.pcbi.1002050', '21637742', 'Midbrain dopaminergic neurons are endowed with endogenous slow pacemaking properties. In recent years, many different groups have studied the basis for this phenomenon, often with conflicting conclusions. In particular, the role of a slowly-inactivating L-type calcium channel in the depolarizing phase between spikes is controversial, and the analysis of slow oscillatory potential (SOP) recordings during the blockade of sodium channels has led to conflicting conclusions. Based on a minimal model of a dopaminergic neuron, our analysis suggests that the same experimental protocol may lead to drastically different observations in almost identical neurons. For example, complete L-type calcium channel blockade eliminates spontaneous firing or has almost no effect in two neurons differing by less than 1% in their maximal sodium conductance. The same prediction can be reproduced in a state of the art detailed model of a dopaminergic neuron. Some of these predictions are confirmed experimentally using single-cell recordings in brain slices. Our minimal model exhibits SOPs when sodium channels are blocked, these SOPs being uncorrelated with the spiking activity, as has been shown experimentally. We also show that block of a specific conductance (in this case, the SK conductance) can have a different effect on these two oscillatory behaviors (pacemaking and SOPs), despite the fact that they have the same initiating mechanism. These results highlight the fact that computational approaches, besides their well known confirmatory and predictive interests in neurophysiology, may also be useful to resolve apparent discrepancies between experimental results.'),
(85028, 2011, 'plos', 'Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation', 'OHara, Thomas|Virág, László|Varró, András|Rudy, Yoram', 'Cardiac Bioelectricity and Arrhythmia Center, Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri, USA.|Cardiac Bioelectricity and Arrhythmia Center, Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri, USA.|Cardiac Bioelectricity and Arrhythmia Center, Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri, USA.|Cardiac Bioelectricity and Arrhythmia Center, Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri, USA.', 'United States|United States|United States|United States', 586, 'Action Potentials|Arrhythmias, Cardiac|Calcium Channels, L-Type|Calmodulin|Computational Biology|Heart Ventricles|Humans|Models, Cardiovascular|Myocytes, Cardiac|Patch-Clamp Techniques|Reproducibility of Results|Sodium Channels|Ventricular Function', 'Journal Article', '10.1371/journal.pcbi.1002061', '21637795', 'Cellular electrophysiology experiments, important for understanding cardiac arrhythmia mechanisms, are usually performed with channels expressed in non myocytes, or with non-human myocytes. Differences between cell types and species affect results. Thus, an accurate model for the undiseased human ventricular action potential (AP) which reproduces a broad range of physiological behaviors is needed. Such a model requires extensive experimental data, but essential elements have been unavailable. Here, we develop a human ventricular AP model using new undiseased human ventricular data: Ca(2+) versus voltage dependent inactivation of L-type Ca(2+) current (I(CaL)), kinetics for the transient outward, rapid delayed rectifier (I(Kr)), Na(+)/Ca(2+) exchange (I(NaCa)), and inward rectifier currents, AP recordings at all physiological cycle lengths, and rate dependence and restitution of AP duration (APD) with and without a variety of specific channel blockers. Simulated APs reproduced the experimental AP morphology, APD rate dependence, and restitution. Using undiseased human mRNA and protein data, models for different transmural cell types were developed. Experiments for rate dependence of Ca(2+) (including peak and decay) and intracellular sodium ([Na(+)](i)) in undiseased human myocytes were quantitatively reproduced by the model. Early afterdepolarizations were induced by I(Kr) block during slow pacing, and AP and Ca(2+) alternans appeared at rates >200 bpm, as observed in the nonfailing human ventricle. Ca(2+)/calmodulin-dependent protein kinase II (CaMK) modulated rate dependence of Ca(2+) cycling. I(NaCa) linked Ca(2+) alternation to AP alternans. CaMK suppression or SERCA upregulation eliminated alternans. Steady state APD rate dependence was caused primarily by changes in [Na(+)](i), via its modulation of the electrogenic Na(+)/K(+) ATPase current. At fast pacing rates, late Na(+) current and I(CaL) were also contributors. APD shortening during restitution was primarily dependent on reduced late Na(+) and I(CaL) currents due to inactivation at short diastolic intervals, with additional contribution from elevated I(Kr) due to incomplete deactivation.'),
(85029, 2011, 'plos', 'Pathway analysis of expression data: deciphering functional building blocks of complex diseases', 'Emmert-Streib, Frank|Glazko, Galina V', 'Computational Biology and Machine Learning Lab, Center for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Belfast, United Kingdom. v@bio-complexity.com|Computational Biology and Machine Learning Lab, Center for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Belfast, United Kingdom. v@bio-complexity.com', 'United Kingdom|United Kingdom', 70, 'Animals|Data Interpretation, Statistical|Databases, Genetic|Diabetes Mellitus, Type 2|Disease|Gene Expression|Humans|Oligonucleotide Array Sequence Analysis|Signal Transduction|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002053', '21637797', '-'),
(85030, 2011, 'plos', 'An acidic loop and cognate phosphorylation sites define a molecular switch that modulates ubiquitin charging activity in Cdc34-like enzymes', 'Papaleo, Elena|Ranzani, Valeria|Tripodi, Farida|Vitriolo, Alessandro|Cirulli, Claudia|Fantucci, Piercarlo|Alberghina, Lilia|Vanoni, Marco|De Gioia, Luca|Coccetti, Paola', 'Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy. elena.papaleo@unimib.it|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy. elena.papaleo@unimib.it|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy. elena.papaleo@unimib.it|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy. elena.papaleo@unimib.it|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy. elena.papaleo@unimib.it|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy. elena.papaleo@unimib.it|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy. elena.papaleo@unimib.it|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy. elena.papaleo@unimib.it|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy. elena.papaleo@unimib.it|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy. elena.papaleo@unimib.it', 'Italy|Italy|Italy|Italy|Italy|Italy|Italy|Italy|Italy|Italy', 24, 'Amino Acid Sequence|Anaphase-Promoting Complex-Cyclosome|Humans|Molecular Dynamics Simulation|Molecular Sequence Annotation|Molecular Sequence Data|Phosphorylation|Principal Component Analysis|Protein Structure, Tertiary|Recombinant Proteins|Saccharomyces cerevisiae Proteins|Thermodynamics|Ubiquitin|Ubiquitin-Conjugating Enzymes|Ubiquitin-Protein Ligase Complexes', 'Journal Article', '10.1371/journal.pcbi.1002056', '21637798', 'E2 ubiquitin-conjugating enzymes are crucial mediators of protein ubiquitination, which strongly influence the ultimate fate of the target substrates. Recently, it has been shown that the activity of several enzymes of the ubiquitination pathway is finely tuned by phosphorylation, an ubiquitous mechanism for cellular regulation, which modulates protein conformation. In this contribution, we provide the first rationale, at the molecular level, of the regulatory mechanism mediated by casein kinase 2 (CK2) phosphorylation of E2 Cdc34-like enzymes. In particular, we identify two co-evolving signature elements in one of the larger families of E2 enzymes: an acidic insertion in xcexb24xcexb12 loop in the proximity of the catalytic cysteine and two conserved key serine residues within the catalytic domain, which are phosphorylated by CK2. Our investigations, using yeast Cdc34 as a model, through 2.5 xc2xb5s molecular dynamics simulations and biochemical assays, define these two elements as an important phosphorylation-controlled switch that modulates opening and closing of the catalytic cleft. The mechanism relies on electrostatic repulsions between a conserved serine phosphorylated by CK2 and the acidic residues of the xcexb24xcexb12 loop, promoting E2 ubiquitin charging activity. Our investigation identifies a new and unexpected pivotal role for the acidic loop, providing the first evidence that this loop is crucial not only for downstream events related to ubiquitin chain assembly, but is also mandatory for the modulation of an upstream crucial step of the ubiquitin pathway: the ubiquitin charging in the E2 catalytic cleft.'),
(85031, 2011, 'plos', 'A role for both conformational selection and induced fit in ligand binding by the LAO protein', 'Silva, Daniel-Adriano|Bowman, Gregory R|Sosa-Peinado, Alejandro|Huang, Xuhui', 'Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.|Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.|Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.|Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.', 'Hong Kong|Hong Kong|Hong Kong|Hong Kong', 141, 'Arginine|Bacterial Proteins|Carrier Proteins|Holoenzymes|Markov Chains|Molecular Dynamics Simulation|Protein Binding|Salmonella typhimurium|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002054', '21637799', 'Molecular recognition is determined by the structure and dynamics of both a protein and its ligand, but it is difficult to directly assess the role of each of these players. In this study, we use Markov State Models (MSMs) built from atomistic simulations to elucidate the mechanism by which the Lysine-, Arginine-, Ornithine-binding (LAO) protein binds to its ligand. We show that our model can predict the bound state, binding free energy, and association rate with reasonable accuracy and then use the model to dissect the binding mechanism. In the past, this binding event has often been assumed to occur via an induced fit mechanism because the proteins binding site is completely closed in the bound state, making it impossible for the ligand to enter the binding site after the protein has adopted the closed conformation. More complex mechanisms have also been hypothesized, but these have remained controversial. Here, we are able to directly observe roles for both the conformational selection and induced fit mechanisms in LAO binding. First, the LAO protein tends to form a partially closed encounter complex via conformational selection (that is, the apo protein can sample this state), though the induced fit mechanism can also play a role here. Then, interactions with the ligand can induce a transition to the bound state. Based on these results, we propose that MSMs built from atomistic simulations may be a powerful way of dissecting ligand-binding mechanisms and may eventually facilitate a deeper understanding of allostery as well as the prediction of new protein-ligand interactions, an important step in drug discovery.'),
(85032, 2011, 'plos', 'Ten simple rules for providing a scientific Web resource', 'Schultheiss, Sebastian J', 'Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.', 'Hong Kong', 4, 'Computational Biology|Information Dissemination|Internet|Reproducibility of Results|Software', 'Editorial', '10.1371/journal.pcbi.1001126', '21637800', '-'),
(85033, 2011, 'plos', 'Neurobiologically realistic determinants of self-organized criticality in networks of spiking neurons', 'Rubinov, Mikail|Sporns, Olaf|Thivierge, Jean-Philippe|Breakspear, Michael', 'Black Dog Institute and School of Psychiatry, University of New South Wales, Sydney, Australia. m.rubinov@student.unsw.edu.au|Black Dog Institute and School of Psychiatry, University of New South Wales, Sydney, Australia. m.rubinov@student.unsw.edu.au|Black Dog Institute and School of Psychiatry, University of New South Wales, Sydney, Australia. m.rubinov@student.unsw.edu.au|Black Dog Institute and School of Psychiatry, University of New South Wales, Sydney, Australia. m.rubinov@student.unsw.edu.au', 'Australia|Australia|Australia|Australia', 137, 'Action Potentials|Algorithms|Cluster Analysis|Humans|Models, Neurological|Nerve Net|Neuronal Plasticity|Neurons|Synapses', 'Journal Article', '10.1371/journal.pcbi.1002038', '21673863', 'Self-organized criticality refers to the spontaneous emergence of self-similar dynamics in complex systems poised between order and randomness. The presence of self-organized critical dynamics in the brain is theoretically appealing and is supported by recent neurophysiological studies. Despite this, the neurobiological determinants of these dynamics have not been previously sought. Here, we systematically examined the influence of such determinants in hierarchically modular networks of leaky integrate-and-fire neurons with spike-timing-dependent synaptic plasticity and axonal conduction delays. We characterized emergent dynamics in our networks by distributions of active neuronal ensemble modules (neuronal avalanches) and rigorously assessed these distributions for power-law scaling. We found that spike-timing-dependent synaptic plasticity enabled a rapid phase transition from random subcritical dynamics to ordered supercritical dynamics. Importantly, modular connectivity and low wiring cost broadened this transition, and enabled a regime indicative of self-organized criticality. The regime only occurred when modular connectivity, low wiring cost and synaptic plasticity were simultaneously present, and the regime was most evident when between-module connection density scaled as a power-law. The regime was robust to variations in other neurobiologically relevant parameters and favored systems with low external drive and strong internal interactions. Increases in system size and connectivity facilitated internal interactions, permitting reductions in external drive and facilitating convergence of postsynaptic-response magnitude and synaptic-plasticity learning rate parameter values towards neurobiologically realistic levels. We hence infer a novel association between self-organized critical neuronal dynamics and several neurobiologically realistic features of structural connectivity. The central role of these features in our model may reflect their importance for neuronal information processing.'),
(85034, 2011, 'plos', 'Effects of heterogeneous and clustered contact patterns on infectious disease dynamics', 'Volz, Erik M|Miller, Joel C|Galvani, Alison|Ancel Meyers, Lauren', 'Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America. erikvolz@umich.edu|Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America. erikvolz@umich.edu|Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America. erikvolz@umich.edu|Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America. erikvolz@umich.edu', 'United States|United States|United States|United States', 104, 'Algorithms|Cluster Analysis|Computational Biology|Contact Tracing|Disease Transmission, Infectious|Epidemics|Family Characteristics|Humans|Interpersonal Relations|Models, Theoretical', 'Journal Article', '10.1371/journal.pcbi.1002042', '21673864', 'The spread of infectious diseases fundamentally depends on the pattern of contacts between individuals. Although studies of contact networks have shown that heterogeneity in the number of contacts and the duration of contacts can have far-reaching epidemiological consequences, models often assume that contacts are chosen at random and thereby ignore the sociological, temporal and/or spatial clustering of contacts. Here we investigate the simultaneous effects of heterogeneous and clustered contact patterns on epidemic dynamics. To model population structure, we generalize the configuration model which has a tunable degree distribution (number of contacts per node) and level of clustering (number of three cliques). To model epidemic dynamics for this class of random graph, we derive a tractable, low-dimensional system of ordinary differential equations that accounts for the effects of network structure on the course of the epidemic. We find that the interaction between clustering and the degree distribution is complex. Clustering always slows an epidemic, but simultaneously increasing clustering and the variance of the degree distribution can increase final epidemic size. We also show that bond percolation-based approximations can be highly biased if one incorrectly assumes that infectious periods are homogeneous, and the magnitude of this bias increases with the amount of clustering in the network. We apply this approach to model the high clustering of contacts within households, using contact parameters estimated from survey data of social interactions, and we identify conditions under which network models that do not account for household structure will be biased.'),
(85035, 2011, 'plos', 'Brownian dynamics simulation of nucleocytoplasmic transport: a coarse-grained model for the functional state of the nuclear pore complex', 'Moussavi-Baygi, Ruhollah|Jamali, Yousef|Karimi, Reza|Mofrad, Mohammad R K', 'Molecular Cell Biomechanics Laboratory, Department of Bioengineering, University of California, Berkeley, California, United States of America.|Molecular Cell Biomechanics Laboratory, Department of Bioengineering, University of California, Berkeley, California, United States of America.|Molecular Cell Biomechanics Laboratory, Department of Bioengineering, University of California, Berkeley, California, United States of America.|Molecular Cell Biomechanics Laboratory, Department of Bioengineering, University of California, Berkeley, California, United States of America.', 'United States|United States|United States|United States', 50, 'Active Transport, Cell Nucleus|Animals|Cytoskeleton|Elastic Modulus|Hydrophobic and Hydrophilic Interactions|Models, Biological|Molecular Dynamics Simulation|Nuclear Pore|Nucleocytoplasmic Transport Proteins|Oocytes|Protein Structure, Tertiary|Viscosity|Xenopus', 'Journal Article', '10.1371/journal.pcbi.1002049', '21673865', 'The nuclear pore complex (NPC) regulates molecular traffic across the nuclear envelope (NE). Selective transport happens on the order of milliseconds and the length scale of tens of nanometers, however, the transport mechanism remains elusive. Central to the transport process is the hydrophobic interactions between karyopherins (kaps) and Phe-Gly (FG) repeat domains. Taking into account the polymeric nature of FG-repeats grafted on the elastic structure of the NPC, and the kap-FG hydrophobic affinity, we have established a coarse-grained model of the NPC structure that mimics nucleocytoplasmic transport. To establish a foundation for future works, the methodology and biophysical rationale behind the model is explained in details. The model predicts that the first-passage time of a 15 nm cargo-complex is about 2.6xc2xb10.13 ms with an inverse Gaussian distribution for statistically adequate number of independent Brownian dynamics simulations. Moreover, the cargo-complex is primarily attached to the channel wall where it interacts with the FG-layer as it passes through the central channel. The kap-FG hydrophobic interaction is highly dynamic and fast, which ensures an efficient translocation through the NPC. Further, almost all eight hydrophobic binding spots on kap-xcexb2 are occupied simultaneously during transport. Finally, as opposed to intact NPCs, cytoplasmic filaments-deficient NPCs show a high degree of permeability to inert cargos, implying the defining role of cytoplasmic filaments in the selectivity barrier.'),
(85036, 2011, 'plos', 'Extracting message inter-departure time distributions from the human electroencephalogram', 'Mixc5xa1ixc4x87, Bratislav|Vakorin, Vasily A|Kovaxc4x8devixc4x87, Nataxc5xa1a|Paus, Tomxc3xa1xc5xa1|McIntosh, Anthony R', 'Rotman Research Institute, Baycrest Centre, Toronto, Ontario, Canada. bmisic@rotman-baycrest.on.ca|Rotman Research Institute, Baycrest Centre, Toronto, Ontario, Canada. bmisic@rotman-baycrest.on.ca|Rotman Research Institute, Baycrest Centre, Toronto, Ontario, Canada. bmisic@rotman-baycrest.on.ca|Rotman Research Institute, Baycrest Centre, Toronto, Ontario, Canada. bmisic@rotman-baycrest.on.ca|Rotman Research Institute, Baycrest Centre, Toronto, Ontario, Canada. bmisic@rotman-baycrest.on.ca', 'Canada|Canada|Canada|Canada|Canada', 4, 'Cerebral Cortex|Child|Cluster Analysis|Electroencephalography|Female|Humans|Least-Squares Analysis|Male|Models, Neurological|Telecommunications|Wavelet Analysis', 'Journal Article', '10.1371/journal.pcbi.1002065', '21673866', 'The complex connectivity of the cerebral cortex is a topic of much study, yet the link between structure and function is still unclear. The processing capacity and throughput of information at individual brain regions remains an open question and one that could potentially bridge these two aspects of neural organization. The rate at which information is emitted from different nodes in the network and how this output process changes under different external conditions are general questions that are not unique to neuroscience, but are of interest in multiple classes of telecommunication networks. In the present study we show how some of these questions may be addressed using tools from telecommunications research. An important system statistic for modeling and performance evaluation of distributed communication systems is the time between successive departures of units of information at each node in the network. We describe a method to extract and fully characterize the distribution of such inter-departure times from the resting-state electroencephalogram (EEG). We show that inter-departure times are well fitted by the two-parameter Gamma distribution. Moreover, they are not spatially or neurophysiologically trivial and instead are regionally specific and sensitive to the presence of sensory input. In both the eyes-closed and eyes-open conditions, inter-departure time distributions were more dispersed over posterior parietal channels, close to regions which are known to have the most dense structural connectivity. The biggest differences between the two conditions were observed at occipital sites, where inter-departure times were significantly more variable in the eyes-open condition. Together, these results suggest that message departure times are indicative of network traffic and capture a novel facet of neural activity.'),
(85037, 2011, 'plos', 'A new view of the bacterial cytosol environment', 'Cossins, Benjamin P|Jacobson, Matthew P|Guallar, Victor', 'Department of Life Science, Barcelona Supercomputer Center, Barcelona, Spain.|Department of Life Science, Barcelona Supercomputer Center, Barcelona, Spain.|Department of Life Science, Barcelona Supercomputer Center, Barcelona, Spain.', 'Spain|Spain|Spain', 31, 'Bacterial Proteins|Cytosol|Diffusion|Electric Conductivity|Escherichia coli|Models, Biological|Molecular Dynamics Simulation|Ubiquitins', 'Journal Article', '10.1371/journal.pcbi.1002066', '21695225', 'The cytosol is the major environment in all bacterial cells. The true physical and dynamical nature of the cytosol solution is not fully understood and here a modeling approach is applied. Using recent and detailed data on metabolite concentrations, we have created a molecular mechanical model of the prokaryotic cytosol environment of Escherichia coli, containing proteins, metabolites and monatomic ions. We use 200 ns molecular dynamics simulations to compute diffusion rates, the extent of contact between molecules and dielectric constants. Large metabolites spend xe2x88xbc80% of their time in contact with other molecules while small metabolites vary with some only spending 20% of time in contact. Large non-covalently interacting metabolite structures mediated by hydrogen-bonds, ionic and xcfx80 stacking interactions are common and often associate with proteins. Mg(2+) ions were prominent in NIMS and almost absent free in solution. xcex9a(+) is generally not involved in NIMSs and populates the solvent fairly uniformly, hence its important role as an osmolyte. In simulations containing ubiquitin, to represent a protein component, metabolite diffusion was reduced owing to long lasting protein-metabolite interactions. Hence, it is likely that with larger proteins metabolites would diffuse even more slowly. The dielectric constant of these simulations was found to differ from that of pure water only through a large contribution from ubiquitin as metabolite and monatomic ion effects cancel. These findings suggest regions of influence specific to particular proteins affecting metabolite diffusion and electrostatics. Also some proteins may have a higher propensity for associations with metabolites owing to their larger electrostatic fields. We hope that future studies may be able to accurately predict how binding interactions differ in the cytosol relative to dilute aqueous solution.'),
(85038, 2011, 'plos', 'Testing the ortholog conjecture with comparative functional genomic data from mammals', 'Nehrt, Nathan L|Clark, Wyatt T|Radivojac, Predrag|Hahn, Matthew W', 'School of Informatics and Computing, Indiana University, Bloomington, Indiana, USA.|School of Informatics and Computing, Indiana University, Bloomington, Indiana, USA.|School of Informatics and Computing, Indiana University, Bloomington, Indiana, USA.|School of Informatics and Computing, Indiana University, Bloomington, Indiana, USA.', 'India|India|India|India', 102, 'Animals|Comparative Genomic Hybridization|Evolution, Molecular|Gene Dosage|Gene Expression Profiling|Genes|Humans|Mice|Oligonucleotide Array Sequence Analysis|Proteins', 'Journal Article', '10.1371/journal.pcbi.1002073', '21695233', 'A common assumption in comparative genomics is that orthologous genes share greater functional similarity than do paralogous genes (the ortholog conjecture). Many methods used to computationally predict protein function are based on this assumption, even though it is largely untested. Here we present the first large-scale test of the ortholog conjecture using comparative functional genomic data from human and mouse. We use the experimentally derived functions of more than 8,900 genes, as well as an independent microarray dataset, to directly assess our ability to predict function using both orthologs and paralogs. Both datasets show that paralogs are often a much better predictor of function than are orthologs, even at lower sequence identities. Among paralogs, those found within the same species are consistently more functionally similar than those found in a different species. We also find that paralogous pairs residing on the same chromosome are more functionally similar than those on different chromosomes, perhaps due to higher levels of interlocus gene conversion between these pairs. In addition to offering implications for the computational prediction of protein function, our results shed light on the relationship between sequence divergence and functional divergence. We conclude that the most important factor in the evolution of function is not amino acid sequence, but rather the cellular context in which proteins act.'),
(85039, 2011, 'plos', 'Mutual inactivation of Notch receptors and ligands facilitates developmental patterning', 'Sprinzak, David|Lakhanpal, Amit|LeBon, Lauren|Garcia-Ojalvo, Jordi|Elowitz, Michael B', 'Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA.|Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA.|Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA.|Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA.|Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA.', 'United States|United States|United States|United States|United States', 62, 'Algorithms|Animals|Body Patterning|Cell Communication|Drosophila|Drosophila Proteins|Intracellular Signaling Peptides and Proteins|Membrane Proteins|Models, Molecular|Receptors, Notch', 'Journal Article', '10.1371/journal.pcbi.1002069', '21695234', 'Developmental patterning requires juxtacrine signaling in order to tightly coordinate the fates of neighboring cells. Recent work has shown that Notch and Delta, the canonical metazoan juxtacrine signaling receptor and ligand, mutually inactivate each other in the same cell. This cis-interaction generates mutually exclusive sending and receiving states in individual cells. It generally remains unclear, however, how this mutual inactivation and the resulting switching behavior can impact developmental patterning circuits. Here we address this question using mathematical modeling in the context of two canonical pattern formation processes: boundary formation and lateral inhibition. For boundary formation, in a model motivated by Drosophila wing vein patterning, we find that mutual inactivation allows sharp boundary formation across a broader range of parameters than models lacking mutual inactivation. This model with mutual inactivation also exhibits robustness to correlated gene expression perturbations. For lateral inhibition, we find that mutual inactivation speeds up patterning dynamics, relieves the need for cooperative regulatory interactions, and expands the range of parameter values that permit pattern formation, compared to canonical models. Furthermore, mutual inactivation enables a simple lateral inhibition circuit architecture which requires only a single downstream regulatory step. Both model systems show how mutual inactivation can facilitate robust fine-grained patterning processes that would be difficult to implement without it, by encoding a difference-promoting feedback within the signaling system itself. Together, these results provide a framework for analysis of more complex Notch-dependent developmental systems.'),
(85040, 2011, 'plos', 'Towards an evolutionary model of transcription networks', 'Xie, Dan|Chen, Chieh-Chun|He, Xin|Cao, Xiaoyi|Zhong, Sheng', 'Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.|Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.|Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.|Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.|Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.', 'United States|United States|United States|United States|United States', 0, 'Animals|Base Sequence|Cattle|Evolution, Molecular|Gene Regulatory Networks|Humans|Mice|Models, Genetic|Molecular Sequence Data|Phylogeny|Protein Binding|Sequence Alignment|Species Specificity|Transcription, Genetic|Yeasts', 'Journal Article', '10.1371/journal.pcbi.1002064', '21695281', 'DNA evolution models made invaluable contributions to comparative genomics, although it seemed formidable to include non-genomic features into these models. In order to build an evolutionary model of transcription networks (TNs), we had to forfeit the substitution model used in DNA evolution and to start from modeling the evolution of the regulatory relationships. We present a quantitative evolutionary model of TNs, subjecting the phylogenetic distance and the evolutionary changes of cis-regulatory sequence, gene expression and network structure to one probabilistic framework. Using the genome sequences and gene expression data from multiple species, this model can predict regulatory relationships between a transcription factor (TF) and its target genes in all species, and thus identify TN re-wiring events. Applying this model to analyze the pre-implantation development of three mammalian species, we identified the conserved and re-wired components of the TNs downstream to a set of TFs including Oct4, Gata3/4/6, cMyc and nMyc. Evolutionary events on the DNA sequence that led to turnover of TF binding sites were identified, including a birth of an Oct4 binding site by a 2nt deletion. In contrast to recent reports of large interspecies differences of TF binding sites and gene expression patterns, the interspecies difference in TF-target relationship is much smaller. The data showed increasing conservation levels from genomic sequences to TF-DNA interaction, gene expression, TN, and finally to morphology, suggesting that evolutionary changes are larger at molecular levels and smaller at functional levels. The data also showed that evolutionarily older TFs are more likely to have conserved target genes, whereas younger TFs tend to have larger re-wiring rates.'),
(85041, 2011, 'plos', 'Impact of microscopic motility on the swimming behavior of parasites: straighter trypanosomes are more directional', 'Uppaluri, Sravanti|Nagler, Jan|Stellamanns, Eric|Heddergott, Niko|Herminghaus, Stephan|Engstler, Markus|Pfohl, Thomas', 'Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany.|Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany.|Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany.|Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany.|Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany.|Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany.|Max-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany', 36, 'Cell Movement|Cell Tracking|Computational Biology|Image Processing, Computer-Assisted|Microscopy, Video|Trypanosoma brucei brucei', 'Journal Article', '10.1371/journal.pcbi.1002058', '21698122', 'Microorganisms, particularly parasites, have developed sophisticated swimming mechanisms to cope with a varied range of environments. African Trypanosomes, causative agents of fatal illness in humans and animals, use an insect vector (the Tsetse fly) to infect mammals, involving many developmental changes in which cell motility is of prime importance. Our studies reveal that differences in cell body shape are correlated with a diverse range of cell behaviors contributing to the directional motion of the cell. Straighter cells swim more directionally while cells that exhibit little net displacement appear to be more bent. Initiation of cell division, beginning with the emergence of a second flagellum at the base, correlates to directional persistence. Cell trajectory and rapid body fluctuation correlation analysis uncovers two characteristic relaxation times: a short relaxation time due to strong body distortions in the range of 20 to 80 ms and a longer time associated with the persistence in average swimming direction in the order of 15 seconds. Different motility modes, possibly resulting from varying body stiffness, could be of consequence for host invasion during distinct infective stages.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85042, 2011, 'plos', 'Integrative analysis of many weighted co-expression networks using tensor computation', 'Li, Wenyuan|Liu, Chun-Chi|Zhang, Tong|Li, Haifeng|Waterman, Michael S|Zhou, Xianghong Jasmine', 'Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, California, USA.|Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, California, USA.|Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, California, USA.|Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, California, USA.|Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, California, USA.|Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, California, USA.', 'United States|United States|United States|United States|United States|United States', 0, 'Algorithms|Computational Biology|Databases, Genetic|Databases, Protein|Gene Expression|Gene Expression Regulation|Gene Regulatory Networks|Humans|Models, Genetic|Oligonucleotide Array Sequence Analysis|Phenotype|Proteins|Signal Processing, Computer-Assisted', 'Journal Article', '10.1371/journal.pcbi.1001106', '21698123', 'The rapid accumulation of biological networks poses new challenges and calls for powerful integrative analysis tools. Most existing methods capable of simultaneously analyzing a large number of networks were primarily designed for unweighted networks, and cannot easily be extended to weighted networks. However, it is known that transforming weighted into unweighted networks by dichotomizing the edges of weighted networks with a threshold generally leads to information loss. We have developed a novel, tensor-based computational framework for mining recurrent heavy subgraphs in a large set of massive weighted networks. Specifically, we formulate the recurrent heavy subgraph identification problem as a heavy 3D subtensor discovery problem with sparse constraints. We describe an effective approach to solving this problem by designing a multi-stage, convex relaxation protocol, and a non-uniform edge sampling technique. We applied our method to 130 co-expression networks, and identified 11,394 recurrent heavy subgraphs, grouped into 2,810 families. We demonstrated that the identified subgraphs represent meaningful biological modules by validating against a large set of compiled biological knowledge bases. We also showed that the likelihood for a heavy subgraph to be meaningful increases significantly with its recurrence in multiple networks, highlighting the importance of the integrative approach to biological network analysis. Moreover, our approach based on weighted graphs detects many patterns that would be overlooked using unweighted graphs. In addition, we identified a large number of modules that occur predominately under specific phenotypes. This analysis resulted in a genome-wide mapping of gene network modules onto the phenome. Finally, by comparing module activities across many datasets, we discovered high-order dynamic cooperativeness in protein complex networks and transcriptional regulatory networks.'),
(85043, 2011, 'plos', 'Generation of diverse biological forms through combinatorial interactions between tissue polarity and growth', 'Kennaway, Richard|Coen, Enrico|Green, Amelia|Bangham, Andrew', 'School of Computing Sciences, University of East Anglia, Norwich, UK.|School of Computing Sciences, University of East Anglia, Norwich, UK.|School of Computing Sciences, University of East Anglia, Norwich, UK.|School of Computing Sciences, University of East Anglia, Norwich, UK.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Anisotropy|Antirrhinum|Cell Polarity|Computational Biology|Computer Simulation|Gene Expression Regulation, Plant|Models, Biological|Morphogenesis', 'Journal Article', '10.1371/journal.pcbi.1002071', '21698124', 'A major problem in biology is to understand how complex tissue shapes may arise through growth. In many cases this process involves preferential growth along particular orientations raising the question of how these orientations are specified. One view is that orientations are specified through stresses in the tissue (axiality-based system). Another possibility is that orientations can be specified independently of stresses through molecular signalling (polarity-based system). The axiality-based system has recently been explored through computational modelling. Here we develop and apply a polarity-based system which we call the Growing Polarised Tissue (GPT) framework. Tissue is treated as a continuous material within which regionally expressed factors under genetic control may interact and propagate. Polarity is established by signals that propagate through the tissue and is anchored in regions termed tissue polarity organisers that are also under genetic control. Rates of growth parallel or perpendicular to the local polarity may then be specified through a regulatory network. The resulting growth depends on how specified growth patterns interact within the constraints of mechanically connected tissue. This constraint leads to the emergence of features such as curvature that were not directly specified by the regulatory networks. Resultant growth feeds back to influence spatial arrangements and local orientations of tissue, allowing complex shapes to emerge from simple rules. Moreover, asymmetries may emerge through interactions between polarity fields. We illustrate the value of the GPT-framework for understanding morphogenesis by applying it to a growing Snapdragon flower and indicate how the underlying hypotheses may be tested by computational simulation. We propose that combinatorial intractions between orientations and rates of growth, which are a key feature of polarity-based systems, have been exploited during evolution to generate a range of observed biological shapes.'),
(85044, 2011, 'plos', 'The role of response elements organization in transcription factor selectivity: the IFN-xcexb2 enhanceosome example', 'Pan, Yongping|Nussinov, Ruth', 'Basic Science Program, SAIC-Frederick, Center for Cancer Research Nanobiology Program, NCI-Frederick, Frederick, Maryland, USA.|Basic Science Program, SAIC-Frederick, Center for Cancer Research Nanobiology Program, NCI-Frederick, Frederick, Maryland, USA.', 'United States|United States', 0, 'Base Sequence|Binding Sites|Computational Biology|Humans|Interferon-beta|Models, Genetic|Molecular Dynamics Simulation|Molecular Sequence Data|Protein Binding|Response Elements|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002077', '21698143', 'What is the mechanism through which transcription factors (TFs) assemble specifically along the enhancer DNA? The IFN-xcexb2 enhanceosome provides a good model system: it is small, its components crystal structures are available, and there are biochemical and cellular data. In the IFN-xcexb2 enhanceosome, there are few protein-protein interactions even though consecutive DNA response elements (REs) overlap. Our molecular dynamics (MD) simulations on different motif combinations from the enhanceosome illustrate that cooperativity is achieved via unique organization of the REs: specific binding of one TF can enhance the binding of another TF to a neighboring RE and restrict others, through overlap of REs, the order of the REs can determine which complexes will form, and the alternation of consensus and non-consensus REs can regulate binding specificity by optimizing the interactions among partners. Our observations offer an explanation of how specificity and cooperativity can be attained despite the limited interactions between neighboring TFs on the enhancer DNA. To date, when addressing selective TF binding, attention has largely focused on RE sequences. Yet, the order of the REs on the DNA and the length of the spacers between them can be a key factor in specific combinatorial assembly of the TFs on the enhancer and thus in function. Our results emphasize cooperativity via RE binding sites organization.'),
(85045, 2011, 'plos', 'Bayesian comparison of neurovascular coupling models using EEG-fMRI', 'Rosa, Maria J|Kilner, James M|Penny, Will D', 'Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, UK. mjoao@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, UK. mjoao@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, UK. mjoao@fil.ion.ucl.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 19, 'Action Potentials|Adult|Bayes Theorem|Electroencephalography|Humans|Magnetic Resonance Imaging|Male|Models, Cardiovascular|Models, Neurological|Oximetry|Photic Stimulation|Signal Processing, Computer-Assisted|Synapses|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1002070', '21698175', 'Functional magnetic resonance imaging (fMRI), with blood oxygenation level-dependent (BOLD) contrast, is a widely used technique for studying the human brain. However, it is an indirect measure of underlying neuronal activity and the processes that link this activity to BOLD signals are still a topic of much debate. In order to relate findings from fMRI research to other measures of neuronal activity it is vital to understand the underlying neurovascular coupling mechanism. Currently, there is no consensus on the relative roles of synaptic and spiking activity in the generation of the BOLD response. Here we designed a modelling framework to investigate different neurovascular coupling mechanisms. We use Electroencephalographic (EEG) and fMRI data from a visual stimulation task together with biophysically informed mathematical models describing how neuronal activity generates the BOLD signals. These models allow us to non-invasively infer the degree of local synaptic and spiking activity in the healthy human brain. In addition, we use Bayesian model comparison to decide between neurovascular coupling mechanisms. We show that the BOLD signal is dependent upon both the synaptic and spiking activity but that the relative contributions of these two inputs are dependent upon the underlying neuronal firing rate. When the underlying neuronal firing is low then the BOLD response is best explained by synaptic activity. However, when the neuronal firing rate is high then both synaptic and spiking activity are required to explain the BOLD signal.'),
(85046, 2011, 'plos', 'Mutation D816V alters the internal structure and dynamics of c-KIT receptor cytoplasmic region: implications for dimerization and activation mechanisms', 'Laine, Elodie|Chauvot de Beauchêne, Isaure|Perahia, David|Auclair, Christian|Tchertanov, Luba', 'LBPA, CNRS-ENS de Cachan, Cachan, France. elodie.laine@lbpa.ens-cachan.fr|LBPA, CNRS-ENS de Cachan, Cachan, France. elodie.laine@lbpa.ens-cachan.fr|LBPA, CNRS-ENS de Cachan, Cachan, France. elodie.laine@lbpa.ens-cachan.fr|LBPA, CNRS-ENS de Cachan, Cachan, France. elodie.laine@lbpa.ens-cachan.fr|LBPA, CNRS-ENS de Cachan, Cachan, France. elodie.laine@lbpa.ens-cachan.fr', 'France|France|France|France|France', 54, 'Antineoplastic Agents|Benzamides|Catalytic Domain|Dimerization|Drug Resistance, Neoplasm|Humans|Imatinib Mesylate|Molecular Dynamics Simulation|Mutation|Piperazines|Principal Component Analysis|Protein Stability|Proto-Oncogene Proteins c-kit|Pyrimidines|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002068', '21698178', 'The type III receptor tyrosine kinase (RTK) KIT plays a crucial role in the transmission of cellular signals through phosphorylation events that are associated with a switching of the protein conformation between inactive and active states. D816V KIT mutation is associated with various pathologies including mastocytosis and cancers. D816V-mutated KIT is constitutively active, and resistant to treatment with the anti-cancer drug Imatinib. To elucidate the activating molecular mechanism of this mutation, we applied a multi-approach procedure combining molecular dynamics (MD) simulations, normal modes analysis (NMA) and binding site prediction. Multiple 50-ns MD simulations of wild-type KIT and its mutant D816V were recorded using the inactive auto-inhibited structure of the protein, characteristic of type III RTKs. Computed free energy differences enabled us to quantify the impact of D816V on protein stability in the inactive state. We evidenced a local structural alteration of the activation loop (A-loop) upon mutation, and a long-range structural re-organization of the juxta-membrane region (JMR) followed by a weakening of the interaction network with the kinase domain. A thorough normal mode analysis of several MD conformations led to a plausible molecular rationale to propose that JMR is able to depart its auto-inhibitory position more easily in the mutant than in wild-type KIT and is thus able to promote kinase mutant dimerization without the need for extra-cellular ligand binding. Pocket detection at the surface of NMA-displaced conformations finally revealed that detachment of JMR from the kinase domain in the mutant was sufficient to open an access to the catalytic and substrate binding sites.'),
(85047, 2011, 'plos', 'The binding of learning to action in motor adaptation', 'Gonzalez Castro, Luis Nicolas|Monsen, Craig Bryant|Smith, Maurice A', 'Harvard School of Engineering and Applied Sciences, Cambridge, Massachusetts, USA.|Harvard School of Engineering and Applied Sciences, Cambridge, Massachusetts, USA.|Harvard School of Engineering and Applied Sciences, Cambridge, Massachusetts, USA.', 'United States|United States|United States', 0, 'Adaptation, Physiological|Adolescent|Adult|Algorithms|Arm|Artificial Intelligence|Bayes Theorem|Computational Biology|Female|Hand Strength|Humans|Learning|Male|Models, Neurological|Motor Activity|Task Performance and Analysis', 'Journal Article', '10.1371/journal.pcbi.1002052', '21731476', 'In motor tasks, errors between planned and actual movements generally result in adaptive changes which reduce the occurrence of similar errors in the future. It has commonly been assumed that the motor adaptation arising from an error occurring on a particular movement is specifically associated with the motion that was planned. Here we show that this is not the case. Instead, we demonstrate the binding of the adaptation arising from an error on a particular trial to the motion experienced on that same trial. The formation of this association means that future movements planned to resemble the motion experienced on a given trial benefit maximally from the adaptation arising from it. This reflects the idea that actual rather than planned motions are assigned credit for motor errors because, in a computational sense, the maximal adaptive response would be associated with the condition credited with the error. We studied this process by examining the patterns of generalization associated with motor adaptation to novel dynamic environments during reaching arm movements in humans. We found that these patterns consistently matched those predicted by adaptation associated with the actual rather than the planned motion, with maximal generalization observed where actual motions were clustered. We followed up these findings by showing that a novel training procedure designed to leverage this newfound understanding of the binding of learning to action, can improve adaptation rates by greater than 50%. Our results provide a mechanistic framework for understanding the effects of partial assistance and error augmentation during neurologic rehabilitation, and they suggest ways to optimize their use.'),
(85048, 2011, 'plos', 'Dynamic structure formation of peripheral membrane proteins', 'Morozova, Diana|Guigas, Gernot|Weiss, Matthias', 'Cellular Biophysics Group, German Cancer Research Center, Heidelberg, Germany.|Cellular Biophysics Group, German Cancer Research Center, Heidelberg, Germany.|Cellular Biophysics Group, German Cancer Research Center, Heidelberg, Germany.', 'Germany|Germany|Germany', 0, 'Cell Membrane|Cluster Analysis|Computational Biology|Hydrophobic and Hydrophilic Interactions|Membrane Microdomains|Membrane Proteins|Models, Biological|Molecular Dynamics Simulation|Multiprotein Complexes', 'Journal Article', '10.1371/journal.pcbi.1002067', '21731477', 'Using coarse-grained membrane simulations we show here that peripheral membrane proteins can form a multitude of higher-order structures due to membrane-mediated interactions. Peripheral membrane proteins characteristically perturb the lipid bilayer in their vicinity which supports the formation of protein assemblies not only within the same but surprisingly also across opposing leaflets of a bilayer. In addition, we also observed the formation of lipid-protein domains on heteregeneous membranes. The clustering ability of proteins, as quantified via the potential of mean force, is enhanced when radius and hydrophobic penetration depth of the proteins increases. Based on our data, we propose that membrane-mediated cluster formation of peripheral proteins supports protein assembly in vivo and hence may play a pivotal role in the formation of templates for signaling cascades and in the emergence of transport intermediates in the secretory pathway.'),
(85049, 2011, 'plos', 'The origin of behavioral bursts in decision-making circuitry', 'Sorribes, Amanda|Armendariz, Beatriz G|Lopez-Pigozzi, Diego|Murga, Cristina|de Polavieja, Gonzalo G', 'Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain. amanda.sorribes@cajal.csic.es|Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain. amanda.sorribes@cajal.csic.es|Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain. amanda.sorribes@cajal.csic.es|Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain. amanda.sorribes@cajal.csic.es|Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain. amanda.sorribes@cajal.csic.es', 'Spain|Spain|Spain|Spain|Spain', 0, 'Animals|Behavior, Animal|Choice Behavior|Dopamine|Drosophila|Models, Biological|Models, Statistical|Mushroom Bodies|Neurons|Poisson Distribution|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002075', '21731478', 'From ants to humans, the timing of many animal behaviors comes in bursts of activity separated by long periods of inactivity. Recently, mathematical modeling has shown that simple algorithms of priority-driven behavioral choice can result in bursty behavior. To experimentally test this link between decision-making circuitry and bursty dynamics, we have turned to Drosophila melanogaster. We have found that the statistics of intervals between activity periods in endogenous activity-rest switches of wild-type Drosophila are very well described by the Weibull distribution, a common distribution of bursty dynamics in complex systems. The bursty dynamics of wild-type Drosophila walking activity are shown to be determined by this inter-event distribution alone and not by memory effects, thus resembling human dynamics. Further, using mutant flies that disrupt dopaminergic signaling or the mushroom body, circuitry implicated in decision-making, we show that the degree of behavioral burstiness can be modified. These results are thus consistent with the proposed link between decision-making circuitry and bursty dynamics, and highlight the importance of using simple experimental systems to test general theoretical models of behavior. The findings further suggest that analysis of bursts could prove useful for the study and evaluation of decision-making circuitry.'),
(85050, 2011, 'plos', 'Generative embedding for model-based classification of fMRI data', 'Brodersen, Kay H|Schofield, Thomas M|Leff, Alexander P|Ong, Cheng Soon|Lomakina, Ekaterina I|Buhmann, Joachim M|Stephan, Klaas E', 'Department of Computer Science, ETH Zurich, Zurich, Switzerland. kay.brodersen@inf.ethz.ch|Department of Computer Science, ETH Zurich, Zurich, Switzerland. kay.brodersen@inf.ethz.ch|Department of Computer Science, ETH Zurich, Zurich, Switzerland. kay.brodersen@inf.ethz.ch|Department of Computer Science, ETH Zurich, Zurich, Switzerland. kay.brodersen@inf.ethz.ch|Department of Computer Science, ETH Zurich, Zurich, Switzerland. kay.brodersen@inf.ethz.ch|Department of Computer Science, ETH Zurich, Zurich, Switzerland. kay.brodersen@inf.ethz.ch|Department of Computer Science, ETH Zurich, Zurich, Switzerland. kay.brodersen@inf.ethz.ch', 'Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland|Switzerland', 102, 'Adult|Aged|Algorithms|Aphasia|Bayes Theorem|Brain|Computational Biology|Databases, Factual|Humans|Magnetic Resonance Imaging|Male|Middle Aged|Models, Neurological|Nervous System Diseases|Pattern Recognition, Automated|Principal Component Analysis|Reproducibility of Results|Speech Perception', 'Journal Article', '10.1371/journal.pcbi.1002079', '21731479', 'Decoding models, such as those underlying multivariate classification algorithms, have been increasingly used to infer cognitive or clinical brain states from measures of brain activity obtained by functional magnetic resonance imaging (fMRI). The practicality of current classifiers, however, is restricted by two major challenges. First, due to the high data dimensionality and low sample size, algorithms struggle to separate informative from uninformative features, resulting in poor generalization performance. Second, popular discriminative methods such as support vector machines (SVMs) rarely afford mechanistic interpretability. In this paper, we address these issues by proposing a novel generative-embedding approach that incorporates neurobiologically interpretable generative models into discriminative classifiers. Our approach extends previous work on trial-by-trial classification for electrophysiological recordings to subject-by-subject classification for fMRI and offers two key advantages over conventional methods: it may provide more accurate predictions by exploiting discriminative information encoded in hidden physiological quantities such as synaptic connection strengths, and it affords mechanistic interpretability of clinical classifications. Here, we introduce generative embedding for fMRI using a combination of dynamic causal models (DCMs) and SVMs. We propose a general procedure of DCM-based generative embedding for subject-wise classification, provide a concrete implementation, and suggest good-practice guidelines for unbiased application of generative embedding in the context of fMRI. We illustrate the utility of our approach by a clinical example in which we classify moderately aphasic patients and healthy controls using a DCM of thalamo-temporal regions during speech processing. Generative embedding achieves a near-perfect balanced classification accuracy of 98% and significantly outperforms conventional activation-based and correlation-based methods. This example demonstrates how disease states can be detected with very high accuracy and, at the same time, be interpreted mechanistically in terms of abnormalities in connectivity. We envisage that future applications of generative embedding may provide crucial advances in dissecting spectrum disorders into physiologically more well-defined subgroups.'),
(85051, 2011, 'plos', 'Predicting binding to p-glycoprotein by flexible receptor docking', 'Dolghih, Elena|Bryant, Clifford|Renslo, Adam R|Jacobson, Matthew P', 'Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA. lena.dolgikh@ucsf.edu|Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA. lena.dolgikh@ucsf.edu|Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA. lena.dolgikh@ucsf.edu|Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA. lena.dolgikh@ucsf.edu', 'United States|United States|United States|United States', 0, 'ATP Binding Cassette Transporter, Subfamily B|ATP Binding Cassette Transporter, Subfamily B, Member 1|Algorithms|Animals|Binding Sites|Cell Line|Cysteine Proteinase Inhibitors|Dogs|Drug Discovery|Humans|Mice|Molecular Dynamics Simulation|Pharmacokinetics|Pliability|Protein Binding|ROC Curve', 'Journal Article', '10.1371/journal.pcbi.1002083', '21731480', 'P-glycoprotein (P-gp) is an ATP-dependent transport protein that is selectively expressed at entry points of xenobiotics where, acting as an efflux pump, it prevents their entering sensitive organs. The protein also plays a key role in the absorption and blood-brain barrier penetration of many drugs, while its overexpression in cancer cells has been linked to multidrug resistance in tumors. The recent publication of the mouse P-gp crystal structure revealed a large and hydrophobic binding cavity with no clearly defined sub-sites that supports an induced-fit ligand binding model. We employed flexible receptor docking to develop a new prediction algorithm for P-gp binding specificity. We tested the ability of this method to differentiate between binders and nonbinders of P-gp using consistently measured experimental data from P-gp efflux and calcein-inhibition assays. We also subjected the model to a blind test on a series of peptidic cysteine protease inhibitors, confirming the ability to predict compounds more likely to be P-gp substrates. Finally, we used the method to predict cellular metabolites that may be P-gp substrates. Overall, our results suggest that many P-gp substrates bind deeper in the cavity than the cyclic peptide in the crystal structure and that specificity in P-gp is better understood in terms of physicochemical properties of the ligands (and the binding site), rather than being defined by specific sub-sites.'),
(85052, 2011, 'plos', 'Robust network topologies for generating switch-like cellular responses', 'Shah, Najaf A|Sarkar, Casim A', 'Graduate Group in Genomics and Computational Biology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Graduate Group in Genomics and Computational Biology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.', 'United States|United States', 66, 'Arabidopsis|Computational Biology|Enzymes|Feedback, Physiological|Models, Biological|Saccharomyces cerevisiae|Signal Transduction|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002085', '21731481', 'Signaling networks that convert graded stimuli into binary, all-or-none cellular responses are critical in processes ranging from cell-cycle control to lineage commitment. To exhaustively enumerate topologies that exhibit this switch-like behavior, we simulated all possible two- and three-component networks on random parameter sets, and assessed the resulting response profiles for both steepness (ultrasensitivity) and extent of memory (bistability). Simulations were used to study purely enzymatic networks, purely transcriptional networks, and hybrid enzymatic/transcriptional networks, and the topologies in each class were rank ordered by parametric robustness (i.e., the percentage of applied parameter sets exhibiting ultrasensitivity or bistability). Results reveal that the distribution of network robustness is highly skewed, with the most robust topologies clustering into a small number of motifs. Hybrid networks are the most robust in generating ultrasensitivity (up to 28%) and bistability (up to 18%), strikingly, a purely transcriptional framework is the most fragile in generating either ultrasensitive (up to 3%) or bistable (up to 1%) responses. The disparity in robustness among the network classes is due in part to zero-order ultrasensitivity, an enzyme-specific phenomenon, which repeatedly emerges as a particularly robust mechanism for generating nonlinearity and can act as a building block for switch-like responses. We also highlight experimentally studied examples of topologies enabling switching behavior, in both native and synthetic systems, that rank highly in our simulations. This unbiased approach for identifying topologies capable of a given response may be useful in discovering new natural motifs and in designing robust synthetic gene networks.'),
(85053, 2011, 'plos', 'Changes of mind in an attractor network of decision-making', 'Albantakis, Larissa|Deco, Gustavo', 'Department of Information and Communication Technologies, Computational Neuroscience, Universitat Pompeu Fabra, Barcelona, Spain. larissa.albantakis@upf.edu|Department of Information and Communication Technologies, Computational Neuroscience, Universitat Pompeu Fabra, Barcelona, Spain. larissa.albantakis@upf.edu', 'Spain|Spain', 0, 'Action Potentials|Cerebral Cortex|Computational Biology|Computer Simulation|Decision Making|Humans|Linear Models|Models, Neurological|Neurons|Nonlinear Dynamics|Psychomotor Performance|Synapses', 'Journal Article', '10.1371/journal.pcbi.1002086', '21731482', 'Attractor networks successfully account for psychophysical and neurophysiological data in various decision-making tasks. Especially their ability to model persistent activity, a property of many neurons involved in decision-making, distinguishes them from other approaches. Stable decision attractors are, however, counterintuitive to changes of mind. Here we demonstrate that a biophysically-realistic attractor network with spiking neurons, in its itinerant transients towards the choice attractors, can replicate changes of mind observed recently during a two-alternative random-dot motion (RDM) task. Based on the assumption that the brain continues to evaluate available evidence after the initiation of a decision, the network predicts neural activity during changes of mind and accurately simulates reaction times, performance and percentage of changes dependent on difficulty. Moreover, the model suggests a low decision threshold and high incoming activity that drives the brain region involved in the decision-making process into a dynamical regime close to a bifurcation, which up to now lacked evidence for physiological relevance. Thereby, we further affirmed the general conformance of attractor networks with higher level neural processes and offer experimental predictions to distinguish nonlinear attractor from linear diffusion models.'),
(85054, 2011, 'plos', 'An evolutionary trade-off between protein turnover rate and protein aggregation favors a higher aggregation propensity in fast degrading proteins', 'De Baets, Greet|Reumers, Joke|Delgado Blanco, Javier|Dopazo, Joaquin|Schymkowitz, Joost|Rousseau, Frederic', 'VIB Switch Laboratory, VIB, Brussels, Belgium.|VIB Switch Laboratory, VIB, Brussels, Belgium.|VIB Switch Laboratory, VIB, Brussels, Belgium.|VIB Switch Laboratory, VIB, Brussels, Belgium.|VIB Switch Laboratory, VIB, Brussels, Belgium.|VIB Switch Laboratory, VIB, Brussels, Belgium.', 'Belgium|Belgium|Belgium|Belgium|Belgium|Belgium', 0, 'Computational Biology|Databases, Protein|Disease Susceptibility|Evolution, Molecular|Gene Expression Profiling|Humans|Membrane Proteins|Protein Array Analysis|Protein Stability|Proteins|Statistics, Nonparametric|Thermodynamics|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1002090', '21731483', 'We previously showed the existence of selective pressure against protein aggregation by the enrichment of aggregation-opposing gatekeeper residues at strategic places along the sequence of proteins. Here we analyzed the relationship between protein lifetime and protein aggregation by combining experimentally determined turnover rates, expression data, structural data and chaperone interaction data on a set of more than 500 proteins. We find that selective pressure on protein sequences against aggregation is not homogeneous but that short-living proteins on average have a higher aggregation propensity and fewer chaperone interactions than long-living proteins. We also find that short-living proteins are more often associated to deposition diseases. These findings suggest that the efficient degradation of high-turnover proteins is sufficient to preclude aggregation, but also that factors that inhibit proteasomal activity, such as physiological ageing, will primarily affect the aggregation of short-living proteins.'),
(85055, 2011, 'plos', 'Activated membrane patches guide chemotactic cell motility', 'Hecht, Inbal|Skoge, Monica L|Charest, Pascale G|Ben-Jacob, Eshel|Firtel, Richard A|Loomis, William F|Levine, Herbert|Rappel, Wouter-Jan', 'Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America. inbal.hecht@gmail.com|Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America. inbal.hecht@gmail.com|Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America. inbal.hecht@gmail.com|Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America. inbal.hecht@gmail.com|Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America. inbal.hecht@gmail.com|Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America. inbal.hecht@gmail.com|Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America. inbal.hecht@gmail.com|Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America. inbal.hecht@gmail.com', 'United States|United States|United States|United States|United States|United States|United States|Un', 53, 'Cell Movement|Chemotaxis|Computer Simulation|Dictyostelium|Guanosine Triphosphate|Microfluidic Analytical Techniques|Models, Biological|Pseudopodia|Signal Transduction|Single-Cell Analysis|ras Proteins', 'Journal Article', '10.1371/journal.pcbi.1002044', '21738453', 'Many eukaryotic cells are able to crawl on surfaces and guide their motility based on environmental cues. These cues are interpreted by signaling systems which couple to cell mechanics, indeed membrane protrusions in crawling cells are often accompanied by activated membrane patches, which are localized areas of increased concentration of one or more signaling components. To determine how these patches are related to cell motion, we examine the spatial localization of RasGTP in chemotaxing Dictyostelium discoideum cells under conditions where the vertical extent of the cell was restricted. Quantitative analyses of the data reveal a high degree of spatial correlation between patches of activated Ras and membrane protrusions. Based on these findings, we formulate a model for amoeboid cell motion that consists of two coupled modules. The first module utilizes a recently developed two-component reaction diffusion model that generates transient and localized areas of elevated concentration of one of the components along the membrane. The activated patches determine the location of membrane protrusions (and overall cell motion) that are computed in the second module, which also takes into account the cortical tension and the availability of protrusion resources. We show that our model is able to produce realistic amoeboid-like motion and that our numerical results are consistent with experimentally observed pseudopod dynamics. Specifically, we show that the commonly observed splitting of pseudopods can result directly from the dynamics of the signaling patches.'),
(85056, 2011, 'plos', 'Differential producibility analysis (DPA) of transcriptomic data with metabolic networks: deconstructing the metabolic response of M tuberculosis', 'Bonde, Bhushan K|Beste, Dany J V|Laing, Emma|Kierzek, Andrzej M|McFadden, Johnjoe', 'Microbial Sciences Division, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.|Microbial Sciences Division, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.|Microbial Sciences Division, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.|Microbial Sciences Division, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.|Microbial Sciences Division, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Algorithms|Anaerobiosis|Cluster Analysis|Escherichia coli|Gene Expression Profiling|Gene Expression Regulation, Bacterial|Host-Pathogen Interactions|Humans|Macrophages|Metabolic Networks and Pathways|Models, Biological|Mycobacterium tuberculosis|Oligonucleotide Array Sequence Analysis|Reproducibility of Results|Sputum|Systems Biology|Tuberculosis', 'Journal Article', '10.1371/journal.pcbi.1002060', '21738454', 'A general paucity of knowledge about the metabolic state of Mycobacterium tuberculosis within the host environment is a major factor impeding development of novel drugs against tuberculosis. Current experimental methods do not allow direct determination of the global metabolic state of a bacterial pathogen in vivo, but the transcriptional activity of all encoded genes has been investigated in numerous microarray studies. We describe a novel algorithm, Differential Producibility Analysis (DPA) that uses a metabolic network to extract metabolic signals from transcriptome data. The method utilizes Flux Balance Analysis (FBA) to identify the set of genes that affect the ability to produce each metabolite in the network. Subsequently, Rank Product Analysis is used to identify those metabolites predicted to be most affected by a transcriptional signal. We first apply DPA to investigate the metabolic response of E. coli to both anaerobic growth and inactivation of the FNR global regulator. DPA successfully extracts metabolic signals that correspond to experimental data and provides novel metabolic insights. We next apply DPA to investigate the metabolic response of M. tuberculosis to the macrophage environment, human sputum and a range of in vitro environmental perturbations. The analysis revealed a previously unrecognized feature of the response of M. tuberculosis to the macrophage environment: a down-regulation of genes influencing metabolites in central metabolism and concomitant up-regulation of genes that influence synthesis of cell wall components and virulence factors. DPA suggests that a significant feature of the response of the tubercle bacillus to the intracellular environment is a channeling of resources towards remodeling of its cell envelope, possibly in preparation for attack by host defenses. DPA may be used to unravel the mechanisms of virulence and persistence of M. tuberculosis and other pathogens and may have general application for extracting metabolic signals from other -omics data.'),
(85057, 2011, 'plos', 'Learning, memory, and the role of neural network architecture', 'Hermundstad, Ann M|Brown, Kevin S|Bassett, Danielle S|Carlson, Jean M', 'Physics Department, University of California, Santa Barbara, Santa Barbara, California, United States of America. ann@physics.ucsb.edu|Physics Department, University of California, Santa Barbara, Santa Barbara, California, United States of America. ann@physics.ucsb.edu|Physics Department, University of California, Santa Barbara, Santa Barbara, California, United States of America. ann@physics.ucsb.edu|Physics Department, University of California, Santa Barbara, Santa Barbara, California, United States of America. ann@physics.ucsb.edu', 'United States|United States|United States|United States', 0, 'Computational Biology|Humans|Learning|Memory|Models, Neurological|Nerve Net|Neural Networks (Computer)', 'Journal Article', '10.1371/journal.pcbi.1002063', '21738455', 'The performance of information processing systems, from artificial neural networks to natural neuronal ensembles, depends heavily on the underlying system architecture. In this study, we compare the performance of parallel and layered network architectures during sequential tasks that require both acquisition and retention of information, thereby identifying tradeoffs between learning and memory processes. During the task of supervised, sequential function approximation, networks produce and adapt representations of external information. Performance is evaluated by statistically analyzing the error in these representations while varying the initial network state, the structure of the external information, and the time given to learn the information. We link performance to complexity in network architecture by characterizing local error landscape curvature. We find that variations in error landscape structure give rise to tradeoffs in performance, these include the ability of the network to maximize accuracy versus minimize inaccuracy and produce specific versus generalizable representations of information. Parallel networks generate smooth error landscapes with deep, narrow minima, enabling them to find highly specific representations given sufficient time. While accurate, however, these representations are difficult to generalize. In contrast, layered networks generate rough error landscapes with a variety of local minima, allowing them to quickly find coarse representations. Although less accurate, these representations are easily adaptable. The presence of measurable performance tradeoffs in both layered and parallel networks has implications for understanding the behavior of a wide variety of natural and artificial learning systems.'),
(85058, 2011, 'plos', 'Eurekometrics: analyzing the nature of discovery', 'Arbesman, Samuel|Christakis, Nicholas A', 'Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts, United States of America. arbesman@hcp.med.harvard.edu|Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts, United States of America. arbesman@hcp.med.harvard.edu', 'United States|United States', 0, 'Biomedical Research|Computational Biology|Humans|Science', 'Journal Article', '10.1371/journal.pcbi.1002072', '21738456', '-'),
(85059, 2011, 'plos', 'How haptic size sensations improve distance perception', 'Battaglia, Peter W|Kersten, Daniel|Schrater, Paul R', 'BCS and CSAIL, MIT, Cambridge, Massachusetts, United States of America. pbatt@mit.edu|BCS and CSAIL, MIT, Cambridge, Massachusetts, United States of America. pbatt@mit.edu|BCS and CSAIL, MIT, Cambridge, Massachusetts, United States of America. pbatt@mit.edu', 'United States|United States|United States', 22, 'Adult|Bayes Theorem|Cognition|Computational Biology|Decision Making|Distance Perception|Humans|Touch Perception', 'Journal Article', '10.1371/journal.pcbi.1002080', '21738457', 'Determining distances to objects is one of the most ubiquitous perceptual tasks in everyday life. Nevertheless, it is challenging because the information from a single image confounds object size and distance. Though our brains frequently judge distances accurately, the underlying computations employed by the brain are not well understood. Our work illuminates these computions by formulating a family of probabilistic models that encompass a variety of distinct hypotheses about distance and size perception. We compare these models predictions to a set of human distance judgments in an interception experiment and use Bayesian analysis tools to quantitatively select the best hypothesis on the basis of its explanatory power and robustness over experimental data. The central question is: whether, and how, human distance perception incorporates size cues to improve accuracy. Our conclusions are: 1) humans incorporate haptic object size sensations for distance perception, 2) the incorporation of haptic sensations is suboptimal given their reliability, 3) humans use environmentally accurate size and distance priors, 4) distance judgments are produced by perceptual posterior sampling. In addition, we compared our models estimated sensory and motor noise parameters with previously reported measurements in the perceptual literature and found good correspondence between them. Taken together, these results represent a major step forward in establishing the computational underpinnings of human distance perception and the role of size information.'),
(85060, 2011, 'plos', 'Colocalization of protein kinase A with adenylyl cyclase enhances protein kinase A activity during induction of long-lasting long-term-potentiation', 'Kim, Myungsook|Park, Alan Jung|Havekes, Robbert|Chay, Andrew|Guercio, Leonardo Antonio|Oliveira, Rodrigo Freire|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.|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|United States|United States|United States|Un', 0, 'A Kinase Anchor Proteins|Adenylyl Cyclases|Animals|CA1 Region, Hippocampal|Calcium|Colforsin|Computer Simulation|Cyclic AMP|Cyclic AMP-Dependent Protein Kinases|Diffusion|Dopamine|Long-Term Potentiation|Mice|Models, Biological|Proteins|Pyramidal Cells|Stochastic Processes|Substrate Specificity|Synaptic Potentials', 'Journal Article', '10.1371/journal.pcbi.1002084', '21738458', 'The ability of neurons to differentially respond to specific temporal and spatial input patterns underlies information storage in neural circuits. One means of achieving spatial specificity is to restrict signaling molecules to particular subcellular compartments using anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Disruption of protein kinase A (PKA) anchoring to AKAPs impairs a PKA-dependent form of long term potentiation (LTP) in the hippocampus. To investigate the role of localized PKA signaling in LTP, we developed a stochastic reaction-diffusion model of the signaling pathways leading to PKA activation in CA1 pyramidal neurons. Simulations investigated whether the role of anchoring is to locate kinases near molecules that activate them, or near their target molecules. The results show that anchoring PKA with adenylyl cyclase (which produces cAMP that activates PKA) produces significantly greater PKA activity, and phosphorylation of both inhibitor-1 and AMPA receptor GluR1 subunit on S845, than when PKA is anchored apart from adenylyl cyclase. The spatial microdomain of cAMP was smaller than that of PKA suggesting that anchoring PKA near its source of cAMP is critical because inactivation by phosphodiesterase limits diffusion of cAMP. The prediction that the role of anchoring is to colocalize PKA near adenylyl cyclase was confirmed by experimentally rescuing the deficit in LTP produced by disruption of PKA anchoring using phosphodiesterase inhibitors. Additional experiments confirm the model prediction that disruption of anchoring impairs S845 phosphorylation produced by forskolin-induced synaptic potentiation. Collectively, these results show that locating PKA near adenylyl cyclase is a critical function of anchoring.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85061, 2011, 'plos', 'Trade-off between responsiveness and noise suppression in biomolecular system responses to environmental cues', 'Ratushny, Alexander V|Shmulevich, Ilya|Aitchison, John D', 'Institute for Systems Biology, Seattle, Washington, United States of America.|Institute for Systems Biology, Seattle, Washington, United States of America.|Institute for Systems Biology, Seattle, Washington, United States of America.', 'United States|United States|United States', 0, 'Animals|Computer Simulation|Environment|Feedback, Physiological|Galactose|Gene Expression Regulation|Gene Regulatory Networks|Lipopolysaccharides|Macrophages|Metabolic Networks and Pathways|Mice|Models, Biological|Oleic Acid|Saccharomyces cerevisiae|Systems Biology|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1002091', '21738459', 'When living systems detect changes in their external environment their response must be measured to balance the need to react appropriately with the need to remain stable, ignoring insignificant signals. Because this is a fundamental challenge of all biological systems that execute programs in response to stimuli, we developed a generalized time-frequency analysis (TFA) framework to systematically explore the dynamical properties of biomolecular networks. Using TFA, we focused on two well-characterized yeast gene regulatory networks responsive to carbon-source shifts and a mammalian innate immune regulatory network responsive to lipopolysaccharides (LPS). The networks are comprised of two different basic architectures. Dual positive and negative feedback loops make up the yeast galactose network, whereas overlapping positive and negative feed-forward loops are common to the yeast fatty-acid response network and the LPS-induced network of macrophages. TFA revealed remarkably distinct network behaviors in terms of trade-offs in responsiveness and noise suppression that are appropriately tuned to each biological response. The wild type galactose network was found to be highly responsive while the oleate network has greater noise suppression ability. The LPS network appeared more balanced, exhibiting less bias toward noise suppression or responsiveness. Exploration of the network parameter space exposed dramatic differences in system behaviors for each network. These studies highlight fundamental structural and dynamical principles that underlie each network, reveal constrained parameters of positive and negative feedback and feed-forward strengths that tune the networks appropriately for their respective biological roles, and demonstrate the general utility of the TFA approach for systems and synthetic biology.'),
(85062, 2011, 'plos', 'Spatio-temporal credit assignment in neuronal population learning', 'Friedrich, Johannes|Urbanczik, Robert|Senn, Walter', 'Department of Physiology, University of Bern, Bern, Switzerland.|Department of Physiology, University of Bern, Bern, Switzerland.|Department of Physiology, University of Bern, Bern, Switzerland.', 'Switzerland|Switzerland|Switzerland', 0, 'Algorithms|Animals|Computational Biology|Computer Simulation|Decision Making|Dogs|Learning|Markov Chains|Memory|Models, Neurological|Neuronal Plasticity|Neurons|Reward|Signal Transduction|Synapses|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1002092', '21738460', 'In learning from trial and error, animals need to relate behavioral decisions to environmental reinforcement even though it may be difficult to assign credit to a particular decision when outcomes are uncertain or subject to delays. When considering the biophysical basis of learning, the credit-assignment problem is compounded because the behavioral decisions themselves result from the spatio-temporal aggregation of many synaptic releases. We present a model of plasticity induction for reinforcement learning in a population of leaky integrate and fire neurons which is based on a cascade of synaptic memory traces. Each synaptic cascade correlates presynaptic input first with postsynaptic events, next with the behavioral decisions and finally with external reinforcement. For operant conditioning, learning succeeds even when reinforcement is delivered with a delay so large that temporal contiguity between decision and pertinent reward is lost due to intervening decisions which are themselves subject to delayed reinforcement. This shows that the model provides a viable mechanism for temporal credit assignment. Further, learning speeds up with increasing population size, so the plasticity cascade simultaneously addresses the spatial problem of assigning credit to synapses in different population neurons. Simulations on other tasks, such as sequential decision making, serve to contrast the performance of the proposed scheme to that of temporal difference-based learning. We argue that, due to their comparative robustness, synaptic plasticity cascades are attractive basic models of reinforcement learning in the brain.'),
(85063, 2011, 'plos', 'Network clustering revealed the systemic alterations of mitochondrial protein expression', 'Jeon, Jouhyun|Jeong, Jae Hoon|Baek, Je-Hyun|Koo, Hyun-Jung|Park, Wook-Ha|Yang, Jae-Seong|Yu, Myeong-Hee|Kim, Sanguk|Pak, Youngmi Kim', 'Division of Molecular and Life Science, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Korea.|Division of Molecular and Life Science, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Korea.|Division of Molecular and Life Science, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Korea.|Division of Molecular and Life Science, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Korea.|Division of Molecular and Life Science, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Korea.|Division of Molecular and Life Science, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Korea.|Division of Molecular and Life Science, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Korea.|Division of Molecular and Life Science, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Korea.|Division of Molecular and Life Science, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Korea.', '-|-|-|-|-|-|-|-|-', 0, 'Cell Line, Tumor|Cluster Analysis|Computational Biology|DNA, Mitochondrial|Gene Expression Profiling|Gene Expression Regulation|Gene Regulatory Networks|Humans|Microscopy, Fluorescence|Mitochondria|Mitochondrial Proteins|Proteome|RNA, Messenger|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1002093', '21738461', 'The mitochondrial protein repertoire varies depending on the cellular state. Protein component modifications caused by mitochondrial DNA (mtDNA) depletion are related to a wide range of human diseases, however, little is known about how nuclear-encoded mitochondrial proteins (mt proteome) changes under such dysfunctional states. In this study, we investigated the systemic alterations of mtDNA-depleted (xcfx81(0)) mitochondria by using network analysis of gene expression data. By modularizing the quantified proteomics data into protein functional networks, systemic properties of mitochondrial dysfunction were analyzed. We discovered that up-regulated and down-regulated proteins were organized into two predominant subnetworks that exhibited distinct biological processes. The down-regulated network modules are involved in typical mitochondrial functions, while up-regulated proteins are responsible for mtDNA repair and regulation of mt protein expression and transport. Furthermore, comparisons of proteome and transcriptome data revealed that xcfx81(0) cells attempted to compensate for mtDNA depletion by modulating the coordinated expression/transport of mt proteins. Our results demonstrate that mt protein composition changed to remodel the functional organization of mitochondrial protein networks in response to dysfunctional cellular states. Human mt protein functional networks provide a framework for understanding how cells respond to mitochondrial dysfunctions.'),
(85064, 2011, 'plos', 'Partially glycosylated dendrimers block MD-2 and prevent TLR4-MD-2-LPS complex mediated cytokine responses', 'Barata, Teresa S|Teo, Ian|Brocchini, Steve|Zloh, Mire|Shaunak, Sunil', 'Center for Structural Chemistry, School of Pharmacy, University of London, London, United Kingdom.|Center for Structural Chemistry, School of Pharmacy, University of London, London, United Kingdom.|Center for Structural Chemistry, School of Pharmacy, University of London, London, United Kingdom.|Center for Structural Chemistry, School of Pharmacy, University of London, London, United Kingdom.|Center for Structural Chemistry, School of Pharmacy, University of London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Animals|Crystallography, X-Ray|Cytokines|Dendrimers|Glucosamine|Humans|Hydrophobic and Hydrophilic Interactions|Inflammation|Lipopolysaccharides|Lymphocyte Antigen 96|Mice|Molecular Dynamics Simulation|Protein Binding|Rabbits|Reproducibility of Results|Toll-Like Receptor 4', 'Journal Article', '10.1371/journal.pcbi.1002095', '21738462', 'The crystal structure of the TLR4-MD-2-LPS complex responsible for triggering powerful pro-inflammatory cytokine responses has recently become available. Central to cell surface complex formation is binding of lipopolysaccharide (LPS) to soluble MD-2. We have previously shown, in biologically based experiments, that a generation 3.5 PAMAM dendrimer with 64 peripheral carboxylic acid groups acts as an antagonist of pro-inflammatory cytokine production after surface modification with 8 glucosamine molecules. We have also shown using molecular modelling approaches that this partially glycosylated dendrimer has the flexibility, cluster density, surface electrostatic charge, and hydrophilicity to make it a therapeutically useful antagonist of complex formation. These studies enabled the computational study of the interactions of the unmodified dendrimer, glucosamine, and of the partially glycosylated dendrimer with TLR4 and MD-2 using molecular docking and molecular dynamics techniques. They demonstrate that dendrimer glucosamine forms co-operative electrostatic interactions with residues lining the entrance to MD-2s hydrophobic pocket. Crucially, dendrimer glucosamine interferes with the electrostatic binding of: (i) the 4phosphate on the di-glucosamine of LPS to Ser118 on MD-2, (ii) LPS to Lys91 on MD-2, (iii) the subsequent binding of TLR4 to Tyr102 on MD-2. This is followed by additional co-operative interactions between several of the dendrimer glucosamines carboxylic acid branches and MD-2. Collectively, these interactions block the entry of the lipid chains of LPS into MD-2s hydrophobic pocket, and also prevent TLR4-MD-2-LPS complex formation. Our studies have therefore defined the first nonlipid-based synthetic MD-2 antagonist using both animal model-based studies of pro-inflammatory cytokine responses and molecular modelling studies of a whole dendrimer with its target protein. Using this approach, it should now be possible to computationally design additional macromolecular dendrimer based antagonists for other Toll Like Receptors. They could be useful for treating a spectrum of infectious, inflammatory and malignant diseases.'),
(85065, 2011, 'plos', 'Heterogeneous host susceptibility enhances prevalence of mixed-genotype micro-parasite infections', 'van der Werf, Wopke|Hemerik, Lia|Vlak, Just M|Zwart, Mark P', 'Centre for Crop Systems Analysis, Wageningen University, Wageningen, The Netherlands.|Centre for Crop Systems Analysis, Wageningen University, Wageningen, The Netherlands.|Centre for Crop Systems Analysis, Wageningen University, Wageningen, The Netherlands.|Centre for Crop Systems Analysis, Wageningen University, Wageningen, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands', 0, 'Animals|Disease Susceptibility|Genotype|Host-Pathogen Interactions|Larva|Models, Biological|Models, Statistical|Moths|Nucleopolyhedrovirus|Species Specificity|Systems Biology|Virion', 'Journal Article', '10.1371/journal.pcbi.1002097', '21738463', 'Dose response in micro-parasite infections is usually shallower than predicted by the independent action model, which assumes that each infectious unit has a probability of infection that is independent of the presence of other infectious units. Moreover, the prevalence of mixed-genotype infections was greater than predicted by this model. No probabilistic infection model has been proposed to account for the higher prevalence of mixed-genotype infections. We use model selection within a set of four alternative models to explain high prevalence of mixed-genotype infections in combination with a shallow dose response. These models contrast dependent versus independent action of micro-parasite infectious units, and homogeneous versus heterogeneous host susceptibility. We specifically consider a situation in which genome differences between genotypes are minimal, and highly unlikely to result in genotype-genotype interactions. Data on dose response and mixed-genotype infection prevalence were collected by challenging fifth instar Spodoptera exigua larvae with two genotypes of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV), differing only in a 100 bp PCR marker sequence. We show that an independent action model that includes heterogeneity in host susceptibility can explain both the shallow dose response and the high prevalence of mixed-genotype infections. Theoretical results indicate that variation in host susceptibility is inextricably linked to increased prevalence of mixed-genotype infections. We have shown, to our knowledge for the first time, how heterogeneity in host susceptibility affects mixed-genotype infection prevalence. No evidence was found that virions operate dependently. While it has been recognized that heterogeneity in host susceptibility must be included in models of micro-parasite transmission and epidemiology to account for dose response, here we show that heterogeneity in susceptibility is also a fundamental principle explaining patterns of pathogen genetic diversity among hosts in a population. This principle has potentially wide implications for the monitoring, modeling and management of infectious diseases.'),
(85066, 2011, 'plos', 'Computational investigation of the changing patterns of subtype specific NMDA receptor activation during physiological glutamatergic neurotransmission', 'Singh, Pallab|Hockenberry, Adam J|Tiruvadi, Vineet R|Meaney, David F', 'Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.', 'United States|United States|United States|United States', 14, 'Analysis of Variance|CA1 Region, Hippocampal|Calcium|Computational Biology|Dendritic Spines|Glutamic Acid|Models, Neurological|Receptors, N-Methyl-D-Aspartate|Signal Transduction|Statistics, Nonparametric|Stochastic Processes|Synapses|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1002106', '21738464', 'NMDA receptors (NMDARs) are the major mediator of the postsynaptic response during synaptic neurotransmission. The diversity of roles for NMDARs in influencing synaptic plasticity and neuronal survival is often linked to selective activation of multiple NMDAR subtypes (NR1/NR2A-NMDARs, NR1/NR2B-NMDARs, and triheteromeric NR1/NR2A/NR2B-NMDARs). However, the lack of available pharmacological tools to block specific NMDAR populations leads to debates on the potential role for each NMDAR subtype in physiological signaling, including different models of synaptic plasticity. Here, we developed a computational model of glutamatergic signaling at a prototypical dendritic spine to examine the patterns of NMDAR subtype activation at temporal and spatial resolutions that are difficult to obtain experimentally. We demonstrate that NMDAR subtypes have different dynamic ranges of activation, with NR1/NR2A-NMDAR activation sensitive at univesicular glutamate release conditions, and NR2B containing NMDARs contributing at conditions of multivesicular release. We further show that NR1/NR2A-NMDAR signaling dominates in conditions simulating long-term depression (LTD), while the contribution of NR2B containing NMDAR significantly increases for stimulation frequencies that approximate long-term potentiation (LTP). Finally, we show that NR1/NR2A-NMDAR content significantly enhances response magnitude and fidelity at single synapses during chemical LTP and spike timed dependent plasticity induction, pointing out an important developmental switch in synaptic maturation. Together, our model suggests that NMDAR subtypes are differentially activated during different types of physiological glutamatergic signaling, enhancing the ability for individual spines to produce unique responses to these different inputs.'),
(85067, 2011, 'plos', 'Ten simple rules for building and maintaining a scientific reputation', 'Bourne, Philip E|Barbour, Virginia', 'Skaggs School of Pharmacy and Pharmaceutical Science, University of California San Diego, La Jolla, California, United States of America. pbourne@ucsd.edu|Skaggs School of Pharmacy and Pharmaceutical Science, University of California San Diego, La Jolla, California, United States of America. pbourne@ucsd.edu', 'United States|United States', 21, 'Career Mobility|Humans|Science|Social Perception', 'Editorial', '10.1371/journal.pcbi.1002108', '21738465', '-'),
(85068, 2011, 'plos', 'The development of computational biology in Pakistan: still a long way to go', 'Ilyas, Muhammad|Sadique, Samrene|Masood, Kahlid|Qamar, Raheel|Chohan, Shahid Nadeem', 'Bioinformatics Laboratory, National Centre of Excellence in Molecular Biology, University of Punjab, Lahore, Pakistan.|Bioinformatics Laboratory, National Centre of Excellence in Molecular Biology, University of Punjab, Lahore, Pakistan.|Bioinformatics Laboratory, National Centre of Excellence in Molecular Biology, University of Punjab, Lahore, Pakistan.|Bioinformatics Laboratory, National Centre of Excellence in Molecular Biology, University of Punjab, Lahore, Pakistan.|Bioinformatics Laboratory, National Centre of Excellence in Molecular Biology, University of Punjab, Lahore, Pakistan.', 'Pakistan|Pakistan|Pakistan|Pakistan|Pakistan', 0, 'Computational Biology|Pakistan', 'Journal Article', '10.1371/journal.pcbi.1001135', '21750669', '-'),
(85069, 2011, 'plos', 'Optimal stimulus shapes for neuronal excitation', 'Forger, Daniel B|Paydarfar, David|Clay, John R', 'Department of Mathematics, University of Michigan, Ann Arbor, MI, USA. forger@umich.edu|Department of Mathematics, University of Michigan, Ann Arbor, MI, USA. forger@umich.edu|Department of Mathematics, University of Michigan, Ann Arbor, MI, USA. forger@umich.edu', 'United States|United States|United States', 16, 'Action Potentials|Animals|Axons|Computational Biology|Decapodiformes|Electric Stimulation|Hydrogen-Ion Concentration|Models, Neurological|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002089', '21760759', 'An important problem in neuronal computation is to discern how features of stimuli control the timing of action potentials. One aspect of this problem is to determine how an action potential, or spike, can be elicited with the least energy cost, e.g., a minimal amount of applied current. Here we show in the Hodgkin & Huxley model of the action potential and in experiments on squid giant axons that: 1) spike generation in a neuron can be highly discriminatory for stimulus shape and 2) the optimal stimulus shape is dependent upon inputs to the neuron. We show how polarity and time course of post-synaptic currents determine which of these optimal stimulus shapes best excites the neuron. These results are obtained mathematically using the calculus of variations and experimentally using a stochastic search methodology. Our findings reveal a surprising complexity of computation at the single cell level that may be relevant for understanding optimization of signaling in neurons and neuronal networks.'),
(85070, 2011, 'plos', 'A dynamical model reveals gene co-localizations in nucleus', 'Kang, Jing|Xu, Bing|Yao, Ye|Lin, Wei|Hennessy, Conor|Fraser, Peter|Feng, Jianfeng', 'Nuclear Dynamics Laboratory, The Babraham Institute, Cambridge, UK.|Nuclear Dynamics Laboratory, The Babraham Institute, Cambridge, UK.|Nuclear Dynamics Laboratory, The Babraham Institute, Cambridge, UK.|Nuclear Dynamics Laboratory, The Babraham Institute, Cambridge, UK.|Nuclear Dynamics Laboratory, The Babraham Institute, Cambridge, UK.|Nuclear Dynamics Laboratory, The Babraham Institute, Cambridge, UK.|Nuclear Dynamics Laboratory, The Babraham Institute, Cambridge, UK.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 28, 'Animals|Cell Nucleus|Chromatin|Computational Biology|Computer Simulation|Diffusion|Gene Expression Regulation|Gene Regulatory Networks|Genes|Mice|Models, Genetic|Reproducibility of Results|Thermodynamics|Transcription Factors|Translocation, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002094', '21760760', 'Co-localization of networks of genes in the nucleus is thought to play an important role in determining gene expression patterns. Based upon experimental data, we built a dynamical model to test whether pure diffusion could account for the observed co-localization of genes within a defined subnuclear region. A simple standard Brownian motion model in two and three dimensions shows that preferential co-localization is possible for co-regulated genes without any direct interaction, and suggests the occurrence may be due to a limitation in the number of available transcription factors. Experimental data of chromatin movements demonstrates that fractional rather than standard Brownian motion is more appropriate to model gene mobilizations, and we tested our dynamical model against recent static experimental data, using a sub-diffusion process by which the genes tend to colocalize more easily. Moreover, in order to compare our model with recently obtained experimental data, we studied the association level between genes and factors, and presented data supporting the validation of this dynamic model. As further applications of our model, we applied it to test against more biological observations. We found that increasing transcription factor number, rather than factory number and nucleus size, might be the reason for decreasing gene co-localization. In the scenario of frequency- or amplitude-modulation of transcription factors, our model predicted that frequency-modulation may increase the co-localization between its targeted genes.'),
(85071, 2011, 'plos', 'Construction and modelling of an inducible positive feedback loop stably integrated in a mammalian cell-line', 'Siciliano, Velia|Menolascina, Filippo|Marucci, Lucia|Fracassi, Chiara|Garzilli, Immacolata|Moretti, Maria Nicoletta|di Bernardo, Diego', 'Telethon Institute of Genetics and Medicine, Naples, Italy.|Telethon Institute of Genetics and Medicine, Naples, Italy.|Telethon Institute of Genetics and Medicine, Naples, Italy.|Telethon Institute of Genetics and Medicine, Naples, Italy.|Telethon Institute of Genetics and Medicine, Naples, Italy.|Telethon Institute of Genetics and Medicine, Naples, Italy.|Telethon Institute of Genetics and Medicine, Naples, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy|Italy', 24, 'Animals|CHO Cells|Cricetinae|Cricetulus|DNA|Doxycycline|Feedback, Physiological|Gene Expression Regulation|HEK293 Cells|Homeostasis|Humans|Models, Genetic|Nonlinear Dynamics|Reverse Transcriptase Polymerase Chain Reaction|Synthetic Biology|Systems Biology|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.1002074', '21765813', 'Understanding the relationship between topology and dynamics of transcriptional regulatory networks in mammalian cells is essential to elucidate the biology of complex regulatory and signaling pathways. Here, we characterised, via a synthetic biology approach, a transcriptional positive feedback loop (PFL) by generating a clonal population of mammalian cells (CHO) carrying a stable integration of the construct. The PFL network consists of the Tetracycline-controlled transactivator (tTA), whose expression is regulated by a tTA responsive promoter (CMV-TET), thus giving rise to a positive feedback. The same CMV-TET promoter drives also the expression of a destabilised yellow fluorescent protein (d2EYFP), thus the dynamic behaviour can be followed by time-lapse microscopy. The PFL network was compared to an engineered version of the network lacking the positive feedback loop (NOPFL), by expressing the tTA mRNA from a constitutive promoter. Doxycycline was used to repress tTA activation (switch off), and the resulting changes in fluorescence intensity for both the PFL and NOPFL networks were followed for up to 43 h. We observed a striking difference in the dynamics of the PFL and NOPFL networks. Using non-linear dynamical models, able to recapitulate experimental observations, we demonstrated a link between network topology and network dynamics. Namely, transcriptional positive autoregulation can significantly slow down the switch off times, as compared to the non-autoregulated system. Doxycycline concentration can modulate the response times of the PFL, whereas the NOPFL always switches off with the same dynamics. Moreover, the PFL can exhibit bistability for a range of Doxycycline concentrations. Since the PFL motif is often found in naturally occurring transcriptional and signaling pathways, we believe our work can be instrumental to characterise their behaviour.'),
(85072, 2011, 'plos', 'Stimulus-dependent state transition between synchronized oscillation and randomly repetitive burst in a model cerebellar granular layer', 'Honda, Takeru|Yamazaki, Tadashi|Tanaka, Shigeru|Nagao, Soichi|Nishino, Tetsuro', 'Department of Information and Communication Engineering, Graduate School of Electro-Communications, The University of Electro-Communications, Chofu-shi, Tokyo, Japan.|Department of Information and Communication Engineering, Graduate School of Electro-Communications, The University of Electro-Communications, Chofu-shi, Tokyo, Japan.|Department of Information and Communication Engineering, Graduate School of Electro-Communications, The University of Electro-Communications, Chofu-shi, Tokyo, Japan.|Department of Information and Communication Engineering, Graduate School of Electro-Communications, The University of Electro-Communications, Chofu-shi, Tokyo, Japan.|Department of Information and Communication Engineering, Graduate School of Electro-Communications, The University of Electro-Communications, Chofu-shi, Tokyo, Japan.', 'Japan|Japan|Japan|Japan|Japan', 0, 'Action Potentials|Animals|Cerebellar Cortex|Computer Simulation|Dendrites|Interneurons|Magnesium|Models, Neurological|N-Methylaspartate|Neurons|Rats|Rest|alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid|gamma-Aminobutyric Acid', 'Journal Article', '10.1371/journal.pcbi.1002087', '21779155', 'Information processing of the cerebellar granular layer composed of granule and Golgi cells is regarded as an important first step toward the cerebellar computation. Our previous theoretical studies have shown that granule cells can exhibit random alternation between burst and silent modes, which provides a basis of population representation of the passage-of-time (POT) from the onset of external input stimuli. On the other hand, another computational study has reported that granule cells can exhibit synchronized oscillation of activity, as consistent with observed oscillation in local field potential recorded from the granular layer while animals keep still. Here we have a question of whether an identical network model can explain these distinct dynamics. In the present study, we carried out computer simulations based on a spiking network model of the granular layer varying two parameters: the strength of a current injected to granule cells and the concentration of Mgxc2xb2xe2x81xba which controls the conductance of NMDA channels assumed on the Golgi cell dendrites. The simulations showed that cells in the granular layer can switch activity states between synchronized oscillation and random burst-silent alternation depending on the two parameters. For higher Mgxc2xb2xe2x81xba concentration and a weaker injected current, granule and Golgi cells elicited spikes synchronously (synchronized oscillation state). In contrast, for lower Mgxc2xb2xe2x81xba concentration and a stronger injected current, those cells showed the random burst-silent alternation (POT-representing state). It is suggested that NMDA channels on the Golgi cell dendrites play an important role for determining how the granular layer works in response to external input.'),
(85073, 2011, 'plos', 'Prediction of cell penetrating peptides by support vector machines', 'Sanders, William S|Johnston, C Ian|Bridges, Susan M|Burgess, Shane C|Willeford, Kenneth O', 'Department of Biochemistry and Molecular Biology, Mississippi State University, Mississippi, United States of America. wss2@msstate.edu|Department of Biochemistry and Molecular Biology, Mississippi State University, Mississippi, United States of America. wss2@msstate.edu|Department of Biochemistry and Molecular Biology, Mississippi State University, Mississippi, United States of America. wss2@msstate.edu|Department of Biochemistry and Molecular Biology, Mississippi State University, Mississippi, United States of America. wss2@msstate.edu|Department of Biochemistry and Molecular Biology, Mississippi State University, Mississippi, United States of America. wss2@msstate.edu', 'United States|United States|United States|United States|United States', 81, 'Algorithms|Amino Acid Sequence|Animals|Artificial Intelligence|Biological Transport|Cell Line|Cell-Penetrating Peptides|Chickens|Computational Biology|Databases, Protein|Fluorescein-5-isothiocyanate|Humans|Microscopy, Fluorescence|Molecular Sequence Data|Quail|Reproducibility of Results|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1002101', '21779156', 'Cell penetrating peptides (CPPs) are those peptides that can transverse cell membranes to enter cells. Once inside the cell, different CPPs can localize to different cellular components and perform different roles. Some generate pore-forming complexes resulting in the destruction of cells while others localize to various organelles. Use of machine learning methods to predict potential new CPPs will enable more rapid screening for applications such as drug delivery. We have investigated the influence of the composition of training datasets on the ability to classify peptides as cell penetrating using support vector machines (SVMs). We identified 111 known CPPs and 34 known non-penetrating peptides from the literature and commercial vendors and used several approaches to build training data sets for the classifiers. Features were calculated from the datasets using a set of basic biochemical properties combined with features from the literature determined to be relevant in the prediction of CPPs. Our results using different training datasets confirm the importance of a balanced training set with approximately equal number of positive and negative examples. The SVM based classifiers have greater classification accuracy than previously reported methods for the prediction of CPPs, and because they use primary biochemical properties of the peptides as features, these classifiers provide insight into the properties needed for cell-penetration. To confirm our SVM classifications, a subset of peptides classified as either penetrating or non-penetrating was selected for synthesis and experimental validation. Of the synthesized peptides predicted to be CPPs, 100% of these peptides were shown to be penetrating.'),
(85074, 2011, 'plos', 'Interconversion of functional motions between mesophilic and thermophilic adenylate kinases', 'Daily, Michael D|Phillips, George N|Cui, Qiang', 'Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.', 'United States|United States|United States', 0, 'Adenylate Kinase|Amino Acid Sequence|Bacteria|Bacterial Proteins|Escherichia coli|Molecular Dynamics Simulation|Molecular Sequence Data|Mutation|Pliability|Proline|Protein Folding|Protein Structure, Tertiary|Sequence Alignment|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002103', '21779157', 'Dynamic properties are functionally important in many proteins, including the enzyme adenylate kinase (AK), for which the open/closed transition limits the rate of catalytic turnover. Here, we compare our previously published coarse-grained (double-well Gxc5x8d) simulation of mesophilic AK from E. coli (AKmeso) to simulations of thermophilic AK from Aquifex aeolicus (AKthermo). In AKthermo, as with AKmeso, the LID domain prefers to close before the NMP domain in the presence of ligand, but LID rigid-body flexibility in the open (O) ensemble decreases significantly. Backbone foldedness in O and/or transition state (TS) ensembles increases significantly relative to AKmeso in some interdomain backbone hinges and within LID. In contact space, the TS of AKthermo has fewer contacts at the CORE-LID interface but a stronger contact network surrounding the CORE-NMP interface than the TS of AKmeso. A heated simulation of AKthermo at 375K slightly increases LID rigid-body flexibility in accordance with the corresponding states hypothesis. Furthermore, while computational mutation of 7 prolines in AKthermo to their AKmeso counterparts produces similar small perturbations, mutation of these sites, especially positions 8 and 155, to glycine is required to achieve LID rigid-body flexibility and hinge flexibilities comparable to AKmeso. Mutating the 7 sites to proline in AKmeso reduces some hinges flexibilities, especially hinge 2, but does not reduce LID rigid-body flexibility, suggesting that these two types of motion are decoupled in AKmeso. In conclusion, our results suggest that hinge flexibility and global functional motions alike are correlated with but not exclusively determined by the hinge residues. This mutational framework can inform the rational design of functionally important flexibility and allostery in other proteins toward engineering novel biochemical pathways.'),
(85075, 2011, 'plos', 'Does the potential for chaos constrain the embryonic cell-cycle oscillator?', 'McIsaac, R Scott|Huang, Kerwyn Casey|Sengupta, Anirvan|Wingreen, Ned S', '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', 0, 'Animals|Calcium|Calcium Signaling|Cell Cycle|Cell Division|Embryo, Nonmammalian|Fertilization|Models, Biological|Xenopus laevis', 'Journal Article', '10.1371/journal.pcbi.1002109', '21779158', 'Although many of the core components of the embryonic cell-cycle network have been elucidated, the question of how embryos achieve robust, synchronous cellular divisions post-fertilization remains unexplored. What are the different schemes that could be implemented by the embryo to achieve synchronization? By extending a cell-cycle model previously developed for embryos of the frog Xenopus laevis to include the spatial dimensions of the embryo, we establish a novel role for the rapid, fertilization-initiated calcium wave that triggers cell-cycle oscillations. Specifically, in our simulations a fast calcium wave results in synchronized cell cycles, while a slow wave results in full-blown spatio-temporal chaos. We show that such chaos would ultimately lead to an unpredictable patchwork of cell divisions across the embryo. Given this potential for chaos, our results indicate a novel design principle whereby the fast calcium-wave trigger following embryo fertilization synchronizes cell divisions.'),
(85076, 2011, 'plos', 'Discovering transcription factor binding sites in highly repetitive regions of genomes with multi-read analysis of ChIP-Seq data', 'Chung, Dongjun|Kuan, Pei Fen|Li, Bo|Sanalkumar, Rajendran|Liang, Kun|Bresnick, Emery H|Dewey, Colin|Kelexc5x9f, Sxc3xbcndxc3xbcz', 'Department of Statistics, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Statistics, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Statistics, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Statistics, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Statistics, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Statistics, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Statistics, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Statistics, University of Wisconsin, Madison, Wisconsin, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 51, 'Animals|Base Composition|Binding Sites|Chromatin Immunoprecipitation|Chromosome Mapping|GATA1 Transcription Factor|Genome|Genomics|HeLa Cells|High-Throughput Screening Assays|Humans|Mice|Repetitive Sequences, Nucleic Acid|Reproducibility of Results|STAT1 Transcription Factor|Sequence Analysis, DNA|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1002111', '21779159', 'Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) is rapidly replacing chromatin immunoprecipitation combined with genome-wide tiling array analysis (ChIP-chip) as the preferred approach for mapping transcription-factor binding sites and chromatin modifications. The state of the art for analyzing ChIP-seq data relies on using only reads that map uniquely to a relevant reference genome (uni-reads). This can lead to the omission of up to 30% of alignable reads. We describe a general approach for utilizing reads that map to multiple locations on the reference genome (multi-reads). Our approach is based on allocating multi-reads as fractional counts using a weighted alignment scheme. Using human STAT1 and mouse GATA1 ChIP-seq datasets, we illustrate that incorporation of multi-reads significantly increases sequencing depths, leads to detection of novel peaks that are not otherwise identifiable with uni-reads, and improves detection of peaks in mappable regions. We investigate various genome-wide characteristics of peaks detected only by utilization of multi-reads via computational experiments. Overall, peaks from multi-read analysis have similar characteristics to peaks that are identified by uni-reads except that the majority of them reside in segmental duplications. We further validate a number of GATA1 multi-read only peaks by independent quantitative real-time ChIP analysis and identify novel target genes of GATA1. These computational and experimental results establish that multi-reads can be of critical importance for studying transcription factor binding in highly repetitive regions of genomes with ChIP-seq experiments.'),
(85077, 2011, 'plos', 'Bridging the resolution gap in structural modeling of 3D genome organization', 'Marti-Renom, Marc A|Mirny, Leonid A', 'Structural Genomics Laboratory, Bioinformatics and Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain. mmarti@cipf.es|Structural Genomics Laboratory, Bioinformatics and Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain. mmarti@cipf.es', 'Spain|Spain', 0, 'Chromatin|Chromosomes|Computational Biology|Genome|Humans|Models, Genetic|Models, Molecular', 'Journal Article', '10.1371/journal.pcbi.1002125', '21779160', 'Over the last decade, and especially after the advent of fluorescent in situ hybridization imaging and chromosome conformation capture methods, the availability of experimental data on genome three-dimensional organization has dramatically increased. We now have access to unprecedented details of how genomes organize within the interphase nucleus. Development of new computational approaches to leverage this data has already resulted in the first three-dimensional structures of genomic domains and genomes. Such approaches expand our knowledge of the chromatin folding principles, which has been classically studied using polymer physics and molecular simulations. Our outlook describes computational approaches for integrating experimental data with polymer physics, thereby bridging the resolution gap for structural determination of genomes and genomic domains.'),
(85078, 2011, 'plos', 'Interrogation of the protein-protein interactions between human BRCA2 BRC repeats and RAD51 reveals atomistic determinants of affinity', 'Cole, Daniel J|Rajendra, Eeson|Roberts-Thomson, Meredith|Hardwick, Bryn|McKenzie, Grahame J|Payne, Mike C|Venkitaraman, Ashok R|Skylaris, Chris-Kriton', 'Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, Cambridge, UK.|Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, Cambridge, UK.|Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, Cambridge, UK.|Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, Cambridge, UK.|Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, Cambridge, UK.|Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, Cambridge, UK.|Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, Cambridge, UK.|Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, Cambridge, UK.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 26, 'Amino Acid Motifs|Amino Acid Sequence|BRCA2 Protein|Fluorescence Polarization Immunoassay|Humans|Models, Molecular|Molecular Sequence Data|Mutation|Protein Binding|Protein Interaction Domains and Motifs|Protein Interaction Mapping|Protein Stability|Rad51 Recombinase|Repetitive Sequences, Amino Acid|Sequence Alignment|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002096', '21789034', 'The breast cancer suppressor BRCA2 controls the recombinase RAD51 in the reactions that mediate homologous DNA recombination, an essential cellular process required for the error-free repair of DNA double-stranded breaks. The primary mode of interaction between BRCA2 and RAD51 is through the BRC repeats, which are xe2x88xbc35 residue peptide motifs that interact directly with RAD51 in vitro. Human BRCA2, like its mammalian orthologues, contains 8 BRC repeats whose sequence and spacing are evolutionarily conserved. Despite their sequence conservation, there is evidence that the different human BRC repeats have distinct capacities to bind RAD51. A previously published crystal structure reports the structural basis of the interaction between human BRC4 and the catalytic core domain of RAD51. However, no structural information is available regarding the binding of the remaining seven BRC repeats to RAD51, nor is it known why the BRC repeats show marked variation in binding affinity to RAD51 despite only subtle sequence variation. To address these issues, we have performed fluorescence polarisation assays to indirectly measure relative binding affinity, and applied computational simulations to interrogate the behaviour of the eight human BRC-RAD51 complexes, as well as a suite of BRC cancer-associated mutations. Our computational approaches encompass a range of techniques designed to link sequence variation with binding free energy. They include MM-PBSA and thermodynamic integration, which are based on classical force fields, and a recently developed approach to computing binding free energies from large-scale quantum mechanical first principles calculations with the linear-scaling density functional code onetep. Our findings not only reveal how sequence variation in the BRC repeats directly affects affinity with RAD51 and provide significant new insights into the control of RAD51 by human BRCA2, but also exemplify a palette of computational and experimental tools for the analysis of protein-protein interactions for chemical biology and molecular therapeutics.'),
(85079, 2011, 'plos', 'MCAM: multiple clustering analysis methodology for deriving hypotheses and insights from high-throughput proteomic datasets', 'Naegle, Kristen M|Welsch, Roy E|Yaffe, Michael B|White, Forest M|Lauffenburger, Douglas A', 'Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.', 'United States|United States|United States|United States|United States', 0, 'Algorithms|Cluster Analysis|Databases, Protein|Humans|Models, Biological|Proteomics', 'Journal Article', '10.1371/journal.pcbi.1002119', '21799663', 'Advances in proteomic technologies continue to substantially accelerate capability for generating experimental data on protein levels, states, and activities in biological samples. For example, studies on receptor tyrosine kinase signaling networks can now capture the phosphorylation state of hundreds to thousands of proteins across multiple conditions. However, little is known about the function of many of these protein modifications, or the enzymes responsible for modifying them. To address this challenge, we have developed an approach that enhances the power of clustering techniques to infer functional and regulatory meaning of protein states in cell signaling networks. We have created a new computational framework for applying clustering to biological data in order to overcome the typical dependence on specific a priori assumptions and expert knowledge concerning the technical aspects of clustering. Multiple clustering analysis methodology (MCAM) employs an array of diverse data transformations, distance metrics, set sizes, and clustering algorithms, in a combinatorial fashion, to create a suite of clustering sets. These sets are then evaluated based on their ability to produce biological insights through statistical enrichment of metadata relating to knowledge concerning protein functions, kinase substrates, and sequence motifs. We applied MCAM to a set of dynamic phosphorylation measurements of the ERRB network to explore the relationships between algorithmic parameters and the biological meaning that could be inferred and report on interesting biological predictions. Further, we applied MCAM to multiple phosphoproteomic datasets for the ERBB network, which allowed us to compare independent and incomplete overlapping measurements of phosphorylation sites in the network. We report specific and global differences of the ERBB network stimulated with different ligands and with changes in HER2 expression. Overall, we offer MCAM as a broadly-applicable approach for analysis of proteomic data which may help increase the current understanding of molecular networks in a variety of biological problems.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85080, 2011, 'plos', 'The dynamical mechanism of auto-inhibition of AMP-activated protein kinase', 'Peng, Cheng|Head-Gordon, Teresa', 'MOE-Microsoft Key Laboratory for Intelligent Computing and Intelligent Systems, Department of Computer Science and Engineering, Shanghai Jiao Tong University, Shanghai, China.|MOE-Microsoft Key Laboratory for Intelligent Computing and Intelligent Systems, Department of Computer Science and Engineering, Shanghai Jiao Tong University, Shanghai, China.', 'China|China', 9, 'AMP-Activated Protein Kinases|Animals|Entropy|Molecular Dynamics Simulation|Mutation|Protein Structure, Tertiary|Rats', 'Journal Article', '10.1371/journal.pcbi.1002082', '21814500', 'We use a novel normal mode analysis of an elastic network model drawn from configurations generated during microsecond all-atom molecular dynamics simulations to analyze the mechanism of auto-inhibition of AMP-activated protein kinase (AMPK). A recent X-ray and mutagenesis experiment (Chen, et al Nature 2009, 459, 1146) of the AMPK homolog S. Pombe sucrose non-fermenting 1 (SNF1) has proposed a new conformational switch model involving the movement of the kinase domain (KD) between an inactive unphosphorylated open state and an active or semi-active phosphorylated closed state, mediated by the autoinhibitory domain (AID), and a similar mutagenesis study showed that rat AMPK has the same auto-inhibition mechanism. However, there is no direct dynamical evidence to support this model and it is not clear whether other functionally important local structural components are equally inhibited. By using the same SNF1 KD-AID fragment as that used in experiment, we show that AID inhibits the catalytic function by restraining the KD into an unproductive open conformation, thereby limiting local structural rearrangements, while mutations that disrupt the interactions between the KD and AID allow for both the local structural rearrangement and global interlobe conformational transition. Our calculations further show that the AID also greatly impacts the structuring and mobility of the activation loop.'),
(85081, 2011, 'plos', 'The Eps8/IRSp53/VASP network differentially controls actin capping and bundling in filopodia formation', 'Vaggi, Federico|Disanza, Andrea|Milanesi, Francesca|Di Fiore, Pier Paolo|Menna, Elisabetta|Matteoli, Michela|Gov, Nir S|Scita, Giorgio|Ciliberto, Andrea', 'IFOM Foundation, Institute FIRC of Molecular Oncology, Milan, Italy.|IFOM Foundation, Institute FIRC of Molecular Oncology, Milan, Italy.|IFOM Foundation, Institute FIRC of Molecular Oncology, Milan, Italy.|IFOM Foundation, Institute FIRC of Molecular Oncology, Milan, Italy.|IFOM Foundation, Institute FIRC of Molecular Oncology, Milan, Italy.|IFOM Foundation, Institute FIRC of Molecular Oncology, Milan, Italy.|IFOM Foundation, Institute FIRC of Molecular Oncology, Milan, Italy.|IFOM Foundation, Institute FIRC of Molecular Oncology, Milan, Italy.|IFOM Foundation, Institute FIRC of Molecular Oncology, Milan, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy|Italy|Italy|Italy', 29, 'Actin Cytoskeleton|Actins|Adaptor Proteins, Signal Transducing|Cell Adhesion Molecules|HeLa Cells|Hippocampus|Histocytochemistry|Humans|Immunoblotting|Intracellular Signaling Peptides and Proteins|Metabolic Networks and Pathways|Microfilament Proteins|Models, Biological|Nerve Tissue Proteins|Neurons|Phosphoproteins|Pseudopodia|Reproducibility of Results|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002088', '21814501', 'There is a body of literature that describes the geometry and the physics of filopodia using either stochastic models or partial differential equations and elasticity and coarse-grained theory. Comparatively, there is a paucity of models focusing on the regulation of the network of proteins that control the formation of different actin structures. Using a combination of in-vivo and in-vitro experiments together with a system of ordinary differential equations, we focused on a small number of well-characterized, interacting molecules involved in actin-dependent filopodia formation: the actin remodeler Eps8, whose capping and bundling activities are a function of its ligands, Abi-1 and IRSp53, respectively, VASP and Capping Protein (CP), which exert antagonistic functions in controlling filament elongation. The model emphasizes the essential role of complexes that contain the membrane deforming protein IRSp53, in the process of filopodia initiation. This model accurately accounted for all observations, including a seemingly paradoxical result whereby genetic removal of Eps8 reduced filopodia in HeLa, but increased them in hippocampal neurons, and generated quantitative predictions, which were experimentally verified. The model further permitted us to explain how filopodia are generated in different cellular contexts, depending on the dynamic interaction established by Eps8, IRSp53 and VASP with actin filaments, thus revealing an unexpected plasticity of the signaling network that governs the multifunctional activities of its components in the formation of filopodia.'),
(85082, 2011, 'plos', 'Automatic annotation of spatial expression patterns via sparse Bayesian factor models', 'Pruteanu-Malinici, Iulian|Mace, Daniel L|Ohler, Uwe', 'Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America.|Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America.|Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America.', 'United States|United States|United States', 0, 'Algorithms|Animals|Area Under Curve|Artificial Intelligence|Bayes Theorem|Cluster Analysis|Computational Biology|Drosophila melanogaster|Gene Expression Profiling|Gene Expression Regulation, Developmental|Humans|Image Processing, Computer-Assisted|Models, Biological|Oligonucleotide Array Sequence Analysis|Pattern Recognition, Automated', 'Journal Article', '10.1371/journal.pcbi.1002098', '21814502', 'Advances in reporters for gene expression have made it possible to document and quantify expression patterns in 2D-4D. In contrast to microarrays, which provide data for many genes but averaged and/or at low resolution, images reveal the high spatial dynamics of gene expression. Developing computational methods to compare, annotate, and model gene expression based on images is imperative, considering that available data are rapidly increasing. We have developed a sparse Bayesian factor analysis model in which the observed expression diversity of among a large set of high-dimensional images is modeled by a small number of hidden common factors. We apply this approach on embryonic expression patterns from a Drosophila RNA in situ image database, and show that the automatically inferred factors provide for a meaningful decomposition and represent common co-regulation or biological functions. The low-dimensional set of factor mixing weights is further used as features by a classifier to annotate expression patterns with functional categories. On human-curated annotations, our sparse approach reaches similar or better classification of expression patterns at different developmental stages, when compared to other automatic image annotation methods using thousands of hard-to-interpret features. Our study therefore outlines a general framework for large microscopy data sets, in which both the generative model itself, as well as its application for analysis tasks such as automated annotation, can provide insight into biological questions.'),
(85083, 2011, 'plos', 'Understanding the origins of bacterial resistance to aminoglycosides through molecular dynamics mutational study of the ribosomal A-site', 'Romanowska, Julia|McCammon, J Andrew|Trylska, Joanna', 'Department of Biophysics, Faculty of Physics, University of Warsaw, Warsaw Poland. jrom@icm.edu.pl|Department of Biophysics, Faculty of Physics, University of Warsaw, Warsaw Poland. jrom@icm.edu.pl|Department of Biophysics, Faculty of Physics, University of Warsaw, Warsaw Poland. jrom@icm.edu.pl', 'Poland|Poland|Poland', 20, 'Anti-Bacterial Agents|Bacteria|Bacterial Proteins|Binding Sites|Drug Resistance, Bacterial|Hydrogen Bonding|Molecular Dynamics Simulation|Mutation|Paromomycin|Protein Binding|RNA, Ribosomal, 16S|Ribosome Subunits, Small, Bacterial', 'Journal Article', '10.1371/journal.pcbi.1002099', '21814503', 'Paromomycin is an aminoglycosidic antibiotic that targets the RNA of the bacterial small ribosomal subunit. It binds in the A-site, which is one of the three tRNA binding sites, and affects translational fidelity by stabilizing two adenines (A1492 and A1493) in the flipped-out state. Experiments have shown that various mutations in the A-site result in bacterial resistance to aminoglycosides. In this study, we performed multiple molecular dynamics simulations of the mutated A-site RNA fragment in explicit solvent to analyze changes in the physicochemical features of the A-site that were introduced by substitutions of specific bases. The simulations were conducted for free RNA and in complex with paromomycin. We found that the specific mutations affect the shape and dynamics of the binding cleft as well as significantly alter its electrostatic properties. The most pronounced changes were observed in the U1406Cxe2x88xb6U1495A mutant, where important hydrogen bonds between the RNA and paromomycin were disrupted. The present study aims to clarify the underlying physicochemical mechanisms of bacterial resistance to aminoglycosides due to target mutations.'),
(85084, 2011, 'plos', 'Modelling the effects of population structure on childhood disease: the case of varicella', 'Silhol, Romain|Boëlle, Pierre-Yves', 'Université Pierre et Marie Curie-Paris 6, Paris, France. silhol@u707.jussieu.fr|Université Pierre et Marie Curie-Paris 6, Paris, France. silhol@u707.jussieu.fr', 'France|France', 0, 'Chickenpox|Child|Child, Preschool|Computational Biology|Computer Simulation|Demography|Herpesvirus 3, Human|Humans|Incidence|Infant|Models, Biological|Schools', 'Journal Article', '10.1371/journal.pcbi.1002105', '21814504', 'Realistic, individual-based models based on detailed census data are increasingly used to study disease transmission. Whether the rich structure of such models improves predictions is debated. This is studied here for the spread of varicella, a childhood disease, in a realistic population of children where infection occurs in the household, at school, or in the community at large. A methodology is first presented for simulating households with births and aging. Transmission probabilities were fitted for schools and community, which reproduced the overall cumulative incidence of varicella over the age range of 0-11 years old.Moreover, the individual-based model structure allowed us to reproduce several observed features of VZV epidemiology which were not included as hypotheses in the model: the age at varicella in first-born children was older than in other children, in accordance with observation, the same was true for children residing in rural areas. Model predicted incidence was comparable to observed incidence over time. These results show that models based on detailed census data on a small scale provide valid small scale prediction. By simulating several scenarios, we evaluate how varicella epidemiology is shaped by policies, such as age at first school enrolment, and school eviction. This supports the use of such models for investigating outcomes of public health measures.'),
(85085, 2011, 'plos', 'Cadherin-dependent cell morphology in an epithelium: constructing a quantitative dynamical model', 'Gemp, Ian M|Carthew, Richard W|Hilgenfeldt, Sascha', 'Engineering Sciences and Applied Mathematics, Northwestern University, Evanston, Illinois, United States of America.|Engineering Sciences and Applied Mathematics, Northwestern University, Evanston, Illinois, United States of America.|Engineering Sciences and Applied Mathematics, Northwestern University, Evanston, Illinois, United States of America.', 'United States|United States|United States', 0, 'Animals|Biomechanical Phenomena|Cadherins|Cell Adhesion|Computer Simulation|Drosophila|Epithelial Cells|Epithelium|Models, Biological|Morphogenesis|Retinal Cone Photoreceptor Cells', 'Journal Article', '10.1371/journal.pcbi.1002115', '21814505', 'Cells in the Drosophila retina have well-defined morphologies that are attained during tissue morphogenesis. We present a computer simulation of the epithelial tissue in which the global interfacial energy between cells is minimized. Experimental data for both normal cells and mutant cells either lacking or misexpressing the adhesion protein N-cadherin can be explained by a simple model incorporating salient features of morphogenesis that include the timing of N-cadherin expression in cells and its temporal relationship to the remodeling of cell-cell contacts. The simulations reproduce the geometries of wild-type and mutant cells, distinguish features of cadherin dynamics, and emphasize the importance of adhesion protein biogenesis and its timing with respect to cell remodeling. The simulations also indicate that N-cadherin protein is recycled from inactive interfaces to active interfaces, thereby modulating adhesion strengths between cells.'),
(85086, 2011, 'plos', 'In silico evidence for gluconeogenesis from fatty acids in humans', 'Kaleta, Christoph|de Figueiredo, Luxc3xads F|Werner, Sarah|Guthke, Reinhard|Ristow, Michael|Schuster, Stefan', 'Department of Bioinformatics, School of Biology and Pharmaceutics, Friedrich Schiller University of Jena, Jena, Germany. christoph.kaleta@uni-jena.de|Department of Bioinformatics, School of Biology and Pharmaceutics, Friedrich Schiller University of Jena, Jena, Germany. christoph.kaleta@uni-jena.de|Department of Bioinformatics, School of Biology and Pharmaceutics, Friedrich Schiller University of Jena, Jena, Germany. christoph.kaleta@uni-jena.de|Department of Bioinformatics, School of Biology and Pharmaceutics, Friedrich Schiller University of Jena, Jena, Germany. christoph.kaleta@uni-jena.de|Department of Bioinformatics, School of Biology and Pharmaceutics, Friedrich Schiller University of Jena, Jena, Germany. christoph.kaleta@uni-jena.de|Department of Bioinformatics, School of Biology and Pharmaceutics, Friedrich Schiller University of Jena, Jena, Germany. christoph.kaleta@uni-jena.de', 'Germany|Germany|Germany|Germany|Germany|Germany', 24, 'Acetyl Coenzyme A|Carbon Dioxide|Computational Biology|Computer Simulation|Energy Metabolism|Fatty Acids|Gluconeogenesis|Glucose|Humans|Metabolic Networks and Pathways|Models, Biological|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002116', '21814506', 'The question whether fatty acids can be converted into glucose in humans has a long standing tradition in biochemistry, and the expected answer is No. Using recent advances in Systems Biology in the form of large-scale metabolic reconstructions, we reassessed this question by performing a global investigation of a genome-scale human metabolic network, which had been reconstructed on the basis of experimental results. By elementary flux pattern analysis, we found numerous pathways on which gluconeogenesis from fatty acids is feasible in humans. On these pathways, four moles of acetyl-CoA are converted into one mole of glucose and two moles of COxe2x82x82. Analyzing the detected pathways in detail we found that their energetic requirements potentially limit their capacity. This study has many other biochemical implications: effect of starvation, sports physiology, practically carbohydrate-free diets of inuit, as well as survival of hibernating animals and embryos of egg-laying animals. Moreover, the energetic loss associated to the usage of gluconeogenesis from fatty acids can help explain the efficiency of carbohydrate reduced and ketogenic diets such as the Atkins diet.'),
(85087, 2011, 'plos', 'Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis', 'Mészáros, Bálint|Tóth, Judit|Vértessy, Beáta G|Dosztányi, Zsuzsanna|Simon, István', 'Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary.|Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary.|Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary.|Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary.|Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary.', 'Hungary|Hungary|Hungary|Hungary|Hungary', 18, 'Amino Acid Sequence|Anti-Bacterial Agents|Antigens, Bacterial|Bacterial Proteins|Cluster Analysis|Conserved Sequence|Drug Design|Genomics|Humans|Molecular Targeted Therapy|Mycobacterium tuberculosis|Protein Structure, Tertiary|Protein-Serine-Threonine Kinases|Proteome|Sequence Analysis, Protein|Tuberculosis', 'Journal Article', '10.1371/journal.pcbi.1002118', '21814507', 'Lengthy co-evolution of Homo sapiens and Mycobacterium tuberculosis, the main causative agent of tuberculosis, resulted in a dramatically successful pathogen species that presents considerable challenge for modern medicine. The continuous and ever increasing appearance of multi-drug resistant mycobacteria necessitates the identification of novel drug targets and drugs with new mechanisms of action. However, further insights are needed to establish automated protocols for target selection based on the available complete genome sequences. In the present study, we perform complete proteome level comparisons between M. tuberculosis, mycobacteria, other prokaryotes and available eukaryotes based on protein domains, local sequence similarities and protein disorder. We show that the enrichment of certain domains in the genome can indicate an important function specific to M. tuberculosis. We identified two families, termed pkn and PE/PPE that stand out in this respect. The common property of these two protein families is a complex domain organization that combines species-specific regions, commonly occurring domains and disordered segments. Besides highlighting promising novel drug target candidates in M. tuberculosis, the presented analysis can also be viewed as a general protocol to identify proteins involved in species-specific functions in a given organism. We conclude that target selection protocols should be extended to include proteins with complex domain architectures instead of focusing on sequentially unique and essential proteins only.'),
(85088, 2011, 'plos', 'In vivo conditions induce faithful encoding of stimuli by reducing nonlinear synchronization in vestibular sensory neurons', 'Schneider, Adam D|Cullen, Kathleen E|Chacron, Maurice J', 'Department of Physics, McGill University, Montreal, Quebec, Canada.|Department of Physics, McGill University, Montreal, Quebec, Canada.|Department of Physics, McGill University, Montreal, Quebec, Canada.', 'Canada|Canada|Canada', 12, 'Action Potentials|Animals|Membrane Potentials|Models, Neurological|Neurons|Nonlinear Dynamics|Vestibular Nuclei', 'Journal Article', '10.1371/journal.pcbi.1002120', '21814508', 'Previous studies have shown that neurons within the vestibular nuclei (VN) can faithfully encode the time course of sensory input through changes in firing rate in vivo. However, studies performed in vitro have shown that these same VN neurons often display nonlinear synchronization (i.e. phase locking) in their spiking activity to the local maxima of sensory input, thereby severely limiting their capacity for faithful encoding of said input through changes in firing rate. We investigated this apparent discrepancy by studying the effects of in vivo conditions on VN neuron activity in vitro using a simple, physiologically based, model of cellular dynamics. We found that membrane potential oscillations were evoked both in response to step and zap current injection for a wide range of channel conductance values. These oscillations gave rise to a resonance in the spiking activity that causes synchronization to sinusoidal current injection at frequencies below 25 Hz. We hypothesized that the apparent discrepancy between VN response dynamics measured in in vitro conditions (i.e., consistent with our modeling results) and the dynamics measured in vivo conditions could be explained by an increase in trial-to-trial variability under in vivo vs. in vitro conditions. Accordingly, we mimicked more physiologically realistic conditions in our model by introducing a noise current to match the levels of resting discharge variability seen in vivo as quantified by the coefficient of variation (CV). While low noise intensities corresponding to CV values in the range 0.04-0.24 only eliminated synchronization for low (<8 Hz) frequency stimulation but not high (>12 Hz) frequency stimulation, higher noise intensities corresponding to CV values in the range 0.5-0.7 almost completely eliminated synchronization for all frequencies. Our results thus predict that, under natural (i.e. in vivo) conditions, the vestibular system uses increased variability to promote fidelity of encoding by single neurons. This prediction can be tested experimentally in vitro.'),
(85089, 2011, 'plos', 'Decelerating spread of West Nile virus by percolation in a heterogeneous urban landscape', 'Magori, Krisztian|Bajwa, Waheed I|Bowden, Sarah|Drake, John M', 'Odum School of Ecology, University of Georgia, Athens, Georgia, United States of America. kmagori@uga.edu|Odum School of Ecology, University of Georgia, Athens, Georgia, United States of America. kmagori@uga.edu|Odum School of Ecology, University of Georgia, Athens, Georgia, United States of America. kmagori@uga.edu|Odum School of Ecology, University of Georgia, Athens, Georgia, United States of America. kmagori@uga.edu', 'Georgia|Georgia|Georgia|Georgia', 0, 'Animals|Birds|Communicable Diseases, Emerging|Computational Biology|Databases, Factual|Disease Outbreaks|Humans|Models, Biological|New York City|Urban Health|West Nile Fever|West Nile virus', 'Journal Article', '10.1371/journal.pcbi.1002104', '21829332', 'Vector-borne diseases are emerging and re-emerging in urban environments throughout the world, presenting an increasing challenge to human health and a major obstacle to development. Currently, more than half of the global population is concentrated in urban environments, which are highly heterogeneous in the extent, degree, and distribution of environmental modifications. Because the prevalence of vector-borne pathogens is so closely coupled to the ecologies of vector and host species, this heterogeneity has the potential to significantly alter the dynamical systems through which pathogens propagate, and also thereby affect the epidemiological patterns of disease at multiple spatial scales. One such pattern is the speed of spread. Whereas standard models hold that pathogens spread as waves with constant or increasing speed, we hypothesized that heterogeneity in urban environments would cause decelerating travelling waves in incipient epidemics. To test this hypothesis, we analysed data on the spread of West Nile virus (WNV) in New York City (NYC), the 1999 epicentre of the North American pandemic, during annual epizootics from 2000-2008. These data show evidence of deceleration in all years studied, consistent with our hypothesis. To further explain these patterns, we developed a spatial model for vector-borne disease transmission in a heterogeneous environment. An emergent property of this model is that deceleration occurs only in the vicinity of a critical point. Geostatistical analysis suggests that NYC may be on the edge of this criticality. Together, these analyses provide the first evidence for the endogenous generation of decelerating travelling waves in an emerging infectious disease. Since the reported deceleration results from the heterogeneity of the environment through which the pathogen percolates, our findings suggest that targeting control at key sites could efficiently prevent pathogen spread to remote susceptible areas or even halt epidemics.'),
(85090, 2011, 'plos', 'Models of neocortical layer 5b pyramidal cells capturing a wide range of dendritic and perisomatic active properties', 'Hay, Etay|Hill, Sean|Schürmann, Felix|Markram, Henry|Segev, Idan', 'Interdisciplinary Center for Neural Computation and Edmond and Lily Safra Center for Brain Sciences, The Hebrew University, Jerusalem, Israel. etay.hay@mail.huji.ac.il|Interdisciplinary Center for Neural Computation and Edmond and Lily Safra Center for Brain Sciences, The Hebrew University, Jerusalem, Israel. etay.hay@mail.huji.ac.il|Interdisciplinary Center for Neural Computation and Edmond and Lily Safra Center for Brain Sciences, The Hebrew University, Jerusalem, Israel. etay.hay@mail.huji.ac.il|Interdisciplinary Center for Neural Computation and Edmond and Lily Safra Center for Brain Sciences, The Hebrew University, Jerusalem, Israel. etay.hay@mail.huji.ac.il|Interdisciplinary Center for Neural Computation and Edmond and Lily Safra Center for Brain Sciences, The Hebrew University, Jerusalem, Israel. etay.hay@mail.huji.ac.il', 'Israel|Israel|Israel|Israel|Israel', 0, 'Action Potentials|Algorithms|Animals|Computational Biology|Dendrites|Ion Channels|Models, Neurological|Neocortex|Pyramidal Cells|Rats|Rats, Wistar|Single-Cell Analysis', 'Journal Article', '10.1371/journal.pcbi.1002107', '21829333', 'The thick-tufted layer 5b pyramidal cell extends its dendritic tree to all six layers of the mammalian neocortex and serves as a major building block for the cortical column. L5b pyramidal cells have been the subject of extensive experimental and modeling studies, yet conductance-based models of these cells that faithfully reproduce both their perisomatic Na(+)-spiking behavior as well as key dendritic active properties, including Ca(2+) spikes and back-propagating action potentials, are still lacking. Based on a large body of experimental recordings from both the soma and dendrites of L5b pyramidal cells in adult rats, we characterized key features of the somatic and dendritic firing and quantified their statistics. We used these features to constrain the density of a set of ion channels over the soma and dendritic surface via multi-objective optimization with an evolutionary algorithm, thus generating a set of detailed conductance-based models that faithfully replicate the back-propagating action potential activated Ca(2+) spike firing and the perisomatic firing response to current steps, as well as the experimental variability of the properties. Furthermore, we show a useful way to analyze model parameters with our sets of models, which enabled us to identify some of the mechanisms responsible for the dynamic properties of L5b pyramidal cells as well as mechanisms that are sensitive to morphological changes. This automated framework can be used to develop a database of faithful models for other neuron types. The models we present provide several experimentally-testable predictions and can serve as a powerful tool for theoretical investigations of the contribution of single-cell dynamics to network activity and its computational capabilities.'),
(85091, 2011, 'plos', 'Bayesian inference for genomic data integration reduces misclassification rate in predicting protein-protein interactions', 'Xing, Chuanhua|Dunson, David B', 'Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, United States of America. chuanhua.xing@gmail.com|Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, United States of America. chuanhua.xing@gmail.com', 'United States|United States', 8, 'Algorithms|Bayes Theorem|Computational Biology|Databases, Protein|Humans|Logistic Models|Protein Interaction Mapping|Proteins|ROC Curve|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1002110', '21829334', 'Protein-protein interactions (PPIs) are essential to most fundamental cellular processes. There has been increasing interest in reconstructing PPIs networks. However, several critical difficulties exist in obtaining reliable predictions. Noticeably, false positive rates can be as high as >80%. Error correction from each generating source can be both time-consuming and inefficient due to the difficulty of covering the errors from multiple levels of data processing procedures within a single test. We propose a novel Bayesian integration method, deemed nonparametric Bayes ensemble learning (NBEL), to lower the misclassification rate (both false positives and negatives) through automatically up-weighting data sources that are most informative, while down-weighting less informative and biased sources. Extensive studies indicate that NBEL is significantly more robust than the classic naïve Bayes to unreliable, error-prone and contaminated data. On a large human data set our NBEL approach predicts many more PPIs than naïve Bayes. This suggests that previous studies may have large numbers of not only false positives but also false negatives. The validation on two human PPIs datasets having high quality supports our observations. Our experiments demonstrate that it is feasible to predict high-throughput PPIs computationally with substantially reduced false positives and false negatives. The ability of predicting large numbers of PPIs both reliably and automatically may inspire people to use computational approaches to correct data errors in general, and may speed up PPIs prediction with high quality. Such a reliable prediction may provide a solid platform to other studies such as protein functions prediction and roles of PPIs in disease susceptibility.'),
(85092, 2011, 'plos', 'Indirect reciprocity under incomplete observation', 'Nakamura, Mitsuhiro|Masuda, Naoki', 'Department of Mathematical Informatics, The University of Tokyo, Tokyo, Japan.|Department of Mathematical Informatics, The University of Tokyo, Tokyo, Japan.', 'Japan|Japan', 29, 'Computational Biology|Computer Simulation|Cooperative Behavior|Game Theory|Humans|Models, Psychological|Social Perception|Social Values', 'Journal Article', '10.1371/journal.pcbi.1002113', '21829335', 'Indirect reciprocity, in which individuals help others with a good reputation but not those with a bad reputation, is a mechanism for cooperation in social dilemma situations when individuals do not repeatedly interact with the same partners. In a relatively large society where indirect reciprocity is relevant, individuals may not know each others reputation even indirectly. Previous studies investigated the situations where individuals playing the game have to determine the action possibly without knowing others reputations. Nevertheless, the possibility that observers of the game, who generate the reputation of the interacting players, assign reputations without complete information about them has been neglected. Because an individual acts as an interacting player and as an observer on different occasions if indirect reciprocity is endogenously sustained in a society, the incompleteness of information may affect either role. We examine the game of indirect reciprocity when the reputations of players are not necessarily known to observers and to interacting players. We find that the trustful discriminator, which cooperates with good and unknown players and defects against bad players, realizes cooperative societies under seven social norms. Among the seven social norms, three of the four suspicious norms under which cooperation (defection) to unknown players leads to a good (bad) reputation enable cooperation down to a relatively small observation probability. In contrast, the three trustful norms under which both cooperation and defection to unknown players lead to a good reputation are relatively efficient.'),
(85093, 2011, 'plos', 'The effect of macromolecular crowding, ionic strength and calcium binding on calmodulin dynamics', 'Wang, Qian|Liang, Kao-Chen|Czader, Arkadiusz|Waxham, M Neal|Cheung, Margaret S', 'Department of Physics, University of Houston, Houston, Texas, United States of America.|Department of Physics, University of Houston, Houston, Texas, United States of America.|Department of Physics, University of Houston, Houston, Texas, United States of America.|Department of Physics, University of Houston, Houston, Texas, United States of America.|Department of Physics, University of Houston, Houston, Texas, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Analysis of Variance|Apoenzymes|Binding Sites|Calcium|Calmodulin|Circular Dichroism|Computational Biology|Computer Simulation|Holoenzymes|Molecular Dynamics Simulation|Osmolar Concentration|Protein Binding|Protein Conformation|Protein Stability|Temperature|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002114', '21829336', 'The flexibility in the structure of calmodulin (CaM) allows its binding to over 300 target proteins in the cell. To investigate the structure-function relationship of CaM, we combined methods of computer simulation and experiments based on circular dichroism (CD) to investigate the structural characteristics of CaM that influence its target recognition in crowded cell-like conditions. We developed a unique multiscale solution of charges computed from quantum chemistry, together with protein reconstruction, coarse-grained molecular simulations, and statistical physics, to represent the charge distribution in the transition from apoCaM to holoCaM upon calcium binding. Computationally, we found that increased levels of macromolecular crowding, in addition to calcium binding and ionic strength typical of that found inside cells, can impact the conformation, helicity and the EF hand orientation of CaM. Because EF hand orientation impacts the affinity of calcium binding and the specificity of CaMs target selection, our results may provide unique insight into understanding the promiscuous behavior of calmodulin in target selection inside cells.'),
(85094, 2011, 'plos', 'A mathematical model for the reciprocal differentiation of T helper 17 cells and induced regulatory T cells', 'Hong, Tian|Xing, Jianhua|Li, Liwu|Tyson, John J', 'Genetics, Bioinformatics, and Computational Biology Program, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.|Genetics, Bioinformatics, and Computational Biology Program, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.|Genetics, Bioinformatics, and Computational Biology Program, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.|Genetics, Bioinformatics, and Computational Biology Program, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.', 'United States|United States|United States|United States', 50, 'Cell Differentiation|Computational Biology|Computer Simulation|Forkhead Transcription Factors|Inflammation|Interleukin-17|Interleukin-6|Models, Immunological|Nuclear Receptor Subfamily 1, Group F, Member 3|Phenotype|Signal Transduction|T-Lymphocytes, Helper-Inducer|T-Lymphocytes, Regulatory|Transforming Growth Factor beta|Tretinoin', 'Journal Article', '10.1371/journal.pcbi.1002122', '21829337', 'The reciprocal differentiation of T helper 17 (T(H)17) cells and induced regulatory T (iT(reg)) cells plays a critical role in both the pathogenesis and resolution of diverse human inflammatory diseases. Although initial studies suggested a stable commitment to either the T(H)17 or the iT(reg) lineage, recent results reveal remarkable plasticity and heterogeneity, reflected in the capacity of differentiated effectors cells to be reprogrammed among T(H)17 and iT(reg) lineages and the intriguing phenomenon that a group of naïve precursor CD4(+) T cells can be programmed into phenotypically diverse populations by the same differentiation signal, transforming growth factor beta. To reconcile these observations, we have built a mathematical model of T(H)17/iT(reg) differentiation that exhibits four different stable steady states, governed by pitchfork bifurcations with certain degrees of broken symmetry. According to the model, a group of precursor cells with some small cell-to-cell variability can differentiate into phenotypically distinct subsets of cells, which exhibit distinct levels of the master transcription-factor regulators for the two T cell lineages. A dynamical control system with these properties is flexible enough to be steered down alternative pathways by polarizing signals, such as interleukin-6 and retinoic acid and it may be used by the immune system to generate functionally distinct effector cells in desired fractions in response to a range of differentiation signals. Additionally, the model suggests a quantitative explanation for the phenotype with high expression levels of both master regulators. This phenotype corresponds to a re-stabilized co-expressing state, appearing at a late stage of differentiation, rather than a bipotent precursor state observed under some other circumstances. Our simulations reconcile most published experimental observations and predict novel differentiation states as well as transitions among different phenotypes that have not yet been observed experimentally.'),
(85095, 2011, 'plos', 'Boltzmann energy-based image analysis demonstrates that extracellular domain size differences explain protein segregation at immune synapses', 'Burroughs, Nigel J|Köhler, Karsten|Miloserdov, Vladimir|Dustin, Michael L|van der Merwe, P Anton|Davis, Daniel M', 'Systems Biology Centre, University of Warwick, Coventry, United Kingdom. N.J.Burroughs@warwick.ac.uk|Systems Biology Centre, University of Warwick, Coventry, United Kingdom. N.J.Burroughs@warwick.ac.uk|Systems Biology Centre, University of Warwick, Coventry, United Kingdom. N.J.Burroughs@warwick.ac.uk|Systems Biology Centre, University of Warwick, Coventry, United Kingdom. N.J.Burroughs@warwick.ac.uk|Systems Biology Centre, University of Warwick, Coventry, United Kingdom. N.J.Burroughs@warwick.ac.uk|Systems Biology Centre, University of Warwick, Coventry, United Kingdom. N.J.Burroughs@warwick.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 14, 'Cell Communication|Cell Line, Transformed|Computational Biology|Computer Simulation|Extracellular Space|Humans|Image Processing, Computer-Assisted|Immunological Synapses|Intercellular Adhesion Molecule-1|Killer Cells, Natural|Kinetics|Membrane Proteins|Particle Size|Pattern Recognition, Automated|Poisson Distribution|Protein Structure, Tertiary|T-Lymphocytes|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002076', '21829338', 'Immune synapses formed by T and NK cells both show segregation of the integrin ICAM1 from other proteins such as CD2 (T cell) or KIR (NK cell). However, the mechanism by which these proteins segregate remains unclear, one key hypothesis is a redistribution based on protein size. Simulations of this mechanism qualitatively reproduce observed segregation patterns, but only in certain parameter regimes. Verifying that these parameter constraints in fact hold has not been possible to date, this requiring a quantitative coupling of theory to experimental data. Here, we address this challenge, developing a new methodology for analysing and quantifying image data and its integration with biophysical models. Specifically we fit a binding kinetics model to 2 colour fluorescence data for cytoskeleton independent synapses (2 and 3D) and test whether the observed inverse correlation between fluorophores conforms to size dependent exclusion, and further, whether patterned states are predicted when model parameters are estimated on individual synapses. All synapses analysed satisfy these conditions demonstrating that the mechanisms of protein redistribution have identifiable signatures in their spatial patterns. We conclude that energy processes implicit in protein size based segregation can drive the patternation observed in individual synapses, at least for the specific examples tested, such that no additional processes need to be invoked. This implies that biophysical processes within the membrane interface have a crucial impact on cell:cell communication and cell signalling, governing protein interactions and protein aggregation.'),
(85096, 2011, 'plos', 'Enzyme kinetics of the mitochondrial deoxyribonucleoside salvage pathway are not sufficient to support rapid mtDNA replication', 'Gandhi, Vishal V|Samuels, David C', 'Center for Human Genetics Research, Department of Molecular Biology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Center for Human Genetics Research, Department of Molecular Biology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.', 'United States|United States', 9, 'Computational Biology|Computer Simulation|DNA Replication|DNA, Mitochondrial|Deoxyribonucleosides|Deoxyribonucleotides|Kinetics|Mitochondria', 'Journal Article', '10.1371/journal.pcbi.1002078', '21829339', 'Using a computational model, we simulated mitochondrial deoxynucleotide metabolism and mitochondrial DNA replication. Our results indicate that the output from the mitochondrial salvage enzymes alone is inadequate to support a mitochondrial DNA replication duration of as long as 10 hours. We find that an external source of deoxyribonucleoside diphosphates or triphosphates (dNTPs), in addition to those supplied by mitochondrial salvage, is essential for the replication of mitochondrial DNA to complete in the experimentally observed duration of approximately 1 to 2 hours. For meeting a relatively fast replication target of 2 hours, almost two-thirds of the dNTP requirements had to be externally supplied as either deoxyribonucleoside di- or triphosphates, at about equal rates for all four dNTPs. Added monophosphates did not suffice. However, for a replication target of 10 hours, mitochondrial salvage was able to provide for most, but not all, of the total substrate requirements. Still, additional dGTPs and dATPs had to be supplied. Our analysis of the enzyme kinetics also revealed that the majority of enzymes of this pathway prefer substrates that are not precursors (canonical deoxyribonucleosides and deoxyribonucleotides) for mitochondrial DNA replication, such as phosphorylated ribonucleotides, instead of the corresponding deoxyribonucleotides. The kinetic constants for reactions between mitochondrial salvage enzymes and deoxyribonucleotide substrates are physiologically unreasonable for achieving efficient catalysis with the expected in situ concentrations of deoxyribonucleotides.'),
(85097, 2011, 'plos', 'From structure prediction to genomic screens for novel non-coding RNAs', 'Gorodkin, Jan|Hofacker, Ivo L', 'Center for non-coding RNA in Technology and Health, IBHV University of Copenhagen, Frederiksberg, Denmark. gorodkin@rth.dk|Center for non-coding RNA in Technology and Health, IBHV University of Copenhagen, Frederiksberg, Denmark. gorodkin@rth.dk', 'Denmark|Denmark', 0, 'Algorithms|Base Sequence|Biotechnology|Computational Biology|Molecular Sequence Data|Nucleic Acid Conformation|RNA Folding|RNA, Untranslated', 'Journal Article', '10.1371/journal.pcbi.1002100', '21829340', 'Non-coding RNAs (ncRNAs) are receiving more and more attention not only as an abundant class of genes, but also as regulatory structural elements (some located in mRNAs). A key feature of RNA function is its structure. Computational methods were developed early for folding and prediction of RNA structure with the aim of assisting in functional analysis. With the discovery of more and more ncRNAs, it has become clear that a large fraction of these are highly structured. Interestingly, a large part of the structure is comprised of regular Watson-Crick and GU wobble base pairs. This and the increased amount of available genomes have made it possible to employ structure-based methods for genomic screens. The field has moved from folding prediction of single sequences to computational screens for ncRNAs in genomic sequence using the RNA structure as the main characteristic feature. Whereas early methods focused on energy-directed folding of single sequences, comparative analysis based on structure preserving changes of base pairs has been efficient in improving accuracy, and today this constitutes a key component in genomic screens. Here, we cover the basic principles of RNA folding and touch upon some of the concepts in current methods that have been applied in genomic screens for de novo RNA structures in searches for novel ncRNA genes and regulatory RNA structure on mRNAs. We discuss the strengths and weaknesses of the different strategies and how they can complement each other.'),
(85098, 2011, 'plos', 'The effect of sustained compression on oxygen metabolic transport in the intervertebral disc decreases with degenerative changes', 'Malandrino, Andrea|Noailly, Jérôme|Lacroix, Damien', 'Institute for Bioengineering of Catalonia, Barcelona, Spain.|Institute for Bioengineering of Catalonia, Barcelona, Spain.|Institute for Bioengineering of Catalonia, Barcelona, Spain.', 'Spain|Spain|Spain', 0, 'Biological Transport|Biomechanical Phenomena|Computer Simulation|Diffusion|Finite Element Analysis|Humans|Intervertebral Disc|Intervertebral Disc Degeneration|Lactic Acid|Models, Biological|Oxygen|Porosity|Stress, Mechanical', 'Journal Article', '10.1371/journal.pcbi.1002112', '21829341', 'Intervertebral disc metabolic transport is essential to the functional spine and provides the cells with the nutrients necessary to tissue maintenance. Disc degenerative changes alter the tissue mechanics, but interactions between mechanical loading and disc transport are still an open issue. A poromechanical finite element model of the human disc was coupled with oxygen and lactate transport models. Deformations and fluid flow were linked to transport predictions by including strain-dependent diffusion and advection. The two solute transport models were also coupled to account for cell metabolism. With this approach, the relevance of metabolic and mechano-transport couplings were assessed in the healthy disc under loading-recovery daily compression. Disc height, cell density and material degenerative changes were parametrically simulated to study their influence on the calculated solute concentrations. The effects of load frequency and amplitude were also studied in the healthy disc by considering short periods of cyclic compression. Results indicate that external loads influence the oxygen and lactate regional distributions within the disc when large volume changes modify diffusion distances and diffusivities, especially when healthy disc properties are simulated. Advection was negligible under both sustained and cyclic compression. Simulating degeneration, mechanical changes inhibited the mechanical effect on transport while disc height, fluid content, nucleus pressure and overall cell density reductions affected significantly transport predictions. For the healthy disc, nutrient concentration patterns depended mostly on the time of sustained compression and recovery. The relevant effect of cell density on the metabolic transport indicates the disturbance of cell number as a possible onset for disc degeneration via alteration of the metabolic balance. Results also suggest that healthy disc properties have a positive effect of loading on metabolic transport. Such relation, relevant to the maintenance of the tissue functional composition, would therefore link disc function with disc nutrition.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85099, 2011, 'plos', 'Integrating signals from the T-cell receptor and the interleukin-2 receptor', 'Beyer, Tilo|Busse, Mandy|Hristov, Kroum|Gurbiel, Slavyana|Smida, Michal|Haus, Utz-Uwe|Ballerstein, Kathrin|Pfeuffer, Frank|Weismantel, Robert|Schraven, Burkhart|Lindquist, Jonathan A', 'Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.|Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.|Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.|Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.|Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.|Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.|Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.|Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.|Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.|Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.|Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany', 16, 'Cells, Cultured|Humans|Models, Biological|Phosphatidylinositol 3-Kinases|Protein Kinase C|Receptor Cross-Talk|Receptors, Antigen, T-Cell|Receptors, Interleukin-2|Reproducibility of Results|STAT Transcription Factors|Signal Transduction|T-Lymphocytes|src-Family Kinases', 'Journal Article', '10.1371/journal.pcbi.1002121', '21829342', 'T cells orchestrate the adaptive immune response, making them targets for immunotherapy. Although immunosuppressive therapies prevent disease progression, they also leave patients susceptible to opportunistic infections. To identify novel drug targets, we established a logical model describing T-cell receptor (TCR) signaling. However, to have a model that is able to predict new therapeutic approaches, the current drug targets must be included. Therefore, as a next step we generated the interleukin-2 receptor (IL-2R) signaling network and developed a tool to merge logical models. For IL-2R signaling, we show that STAT activation is independent of both Src- and PI3-kinases, while ERK activation depends upon both kinases and additionally requires novel PKCs. In addition, our merged model correctly predicted TCR-induced STAT activation. The combined network also allows information transfer from one receptor to add detail to another, thereby predicting that LAT mediates JNK activation in IL-2R signaling. In summary, the merged model not only enables us to unravel potential cross-talk, but it also suggests new experimental designs and provides a critical step towards designing strategies to reprogram T cells.'),
(85100, 2011, 'plos', 'Inter-domain communication mechanisms in an ABC importer: a molecular dynamics study of the MalFGK2E complex', 'Oliveira, A Sofia F|Baptista, António M|Soares, Cláudio M', 'Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal.|Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal.|Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal.', 'Portugal|Portugal|Portugal', 29, 'ATP-Binding Cassette Transporters|Adenosine Diphosphate|Adenosine Triphosphate|Amino Acid Motifs|Crystallography, X-Ray|Escherichia coli Proteins|Hydrolysis|Maltose|Molecular Dynamics Simulation|Protein Conformation|Protein Structure, Tertiary|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002128', '21829343', 'ATP-Binding Cassette transporters are ubiquitous membrane proteins that convert the energy from ATP-binding and hydrolysis into conformational changes of the transmembrane region to allow the translocation of substrates against their concentration gradient. Despite the large amount of structural and biochemical data available for this family, it is still not clear how the energy obtained from ATP hydrolysis in the ATPase domains is transmitted to the transmembrane domains. In this work, we focus our attention on the consequences of hydrolysis and inorganic phosphate exit in the maltose uptake system (MalFGK(2)E) from Escherichia coli. The prime goal is to identify and map the structural changes occurring during an ATP-hydrolytic cycle. For that, we use extensive molecular dynamics simulations to study three potential intermediate states (with 10 replicates each): an ATP-bound, an ADP plus inorganic phosphate-bound and an ADP-bound state. Our results show that the residues presenting major rearrangements are located in the A-loop, in the helical sub-domain, and in the EAA motif (especially in the coupling helices region). Additionally, in one of the simulations with ADP we were able to observe the opening of the NBD dimer accompanied by the dissociation of ADP from the ABC signature motif, but not from its corresponding P-loop motif. This work, together with several other MD studies, suggests a common communication mechanism both for importers and exporters, in which ATP-hydrolysis induces conformational changes in the helical sub-domain region, in turn transferred to the transmembrane domains via the coupling helices.'),
(85101, 2011, 'plos', 'Alterations in brain connectivity underlying beta oscillations in Parkinsonism', 'Moran, Rosalyn J|Mallet, Nicolas|Litvak, Vladimir|Dolan, Raymond J|Magill, Peter J|Friston, Karl J|Brown, Peter', 'Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, United Kingdom. r.moran@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, United Kingdom. r.moran@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, United Kingdom. r.moran@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, United Kingdom. r.moran@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, United Kingdom. r.moran@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, United Kingdom. r.moran@fil.ion.ucl.ac.uk|Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, United Kingdom. r.moran@fil.ion.ucl.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Animals|Beta Rhythm|Brain|Computational Biology|Dopamine|Male|Models, Neurological|Nerve Net|Oxidopamine|Parkinsonian Disorders|Rats|Rats, Sprague-Dawley', 'Journal Article', '10.1371/journal.pcbi.1002124', '21852943', 'Cortico-basal ganglia-thalamocortical circuits are severely disrupted by the dopamine depletion of Parkinsons disease (PD), leading to pathologically exaggerated beta oscillations. Abnormal rhythms, found in several circuit nodes are correlated with movement impairments but their neural basis remains unclear. Here, we used dynamic causal modelling (DCM) and the 6-hydroxydopamine-lesioned rat model of PD to examine the effective connectivity underlying these spectral abnormalities. We acquired auto-spectral and cross-spectral measures of beta oscillations (10-35 Hz) from local field potential recordings made simultaneously in the frontal cortex, striatum, external globus pallidus (GPe) and subthalamic nucleus (STN), and used these data to optimise neurobiologically plausible models. Chronic dopamine depletion reorganised the cortico-basal ganglia-thalamocortical circuit, with increased effective connectivity in the pathway from cortex to STN and decreased connectivity from STN to GPe. Moreover, a contribution analysis of the Parkinsonian circuit distinguished between pathogenic and compensatory processes and revealed how effective connectivity along the indirect pathway acquired a strategic importance that underpins beta oscillations. In modelling excessive beta synchrony in PD, these findings provide a novel perspective on how altered connectivity in basal ganglia-thalamocortical circuits reflects a balance between pathogenesis and compensation, and predicts potential new therapeutic targets to overcome dysfunctional oscillations.'),
(85102, 2011, 'plos', 'Structure and dynamics of the membrane-bound cytochrome P450 2C9', 'Cojocaru, Vlad|Balali-Mood, Kia|Sansom, Mark S P|Wade, Rebecca C', 'Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany. vlad.cojocaru@mpi-muenster.mpg.de|Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany. vlad.cojocaru@mpi-muenster.mpg.de|Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany. vlad.cojocaru@mpi-muenster.mpg.de|Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany. vlad.cojocaru@mpi-muenster.mpg.de', 'Germany|Germany|Germany|Germany', 109, 'Aryl Hydrocarbon Hydroxylases|Catalytic Domain|Cell Membrane|Cytochrome P-450 CYP2C9|Humans|Microsomes|Molecular Dynamics Simulation|Pliability|Protein Binding|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1002152', '21852944', 'The microsomal, membrane-bound, human cytochrome P450 (CYP) 2C9 is a liver-specific monooxygenase essential for drug metabolism. CYPs require electron transfer from the membrane-bound CYP reductase (CPR) for catalysis. The structural details and functional relevance of the CYP-membrane interaction are not understood. From multiple coarse grained molecular simulations started with arbitrary configurations of protein-membrane complexes, we found two predominant orientations of CYP2C9 in the membrane, both consistent with experiments and conserved in atomic-resolution simulations. The dynamics of membrane-bound and soluble CYP2C9 revealed correlations between opening and closing of different tunnels from the enzymes buried active site. The membrane facilitated the opening of a tunnel leading into it by stabilizing the open state of an internal aromatic gate. Other tunnels opened selectively in the simulations of product-bound CYP2C9. We propose that the membrane promotes binding of liposoluble substrates by stabilizing protein conformations with an open access tunnel and provide evidence for selective substrate access and product release routes in mammalian CYPs. The models derived here are suitable for extension to incorporate other CYPs for oligomerization studies or the CYP reductase for studies of the electron transfer mechanism, whereas the modeling procedure is generally applicable to study proteins anchored in the bilayer by a single transmembrane helix.'),
(85103, 2011, 'plos', 'Categorial compositionality II: universal constructions and a general theory of (quasi-)systematicity in human cognition', 'Phillips, Steven|Wilson, William H', 'Mathematical Neuroinformatics Group, Human Technology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan. steve@ni.aist.go.jp|Mathematical Neuroinformatics Group, Human Technology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan. steve@ni.aist.go.jp', 'Japan|Japan', 14, 'Cognition|Computational Biology|Humans|Models, Psychological|Neurosciences|Psychological Theory', 'Journal Article', '10.1371/journal.pcbi.1002102', '21857816', 'A complete theory of cognitive architecture (i.e., the basic processes and modes of composition that together constitute cognitive behaviour) must explain the systematicity property--why our cognitive capacities are organized into particular groups of capacities, rather than some other, arbitrary collection. The classical account supposes: (1) syntactically compositional representations, and (2) processes that are sensitive to--compatible with--their structure. Classical compositionality, however, does not explain why these two components must be compatible, they are only compatible by the ad hoc assumption (convention) of employing the same mode of (concatenative) compositionality (e.g., prefix/postfix, where a relation symbol is always prepended/appended to the symbols for the related entities). Architectures employing mixed modes do not support systematicity. Recently, we proposed an alternative explanation without ad hoc assumptions, using category theory. Here, we extend our explanation to domains that are quasi-systematic (e.g., aspects of most languages), where the domain includes some but not all possible combinations of constituents. The central category-theoretic construct is an adjunction involving pullbacks, where the primary focus is on the relationship between processes modelled as functors, rather than the representations. A functor is a structure-preserving map (or construction, for our purposes). An adjunction guarantees that the only pairings of functors are the systematic ones. Thus, (quasi-)systematicity is a necessary consequence of a categorial cognitive architecture whose basic processes are functors that participate in adjunctions.'),
(85104, 2011, 'plos', 'A neurocomputational model of stimulus-specific adaptation to oddball and Markov sequences', 'Mill, Robert|Coath, Martin|Wennekers, Thomas|Denham, Susan L', 'School of Psychology/Centre for Robotics and Neural Systems, University of Plymouth, Plymouth, United Kingdom. robert.mill@plymouth.ac.uk|School of Psychology/Centre for Robotics and Neural Systems, University of Plymouth, Plymouth, United Kingdom. robert.mill@plymouth.ac.uk|School of Psychology/Centre for Robotics and Neural Systems, University of Plymouth, Plymouth, United Kingdom. robert.mill@plymouth.ac.uk|School of Psychology/Centre for Robotics and Neural Systems, University of Plymouth, Plymouth, United Kingdom. robert.mill@plymouth.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Acoustic Stimulation|Adaptation, Physiological|Animals|Auditory Cortex|Computational Biology|Evoked Potentials, Auditory|Markov Chains|Models, Neurological|Neurons|Rats|Synapses|Wakefulness', 'Journal Article', '10.1371/journal.pcbi.1002117', '21876661', 'Stimulus-specific adaptation (SSA) occurs when the spike rate of a neuron decreases with repetitions of the same stimulus, but recovers when a different stimulus is presented. It has been suggested that SSA in single auditory neurons may provide information to change detection mechanisms evident at other scales (e.g., mismatch negativity in the event related potential), and participate in the control of attention and the formation of auditory streams. This article presents a spiking-neuron model that accounts for SSA in terms of the convergence of depressing synapses that convey feature-specific inputs. The model is anatomically plausible, comprising just a few homogeneously connected populations, and does not require organised feature maps. The model is calibrated to match the SSA measured in the cortex of the awake rat, as reported in one study. The effect of frequency separation, deviant probability, repetition rate and duration upon SSA are investigated. With the same parameter set, the model generates responses consistent with a wide range of published data obtained in other auditory regions using other stimulus configurations, such as block, sequential and random stimuli. A new stimulus paradigm is introduced, which generalises the oddball concept to Markov chains, allowing the experimenter to vary the tone probabilities and the rate of switching independently. The model predicts greater SSA for higher rates of switching. Finally, the issue of whether rarity or novelty elicits SSA is addressed by comparing the responses of the model to deviants in the context of a sequence of a single standard or many standards. The results support the view that synaptic adaptation alone can explain almost all aspects of SSA reported to date, including its purported novelty component, and that non-trivial networks of depressing synapses can intensify this novelty response.'),
(85105, 2011, 'plos', 'Binding free energy landscape of domain-peptide interactions', 'Staneva, Iskra|Wallin, Stefan', 'Department of Astronomy and Theoretical Physics, Computational Biology and Biological Physics Group, Lund University, Lund, Sweden.|Department of Astronomy and Theoretical Physics, Computational Biology and Biological Physics Group, Lund University, Lund, Sweden.', 'Sweden|Sweden', 18, 'Computer Simulation|Humans|Kinetics|Models, Chemical|Models, Molecular|Monte Carlo Method|PDZ Domains|Peptides|Protein Binding|Protein Folding|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.1002131', '21876662', 'Peptide recognition domains (PRDs) are ubiquitous protein domains which mediate large numbers of protein interactions in the cell. How these PRDs are able to recognize peptide sequences in a rapid and specific manner is incompletely understood. We explore the peptide binding process of PDZ domains, a large PRD family, from an equilibrium perspective using an all-atom Monte Carlo (MC) approach. Our focus is two different PDZ domains representing two major PDZ classes, I and II. For both domains, a binding free energy surface with a strong bias toward the native bound state is found. Moreover, both domains exhibit a binding process in which the peptides are mostly either bound at the PDZ binding pocket or else interact little with the domain surface. Consistent with this, various binding observables show a temperature dependence well described by a simple two-state model. We also find important differences in the details between the two domains. While both domains exhibit well-defined binding free energy barriers, the class I barrier is significantly weaker than the one for class II. To probe this issue further, we apply our method to a PDZ domain with dual specificity for class I and II peptides, and find an analogous difference in their binding free energy barriers. Lastly, we perform a large number of fixed-temperature MC kinetics trajectories under binding conditions. These trajectories reveal significantly slower binding dynamics for the class II domain relative to class I. Our combined results are consistent with a binding mechanism in which the peptide C terminal residue binds in an initial, rate-limiting step.'),
(85106, 2011, 'plos', 'Effective stimuli for constructing reliable neuron models', 'Druckmann, Shaul|Berger, Thomas K|Schürmann, Felix|Hill, Sean|Markram, Henry|Segev, Idan', 'Interdisciplinary Center for Neural Computation, Hebrew University of Jerusalem, Jerusalem, Israel.|Interdisciplinary Center for Neural Computation, Hebrew University of Jerusalem, Jerusalem, Israel.|Interdisciplinary Center for Neural Computation, Hebrew University of Jerusalem, Jerusalem, Israel.|Interdisciplinary Center for Neural Computation, Hebrew University of Jerusalem, Jerusalem, Israel.|Interdisciplinary Center for Neural Computation, Hebrew University of Jerusalem, Jerusalem, Israel.|Interdisciplinary Center for Neural Computation, Hebrew University of Jerusalem, Jerusalem, Israel.', 'Israel|Israel|Israel|Israel|Israel|Israel', 27, 'Action Potentials|Algorithms|Animals|Computational Biology|Electric Conductivity|Electrophysiology|Interneurons|Mice|Models, Neurological|Neurons|Patch-Clamp Techniques|Pyramidal Cells|Rats|Rats, Wistar', 'Journal Article', '10.1371/journal.pcbi.1002133', '21876663', 'The rich dynamical nature of neurons poses major conceptual and technical challenges for unraveling their nonlinear membrane properties. Traditionally, various current waveforms have been injected at the soma to probe neuron dynamics, but the rationale for selecting specific stimuli has never been rigorously justified. The present experimental and theoretical study proposes a novel framework, inspired by learning theory, for objectively selecting the stimuli that best unravel the neurons dynamics. The efficacy of stimuli is assessed in terms of their ability to constrain the parameter space of biophysically detailed conductance-based models that faithfully replicate the neurons dynamics as attested by their ability to generalize well to the neurons response to novel experimental stimuli. We used this framework to evaluate a variety of stimuli in different types of cortical neurons, ages and animals. Despite their simplicity, a set of stimuli consisting of step and ramp current pulses outperforms synaptic-like noisy stimuli in revealing the dynamics of these neurons. The general framework that we propose paves a new way for defining, evaluating and standardizing effective electrical probing of neurons and will thus lay the foundation for a much deeper understanding of the electrical nature of these highly sophisticated and non-linear devices and of the neuronal networks that they compose.'),
(85107, 2011, 'plos', 'Evolutionary accessibility of mutational pathways', 'Franke, Jasper|Klözer, Alexander|de Visser, J Arjan G M|Krug, Joachim', 'Institute of Theoretical Physics, University of Cologne, Köln, Germany.|Institute of Theoretical Physics, University of Cologne, Köln, Germany.|Institute of Theoretical Physics, University of Cologne, Köln, Germany.|Institute of Theoretical Physics, University of Cologne, Köln, Germany.', 'Germany|Germany|Germany|Germany', 0, 'Aspergillus niger|Computational Biology|Computer Simulation|Evolution, Molecular|Genes, Fungal|Genetic Fitness|Models, Genetic|Mutagenesis|Mutation', 'Journal Article', '10.1371/journal.pcbi.1002134', '21876664', 'Functional effects of different mutations are known to combine to the total effect in highly nontrivial ways. For the trait under evolutionary selection (fitness), measured values over all possible combinations of a set of mutations yield a fitness landscape that determines which mutational states can be reached from a given initial genotype. Understanding the accessibility properties of fitness landscapes is conceptually important in answering questions about the predictability and repeatability of evolutionary adaptation. Here we theoretically investigate accessibility of the globally optimal state on a wide variety of model landscapes, including landscapes with tunable ruggedness as well as neutral holey landscapes. We define a mutational pathway to be accessible if it contains the minimal number of mutations required to reach the target genotype, and if fitness increases in each mutational step. Under this definition accessibility is high, in the sense that at least one accessible pathway exists with a substantial probability that approaches unity as the dimensionality of the fitness landscape (set by the number of mutational loci) becomes large. At the same time the number of alternative accessible pathways grows without bounds. We test the model predictions against an empirical 8-locus fitness landscape obtained for the filamentous fungus Aspergillus niger. By analyzing subgraphs of the full landscape containing different subsets of mutations, we are able to probe the mutational distance scale in the empirical data. The predicted effect of high accessibility is supported by the empirical data and is very robust, which we argue reflects the generic topology of sequence spaces. Together with the restrictive assumptions that lie in our definition of accessibility, this implies that the globally optimal configuration should be accessible to genome wide evolution, but the repeatability of evolutionary trajectories is limited owing to the presence of a large number of alternative mutational pathways.'),
(85108, 2011, 'plos', 'Statistical inference for multi-pathogen systems', 'Shrestha, Sourya|King, Aaron A|Rohani, Pejman', 'Department of Ecology & Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America. sourya@umich.edu|Department of Ecology & Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America. sourya@umich.edu|Department of Ecology & Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America. sourya@umich.edu', 'United States|United States|United States', 36, 'Coinfection|Communicable Diseases|Computational Biology|Computer Simulation|Microbial Interactions|Models, Biological|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002135', '21876665', 'There is growing interest in understanding the nature and consequences of interactions among infectious agents. Pathogen interactions can be operational at different scales, either within a co-infected host or in host populations where they co-circulate, and can be either cooperative or competitive. The detection of interactions among pathogens has typically involved the study of synchrony in the oscillations of the protagonists, but as we show here, phase association provides an unreliable dynamical fingerprint for this task. We assess the capacity of a likelihood-based inference framework to accurately detect and quantify the presence and nature of pathogen interactions on the basis of realistic amounts and kinds of simulated data. We show that when epidemiological and demographic processes are well understood, noisy time series data can contain sufficient information to allow correct inference of interactions in multi-pathogen systems. The inference power is dependent on the strength and time-course of the underlying mechanism: stronger and longer-lasting interactions are more easily and more precisely quantified. We examine the limitations of our approach to stochastic temporal variation, under-reporting, and over-aggregation of data. We propose that likelihood shows promise as a basis for detection and quantification of the effects of pathogen interactions and the determination of their (competitive or cooperative) nature on the basis of population-level time-series data.'),
(85109, 2011, 'plos', 'Essential requirements for robust signaling in Hfq dependent small RNA networks', 'Adamson, David N|Lim, Han N', 'Biophysics Graduate Group, University of California, Berkeley, California, United States of America.|Biophysics Graduate Group, University of California, Berkeley, California, United States of America.', 'United States|United States', 17, 'Bacterial Physiological Phenomena|Gene Expression Regulation, Bacterial|Host Factor 1 Protein|Kinetics|Models, Genetic|Protein Binding|RNA, Bacterial|RNA, Messenger|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1002138', '21876666', 'Bacteria possess networks of small RNAs (sRNAs) that are important for modulating gene expression. At the center of many of these sRNA networks is the Hfq protein. Hfqs role is to quickly match cognate sRNAs and target mRNAs from among a large number of possible combinations and anneal them to form duplexes. Here we show using a kinetic model that Hfq can efficiently and robustly achieve this difficult task by minimizing the sequestration of sRNAs and target mRNAs in Hfq complexes. This sequestration can be reduced by two non-mutually exclusive kinetic mechanisms. The first mechanism involves heterotropic cooperativity (where sRNA and target mRNA binding to Hfq is influenced by other RNAs bound to Hfq), this cooperativity can selectively decrease singly-bound Hfq complexes and ternary complexes with non-cognate sRNA-target mRNA pairs while increasing cognate ternary complexes. The second mechanism relies on frequent RNA dissociation enabling the rapid cycling of sRNAs and target mRNAs among different Hfq complexes, this increases the probability the cognate ternary complex forms before the sRNAs and target mRNAs degrade. We further demonstrate that the performance of sRNAs in isolation is not predictive of their performance within a network. These findings highlight the importance of experimentally characterizing duplex formation in physiologically relevant contexts with multiple RNAs competing for Hfq. The model will provide a valuable framework for guiding and interpreting these experiments.'),
(85110, 2011, 'plos', 'Spatial stereoresolution for depth corrugations may be set in primary visual cortex', 'Allenmark, Fredrik|Read, Jenny C A', 'Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom. fredrik.allenmark@ncl.ac.uk|Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom. fredrik.allenmark@ncl.ac.uk', 'United Kingdom|United Kingdom', 23, 'Computational Biology|Depth Perception|Humans|Models, Neurological|Photic Stimulation|Vision Disparity|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1002142', '21876667', 'Stereo 3D depth perception requires the visual system to extract binocular disparities between the two eyes images. Several current models of this process, based on the known physiology of primary visual cortex (V1), do this by computing a piecewise-frontoparallel local cross-correlation between the left and right eyes images. The size of the window within which detectors examine the local cross-correlation corresponds to the receptive field size of V1 neurons. This basic model has successfully captured many aspects of human depth perception. In particular, it accounts for the low human stereoresolution for sinusoidal depth corrugations, suggesting that the limit on stereoresolution may be set in primary visual cortex. An important feature of the model, reflecting a key property of V1 neurons, is that the initial disparity encoding is performed by detectors tuned to locally uniform patches of disparity. Such detectors respond better to square-wave depth corrugations, since these are locally flat, than to sinusoidal corrugations which are slanted almost everywhere. Consequently, for any given window size, current models predict better performance for square-wave disparity corrugations than for sine-wave corrugations at high amplitudes. We have recently shown that this prediction is not borne out: humans perform no better with square-wave than with sine-wave corrugations, even at high amplitudes. The failure of this prediction raised the question of whether stereoresolution may actually be set at later stages of cortical processing, perhaps involving neurons tuned to disparity slant or curvature. Here we extend the local cross-correlation model to include existing physiological and psychophysical evidence indicating that larger disparities are detected by neurons with larger receptive fields (a size/disparity correlation). We show that this simple modification succeeds in reconciling the model with human results, confirming that stereoresolution for disparity gratings may indeed be limited by the size of receptive fields in primary visual cortex.'),
(85111, 2011, 'plos', 'Understanding auditory spectro-temporal receptive fields and their changes with input statistics by efficient coding principles', 'Zhao, Lingyun|Zhaoping, Li', 'Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, PR China.|Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, PR China.', 'China|China', 9, 'Acoustic Stimulation|Animals|Auditory Cortex|Auditory Perception|Computational Biology|Neurons', 'Journal Article', '10.1371/journal.pcbi.1002123', '21887121', 'Spectro-temporal receptive fields (STRFs) have been widely used as linear approximations to the signal transform from sound spectrograms to neural responses along the auditory pathway. Their dependence on statistical attributes of the stimuli, such as sound intensity, is usually explained by nonlinear mechanisms and models. Here, we apply an efficient coding principle which has been successfully used to understand receptive fields in early stages of visual processing, in order to provide a computational understanding of the STRFs. According to this principle, STRFs result from an optimal tradeoff between maximizing the sensory information the brain receives, and minimizing the cost of the neural activities required to represent and transmit this information. Both terms depend on the statistical properties of the sensory inputs and the noise that corrupts them. The STRFs should therefore depend on the input power spectrum and the signal-to-noise ratio, which is assumed to increase with input intensity. We analytically derive the optimal STRFs when signal and noise are approximated as Gaussians. Under the constraint that they should be spectro-temporally local, the STRFs are predicted to adapt from being band-pass to low-pass filters as the input intensity reduces, or the input correlation becomes longer range in sound frequency or time. These predictions qualitatively match physiological observations. Our prediction as to how the STRFs should be determined by the input power spectrum could readily be tested, since this spectrum depends on the stimulus ensemble. The potentials and limitations of the efficient coding principle are discussed.'),
(85112, 2011, 'plos', 'Towards a system level understanding of non-model organisms sampled from the environment: a network biology approach', 'Williams, Tim D|Turan, Nil|Diab, Amer M|Wu, Huifeng|Mackenzie, Carolynn|Bartie, Katie L|Hrydziuszko, Olga|Lyons, Brett P|Stentiford, Grant D|Herbert, John M|Abraham, Joseph K|Katsiadaki, Ioanna|Leaver, Michael J|Taggart, John B|George, Stephen G|Viant, Mark R|Chipman, Kevin J|Falciani, Francesco', 'School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.|School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 65, 'Analysis of Variance|Animals|Cluster Analysis|Ecosystem|Environmental Exposure|Flounder|Gene Expression Regulation|Gene Regulatory Networks|Geologic Sediments|Humans|Liver|Metabolic Networks and Pathways|Metabolomics|Models, Biological|Systems Biology|Transcriptome', 'Journal Article', '10.1371/journal.pcbi.1002126', '21901081', 'The acquisition and analysis of datasets including multi-level omics and physiology from non-model species, sampled from field populations, is a formidable challenge, which so far has prevented the application of systems biology approaches. If successful, these could contribute enormously to improving our understanding of how populations of living organisms adapt to environmental stressors relating to, for example, pollution and climate. Here we describe the first application of a network inference approach integrating transcriptional, metabolic and phenotypic information representative of wild populations of the European flounder fish, sampled at seven estuarine locations in northern Europe with different degrees and profiles of chemical contaminants. We identified network modules, whose activity was predictive of environmental exposure and represented a link between molecular and morphometric indices. These sub-networks represented both known and candidate novel adverse outcome pathways representative of several aspects of human liver pathophysiology such as liver hyperplasia, fibrosis, and hepatocellular carcinoma. At the molecular level these pathways were linked to TNF alpha, TGF beta, PDGF, AGT and VEGF signalling. More generally, this pioneering study has important implications as it can be applied to model molecular mechanisms of compensatory adaptation to a wide range of scenarios in wild populations.'),
(85113, 2011, 'plos', 'Inference for nonlinear epidemiological models using genealogies and time series', 'Rasmussen, David A|Ratmann, Oliver|Koelle, Katia', 'Department of Biology, Duke University, Durham, North Carolina, United States of America. dar24@duke.edu|Department of Biology, Duke University, Durham, North Carolina, United States of America. dar24@duke.edu|Department of Biology, Duke University, Durham, North Carolina, United States of America. dar24@duke.edu', 'United States|United States|United States', 74, 'Algorithms|Bayes Theorem|Computational Biology|Disease Transmission, Infectious|Epidemics|Epidemiologic Methods|Models, Biological|Monte Carlo Method|Nonlinear Dynamics|Phylogeny|Population Dynamics|Prevalence|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002136', '21901082', 'Phylodynamics - the field aiming to quantitatively integrate the ecological and evolutionary dynamics of rapidly evolving populations like those of RNA viruses - increasingly relies upon coalescent approaches to infer past population dynamics from reconstructed genealogies. As sequence data have become more abundant, these approaches are beginning to be used on populations undergoing rapid and rather complex dynamics. In such cases, the simple demographic models that current phylodynamic methods employ can be limiting. First, these models are not ideal for yielding biological insight into the processes that drive the dynamics of the populations of interest. Second, these models differ in form from mechanistic and often stochastic population dynamic models that are currently widely used when fitting models to time series data. As such, their use does not allow for both genealogical data and time series data to be considered in tandem when conducting inference. Here, we present a flexible statistical framework for phylodynamic inference that goes beyond these current limitations. The framework we present employs a recently developed method known as particle MCMC to fit stochastic, nonlinear mechanistic models for complex population dynamics to gene genealogies and time series data in a Bayesian framework. We demonstrate our approach using a nonlinear Susceptible-Infected-Recovered (SIR) model for the transmission dynamics of an infectious disease and show through simulations that it provides accurate estimates of past disease dynamics and key epidemiological parameters from genealogies with or without accompanying time series data.'),
(85114, 2011, 'plos', 'Bistability versus bimodal distributions in gene regulatory processes from population balance', 'Shu, Che-Chi|Chatterjee, Anushree|Dunny, Gary|Hu, Wei-Shou|Ramkrishna, Doraiswami', 'School of Chemical Engineering, Purdue University, Indiana, United States of America.|School of Chemical Engineering, Purdue University, Indiana, United States of America.|School of Chemical Engineering, Purdue University, Indiana, United States of America.|School of Chemical Engineering, Purdue University, Indiana, United States of America.|School of Chemical Engineering, Purdue University, Indiana, United States of America.', 'India|India|India|India|India', 31, 'Cells, Cultured|Computational Biology|Computer Simulation|Enterococcus faecalis|Gene Expression Regulation|Models, Genetic|Population Dynamics|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002140', '21901083', 'In recent times, stochastic treatments of gene regulatory processes have appeared in the literature in which a cell exposed to a signaling molecule in its environment triggers the synthesis of a specific protein through a network of intracellular reactions. The stochastic nature of this process leads to a distribution of protein levels in a population of cells as determined by a Fokker-Planck equation. Often instability occurs as a consequence of two (stable) steady state protein levels, one at the low end representing the off state, and the other at the high end representing the on state for a given concentration of the signaling molecule within a suitable range. A consequence of such bistability has been the appearance of bimodal distributions indicating two different populations, one in the off state and the other in the on state. The bimodal distribution can come about from stochastic analysis of a single cell. However, the concerted action of the population altering the extracellular concentration in the environment of individual cells and hence their behavior can only be accomplished by an appropriate population balance model which accounts for the reciprocal effects of interaction between the population and its environment. In this study, we show how to formulate a population balance model in which stochastic gene expression in individual cells is incorporated. Interestingly, the simulation of the model shows that bistability is neither sufficient nor necessary for bimodal distributions in a population. The original notion of linking bistability with bimodal distribution from single cell stochastic model is therefore only a special consequence of a population balance model.'),
(85115, 2011, 'plos', 'Using electronic patient records to discover disease correlations and stratify patient cohorts', 'Roque, Francisco S|Jensen, Peter B|Schmock, Henriette|Dalgaard, Marlene|Andreatta, Massimo|Hansen, Thomas|Søeby, Karen|Bredkjær, Søren|Juul, Anders|Werge, Thomas|Jensen, Lars J|Brunak, Søren', 'Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.', 'Denmark|Denmark|Denmark|Denmark|Denmark|Denmark|Denmark|Denmark|Denmark|Denmark|Denmark|Denmark', 170, 'Cluster Analysis|Cohort Studies|Comorbidity|Computational Biology|Data Collection|Data Mining|Electronic Health Records|Humans|International Classification of Diseases|Reproducibility of Results', 'Journal Article', '10.1371/journal.pcbi.1002141', '21901084', 'Electronic patient records remain a rather unexplored, but potentially rich data source for discovering correlations between diseases. We describe a general approach for gathering phenotypic descriptions of patients from medical records in a systematic and non-cohort dependent manner. By extracting phenotype information from the free-text in such records we demonstrate that we can extend the information contained in the structured record data, and use it for producing fine-grained patient stratification and disease co-occurrence statistics. The approach uses a dictionary based on the International Classification of Disease ontology and is therefore in principle language independent. As a use case we show how records from a Danish psychiatric hospital lead to the identification of disease correlations, which subsequently can be mapped to systems biology frameworks.'),
(85116, 2011, 'plos', 'Biomedical cloud computing with Amazon Web Services', 'Fusaro, Vincent A|Patil, Prasad|Gafni, Erik|Wall, Dennis P|Tonellato, Peter J', 'Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, United States of America. vfusaro@hms.harvard.edu|Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, United States of America. vfusaro@hms.harvard.edu|Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, United States of America. vfusaro@hms.harvard.edu|Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, United States of America. vfusaro@hms.harvard.edu|Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, United States of America. vfusaro@hms.harvard.edu', 'United States|United States|United States|United States|United States', 85, 'Computational Biology|Computer Security|Information Storage and Retrieval|Internet|Software', 'Journal Article', '10.1371/journal.pcbi.1002147', '21901085', 'In this overview to biomedical computing in the cloud, we discussed two primary ways to use the cloud (a single instance or cluster), provided a detailed example using NGS mapping, and highlighted the associated costs. While many users new to the cloud may assume that entry is as straightforward as uploading an application and selecting an instance type and storage options, we illustrated that there is substantial up-front effort required before an application can make full use of the clouds vast resources. Our intention was to provide a set of best practices and to illustrate how those apply to a typical application pipeline for biomedical informatics, but also general enough for extrapolation to other types of computational problems. Our mapping example was intended to illustrate how to develop a scalable project and not to compare and contrast alignment algorithms for read mapping and genome assembly. Indeed, with a newer aligner such as Bowtie, it is possible to map the entire African genome using one m2.2xlarge instance in 48 hours for a total cost of approximately $48 in computation time. In our example, we were not concerned with data transfer rates, which are heavily influenced by the amount of available bandwidth, connection latency, and network availability. When transferring large amounts of data to the cloud, bandwidth limitations can be a major bottleneck, and in some cases it is more efficient to simply mail a storage device containing the data to AWS (http://aws.amazon.com/importexport/). More information about cloud computing, detailed cost analysis, and security can be found in references.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(85117, 2011, 'plos', 'Podbat: a novel genomic tool reveals Swr1-independent H2AZ incorporation at gene coding sequences through epigenetic meta-analysis', 'Sadeghi, Laia|Bonilla, Carolina|Strålfors, Annelie|Ekwall, Karl|Svensson, J Peter', 'Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.|Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.|Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.|Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.|Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.', 'Sweden|Sweden|Sweden|Sweden|Sweden', 25, 'Adenosine Triphosphatases|Algorithms|Cell Cycle|Chromatin Assembly and Disassembly|DNA Damage|Database Management Systems|Epigenesis, Genetic|Epigenomics|Genome, Fungal|Histones|Markov Chains|Models, Genetic|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Schizosaccharomyces', 'Journal Article', '10.1371/journal.pcbi.1002163', '21901086', 'Epigenetic regulation consists of a multitude of different modifications that determine active and inactive states of chromatin. Conditions such as cell differentiation or exposure to environmental stress require concerted changes in gene expression. To interpret epigenomics data, a spectrum of different interconnected datasets is needed, ranging from the genome sequence and positions of histones, together with their modifications and variants, to the transcriptional output of genomic regions. Here we present a tool, Podbat (Positioning database and analysis tool), that incorporates data from various sources and allows detailed dissection of the entire range of chromatin modifications simultaneously. Podbat can be used to analyze, visualize, store and share epigenomics data. Among other functions, Podbat allows data-driven determination of genome regions of differential protein occupancy or RNA expression using Hidden Markov Models. Comparisons between datasets are facilitated to enable the study of the comprehensive chromatin modification system simultaneously, irrespective of data-generating technique. Any organism with a sequenced genome can be accommodated. We exemplify the power of Podbat by reanalyzing all to-date published genome-wide data for the histone variant H2A.Z in fission yeast together with other histone marks and also phenotypic response data from several sources. This meta-analysis led to the unexpected finding of H2A.Z incorporation in the coding regions of genes encoding proteins involved in the regulation of meiosis and genotoxic stress responses. This incorporation was partly independent of the H2A.Z-incorporating remodeller Swr1. We verified an Swr1-independent role for H2A.Z following genotoxic stress in vivo. Podbat is open source software freely downloadable from www.podbat.org, distributed under the GNU LGPL license. User manuals, test data and instructions are available at the website, as well as a repository for third party-developed plug-in modules. Podbat requires Java version 1.6 or higher.'),
(85118, 2011, 'plos', 'Are there laws of genome evolution?', 'Koonin, Eugene V', 'National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America. koonin@ncbi.nlm.nih.gov', 'United States', 58, 'Computer Simulation|Evolution, Molecular|Genome|Genomics|Models, Genetic|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1002173', '21901087', 'Research in quantitative evolutionary genomics and systems biology led to the discovery of several universal regularities connecting genomic and molecular phenomic variables. These universals include the log-normal distribution of the evolutionary rates of orthologous genes, the power law-like distributions of paralogous family size and node degree in various biological networks, the negative correlation between a genes sequence evolution rate and expression level, and differential scaling of functional classes of genes with genome size. The universals of genome evolution can be accounted for by simple mathematical models similar to those used in statistical physics, such as the birth-death-innovation model. These models do not explicitly incorporate selection, therefore, the observed universal regularities do not appear to be shaped by selection but rather are emergent properties of gene ensembles. Although a complete physical theory of evolutionary biology is inconceivable, the universals of genome evolution might qualify as laws of evolutionary genomics in the same sense law is understood in modern physics.'),
(85119, 2011, 'plos', 'Genome-scale analysis of translation elongation with a ribosome flow model', 'Reuveni, Shlomi|Meilijson, Isaac|Kupiec, Martin|Ruppin, Eytan|Tuller, Tamir', 'Department of Statistics and Operations Research, School of Mathematical Sciences, Tel Aviv University, Ramat Aviv, Israel.|Department of Statistics and Operations Research, School of Mathematical Sciences, Tel Aviv University, Ramat Aviv, Israel.|Department of Statistics and Operations Research, School of Mathematical Sciences, Tel Aviv University, Ramat Aviv, Israel.|Department of Statistics and Operations Research, School of Mathematical Sciences, Tel Aviv University, Ramat Aviv, Israel.|Department of Statistics and Operations Research, School of Mathematical Sciences, Tel Aviv University, Ramat Aviv, Israel.', 'Israel|Israel|Israel|Israel|Israel', 107, 'Codon|Genomics|Humans|Models, Genetic|Peptide Chain Elongation, Translational|Protein Biosynthesis|Ribosomes|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.1002127', '21909250', 'We describe the first large scale analysis of gene translation that is based on a model that takes into account the physical and dynamical nature of this process. The Ribosomal Flow Model (RFM) predicts fundamental features of the translation process, including translation rates, protein abundance levels, ribosomal densities and the relation between all these variables, better than alternative (non-physical) approaches. In addition, we show that the RFM can be used for accurate inference of various other quantities including genes initiation rates and translation costs. These quantities could not be inferred by previous predictors. We find that increasing the number of available ribosomes (or equivalently the initiation rate) increases the genomic translation rate and the mean ribosome density only up to a certain point, beyond which both saturate. Strikingly, assuming that the translation system is tuned to work at the pre-saturation point maximizes the predictive power of the model with respect to experimental data. This result suggests that in all organisms that were analyzed (from bacteria to Human), the global initiation rate is optimized to attain the pre-saturation point. The fact that similar results were not observed for heterologous genes indicates that this feature is under selection. Remarkably, the gap between the performance of the RFM and alternative predictors is strikingly large in the case of heterologous genes, testifying to the models promising biotechnological value in predicting the abundance of heterologous proteins before expressing them in the desired host.'),
(85120, 2011, 'plos', 'A systems biology approach identifies molecular networks defining skeletal muscle abnormalities in chronic obstructive pulmonary disease', 'Turan, Nil|Kalko, Susana|Stincone, Anna|Clarke, Kim|Sabah, Ayesha|Howlett, Katherine|Curnow, S John|Rodriguez, Diego A|Cascante, Marta|ONeill, Laura|Egginton, Stuart|Roca, Josep|Falciani, Francesco', 'School of Biosciences, University of Birmingham, Birmingham, UK.|School of Biosciences, University of Birmingham, Birmingham, UK.|School of Biosciences, University of Birmingham, Birmingham, UK.|School of Biosciences, University of Birmingham, Birmingham, UK.|School of Biosciences, University of Birmingham, Birmingham, UK.|School of Biosciences, University of Birmingham, Birmingham, UK.|School of Biosciences, University of Birmingham, Birmingham, UK.|School of Biosciences, University of Birmingham, Birmingham, UK.|School of Biosciences, University of Birmingham, Birmingham, UK.|School of Biosciences, University of Birmingham, Birmingham, UK.|School of Biosciences, University of Birmingham, Birmingham, UK.|School of Biosciences, University of Birmingham, Birmingham, UK.|School of Biosciences, University of Birmingham, Birmingham, UK.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 53, 'Aged|Animals|Cell Hypoxia|Cytokines|Energy Metabolism|Female|Gene Expression Profiling|Histones|Humans|Interleukin-1beta|Male|Metabolic Networks and Pathways|Mice|Mice, Inbred C57BL|Middle Aged|Muscle, Skeletal|Oxygen Consumption|Pulmonary Disease, Chronic Obstructive|RNA, Messenger|Systems Biology|Up-Regulation', 'Journal Article', '10.1371/journal.pcbi.1002129', '21909251', 'Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory process of the lung inducing persistent airflow limitation. Extensive systemic effects, such as skeletal muscle dysfunction, often characterize these patients and severely limit life expectancy. Despite considerable research efforts, the molecular basis of muscle degeneration in COPD is still a matter of intense debate. In this study, we have applied a network biology approach to model the relationship between muscle molecular and physiological response to training and systemic inflammatory mediators. Our model shows that failure to co-ordinately activate expression of several tissue remodelling and bioenergetics pathways is a specific landmark of COPD diseased muscles. Our findings also suggest that this phenomenon may be linked to an abnormal expression of a number of histone modifiers, which we discovered correlate with oxygen utilization. These observations raised the interesting possibility that cell hypoxia may be a key factor driving skeletal muscle degeneration in COPD patients.'),
(85121, 2011, 'plos', 'A computational approach to finding novel targets for existing drugs', 'Li, Yvonne Y|An, Jianghong|Jones, Steven J M', 'Canadas Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. yli@bcgsc.ca|Canadas Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. yli@bcgsc.ca|Canadas Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. yli@bcgsc.ca', 'Canada|Canada|Canada', 0, 'Computational Biology|Databases, Protein|Drug Discovery|Humans|Mitogen-Activated Protein Kinase 14|Models, Molecular|Molecular Targeted Therapy|Pharmaceutical Preparations|Protein Binding|Protein Kinase C|Protein Kinase Inhibitors|Proteins|Pyrimidines|Reproducibility of Results|Tosyl Compounds', 'Journal Article', '10.1371/journal.pcbi.1002139', '21909252', 'Repositioning existing drugs for new therapeutic uses is an efficient approach to drug discovery. We have developed a computational drug repositioning pipeline to perform large-scale molecular docking of small molecule drugs against protein drug targets, in order to map the drug-target interaction space and find novel interactions. Our method emphasizes removing false positive interaction predictions using criteria from known interaction docking, consensus scoring, and specificity. In all, our database contains 252 human protein drug targets that we classify as reliable-for-docking as well as 4621 approved and experimental small molecule drugs from DrugBank. These were cross-docked, then filtered through stringent scoring criteria to select top drug-target interactions. In particular, we used MAPK14 and the kinase inhibitor BIM-8 as examples where our stringent thresholds enriched the predicted drug-target interactions with known interactions up to 20 times compared to standard score thresholds. We validated nilotinib as a potent MAPK14 inhibitor in vitro (IC50 40 nM), suggesting a potential use for this drug in treating inflammatory diseases. The published literature indicated experimental evidence for 31 of the top predicted interactions, highlighting the promising nature of our approach. Novel interactions discovered may lead to the drug being repositioned as a therapeutic treatment for its off-targets associated disease, added insight into the drugs mechanism of action, and added insight into the drugs side effects.'),
(85122, 2011, 'plos', 'Analyzing the functional properties of the creatine kinase system with multiscale sloppy modeling', 'Hettling, Hannes|van Beek, Johannes H G M', 'Centre for Integrative Bioinformatics VU, VU University Amsterdam, Amsterdam, The Netherlands. hettling@few.vu.nl|Centre for Integrative Bioinformatics VU, VU University Amsterdam, Amsterdam, The Netherlands. hettling@few.vu.nl', 'Netherlands|Netherlands', 19, 'Adenosine Triphosphate|Animals|Computational Biology|Creatine Kinase|Cytosol|Energy Metabolism|Isoenzymes|Mitochondria|Mitochondrial Membranes|Models, Biological|Monte Carlo Method|Myocardial Contraction|Myocardium|Phosphocreatine|Rabbits|Rats', 'Journal Article', '10.1371/journal.pcbi.1002130', '21912519', 'In this study the function of the two isoforms of creatine kinase (CK, EC 2.7.3.2) in myocardium is investigated. The phosphocreatine shuttle hypothesis states that mitochondrial and cytosolic CK plays a pivotal role in the transport of high-energy phosphate (HEP) groups from mitochondria to myofibrils in contracting muscle. Temporal buffering of changes in ATP and ADP is another potential role of CK. With a mathematical model, we analyzed energy transport and damping of high peaks of ATP hydrolysis during the cardiac cycle. The analysis was based on multiscale data measured at the level of isolated enzymes, isolated mitochondria and on dynamic response times of oxidative phosphorylation measured at the whole heart level. Using sloppy modeling ensemble simulations, we derived confidence intervals for predictions of the contributions by phosphocreatine (PCr) and ATP to the transfer of HEP from mitochondria to sites of ATP hydrolysis. Our calculations indicate that only 15±8% (mean±SD) of transcytosolic energy transport is carried by PCr, contradicting the PCr shuttle hypothesis. We also predicted temporal buffering capabilities of the CK isoforms protecting against high peaks of ATP hydrolysis (3750 µM*s(-1)) in myofibrils. CK inhibition by 98% in silico leads to an increase in amplitude of mitochondrial ATP synthesis pulsation from 215±23 to 566±31 µM*s(-1), while amplitudes of oscillations in cytosolic ADP concentration double from 77±11 to 146±1 µM. Our findings indicate that CK acts as a large bandwidth high-capacity temporal energy buffer maintaining cellular ATP homeostasis and reducing oscillations in mitochondrial metabolism. However, the contribution of CK to the transport of high-energy phosphate groups appears limited. Mitochondrial CK activity lowers cytosolic inorganic phosphate levels while cytosolic CK has the opposite effect.'),
(85123, 2011, 'plos', 'Structured pathway across the transition state for peptide folding revealed by molecular dynamics simulations', 'Thukral, Lipi|Daidone, Isabella|Smith, Jeremy C', 'Interdisciplinary Center for Scientific Computing, University of Heidelberg, Heidelberg, Germany.|Interdisciplinary Center for Scientific Computing, University of Heidelberg, Heidelberg, Germany.|Interdisciplinary Center for Scientific Computing, University of Heidelberg, Heidelberg, Germany.', 'Germany|Germany|Germany', 6, 'Computational Biology|Kinetics|Molecular Dynamics Simulation|Nuclear Magnetic Resonance, Biomolecular|Peptides|Protein Conformation|Protein Folding|Thermodynamics|Tryptophan', 'Journal Article', '10.1371/journal.pcbi.1002137', '21931542', 'Small globular proteins and peptides commonly exhibit two-state folding kinetics in which the rate limiting step of folding is the surmounting of a single free energy barrier at the transition state (TS) separating the folded and the unfolded states. An intriguing question is whether the polypeptide chain reaches, and leaves, the TS by completely random fluctuations, or whether there is a directed, stepwise process. Here, the folding TS of a 15-residue xcexb2-hairpin peptide, Peptide 1, is characterized using independent 2.5 xcexbcs-long unbiased atomistic molecular dynamics (MD) simulations (a total of 15 xcexbcs). The trajectories were started from fully unfolded structures. Multiple (spontaneous) folding events to the NMR-derived conformation are observed, allowing both structural and dynamical characterization of the folding TS. A common loop-like topology is observed in all the TS structures with native end-to-end and turn contacts, while the central segments of the strands are not in contact. Non-native sidechain contacts are present in the TS between the only tryptophan (W11) and the turn region (P7-G9). Prior to the TS the turn is found to be already locked by the W11 sidechain, while the ends are apart. Once the ends have also come into contact, the TS is reached. Finally, along the reactive folding paths the cooperative loss of the W11 non-native contacts and the formation of the central inter-strand native contacts lead to the peptide rapidly proceeding from the TS to the native state. The present results indicate a directed stepwise process to folding the peptide.'),
(85124, 2011, 'plos', 'A combined experimental and mathematical approach for molecular-based optimization of irinotecan circadian delivery', 'Ballesta, Annabelle|Dulong, Sandrine|Abbara, Chadi|Cohen, Boris|Okyar, Alper|Clairambault, Jean|Levi, Francis', 'INRIA Rocquencourt, BANG project team, Le Chesnay Cedex, France. annabelle.ballesta@inria.fr|INRIA Rocquencourt, BANG project team, Le Chesnay Cedex, France. annabelle.ballesta@inria.fr|INRIA Rocquencourt, BANG project team, Le Chesnay Cedex, France. annabelle.ballesta@inria.fr|INRIA Rocquencourt, BANG project team, Le Chesnay Cedex, France. annabelle.ballesta@inria.fr|INRIA Rocquencourt, BANG project team, Le Chesnay Cedex, France. annabelle.ballesta@inria.fr|INRIA Rocquencourt, BANG project team, Le Chesnay Cedex, France. annabelle.ballesta@inria.fr|INRIA Rocquencourt, BANG project team, Le Chesnay Cedex, France. annabelle.ballesta@inria.fr', 'France|France|France|France|France|France|France', 0, 'Antineoplastic Agents, Phytogenic|Caco-2 Cells|Camptothecin|Circadian Rhythm|Circadian Rhythm Signaling Peptides and Proteins|Computational Biology|DNA Topoisomerases, Type I|Drug Administration Schedule|Drug Chronotherapy|Gene Expression Profiling|Gene Expression Regulation, Neoplastic|Humans|Irinotecan|Models, Biological|RNA, Messenger', 'Journal Article', '10.1371/journal.pcbi.1002143', '21931543', 'Circadian timing largely modifies efficacy and toxicity of many anticancer drugs. Recent findings suggest that optimal circadian delivery patterns depend on the patient genetic background. We present here a combined experimental and mathematical approach for the design of chronomodulated administration schedules tailored to the patient molecular profile. As a proof of concept we optimized exposure of Caco-2 colon cancer cells to irinotecan (CPT11), a cytotoxic drug approved for the treatment of colorectal cancer. CPT11 was bioactivated into SN38 and its efflux was mediated by ATP-Binding-Cassette (ABC) transporters in Caco-2 cells. After cell synchronization with a serum shock defining Circadian Time (CT) 0, circadian rhythms with a period of 26 h 50 (SD 63 min) were observed in the mRNA expression of clock genes REV-ERBxcexb1, PER2, BMAL1, the drug target topoisomerase 1 (TOP1), the activation enzyme carboxylesterase 2 (CES2), the deactivation enzyme UDP-glucuronosyltransferase 1, polypeptide A1 (UGT1A1), and efflux transporters ABCB1, ABCC1, ABCC2 and ABCG2. DNA-bound TOP1 protein amount in presence of CPT11, a marker of the drug PD, also displayed circadian variations. A mathematical model of CPT11 molecular pharmacokinetics-pharmacodynamics (PK-PD) was designed and fitted to experimental data. It predicted that CPT11 bioactivation was the main determinant of CPT11 PD circadian rhythm. We then adopted the therapeutics strategy of maximizing efficacy in non-synchronized cells, considered as cancer cells, under a constraint of maximum toxicity in synchronized cells, representing healthy ones. We considered exposure schemes in the form of an initial concentration of CPT11 given at a particular CT, over a duration ranging from 1 to 27 h. For any dose of CPT11, optimal exposure durations varied from 3h40 to 7h10. Optimal schemes started between CT2h10 and CT2h30, a time interval corresponding to 1h30 to 1h50 before the nadir of CPT11 bioactivation rhythm in healthy cells.'),
(85125, 2011, 'plos', 'Efficacy of synaptic inhibition depends on multiple, dynamically interacting mechanisms implicated in chloride homeostasis', 'Doyon, Nicolas|Prescott, Steven A|Castonguay, Annie|Godin, Antoine G|Kröger, Helmut|De Koninck, Yves', 'Division of Cellular and Molecular Neuroscience, Centre de recherche Université Laval Robert-Giffard, Québec, Québec, Canada.|Division of Cellular and Molecular Neuroscience, Centre de recherche Université Laval Robert-Giffard, Québec, Québec, Canada.|Division of Cellular and Molecular Neuroscience, Centre de recherche Université Laval Robert-Giffard, Québec, Québec, Canada.|Division of Cellular and Molecular Neuroscience, Centre de recherche Université Laval Robert-Giffard, Québec, Québec, Canada.|Division of Cellular and Molecular Neuroscience, Centre de recherche Université Laval Robert-Giffard, Québec, Québec, Canada.|Division of Cellular and Molecular Neuroscience, Centre de recherche Université Laval Robert-Giffard, Québec, Québec, Canada.', 'Canada|Canada|Canada|Canada|Canada|Canada', 85, 'Animals|Cell Membrane|Cells, Cultured|Chlorides|Computational Biology|Computer Simulation|Diffusion|Electrical Synapses|GABA-A Receptor Antagonists|Hippocampus|Hydrogen-Ion Concentration|Immunohistochemistry|Intracellular Space|Microscopy, Fluorescence|Models, Biological|Neurons|Potassium|Rats|Rats, Sprague-Dawley|Receptors, GABA-A|Reproducibility of Results|Sodium|Symporters|gamma-Aminobutyric Acid', 'Journal Article', '10.1371/journal.pcbi.1002149', '21931544', 'Chloride homeostasis is a critical determinant of the strength and robustness of inhibition mediated by GABA(A) receptors (GABA(A)Rs). The impact of changes in steady state Cl(-) gradient is relatively straightforward to understand, but how dynamic interplay between Cl(-) influx, diffusion, extrusion and interaction with other ion species affects synaptic signaling remains uncertain. Here we used electrodiffusion modeling to investigate the nonlinear interactions between these processes. Results demonstrate that diffusion is crucial for redistributing intracellular Cl(-) load on a fast time scale, whereas Cl(-)extrusion controls steady state levels. Interaction between diffusion and extrusion can result in a somato-dendritic Cl(-) gradient even when KCC2 is distributed uniformly across the cell. Reducing KCC2 activity led to decreased efficacy of GABA(A)R-mediated inhibition, but increasing GABA(A)R input failed to fully compensate for this form of disinhibition because of activity-dependent accumulation of Cl(-). Furthermore, if spiking persisted despite the presence of GABA(A)R input, Cl(-) accumulation became accelerated because of the large Cl(-) driving force that occurs during spikes. The resulting positive feedback loop caused catastrophic failure of inhibition. Simulations also revealed other feedback loops, such as competition between Cl(-) and pH regulation. Several model predictions were tested and confirmed by [Cl(-)](i) imaging experiments. Our study has thus uncovered how Cl(-) regulation depends on a multiplicity of dynamically interacting mechanisms. Furthermore, the model revealed that enhancing KCC2 activity beyond normal levels did not negatively impact firing frequency or cause overt extracellular K(-) accumulation, demonstrating that enhancing KCC2 activity is a valid strategy for therapeutic intervention.'),
(85126, 2011, 'plos', 'Retracing micro-epidemics of Chagas disease using epicenter regression', 'Levy, Michael Z|Small, Dylan S|Vilhena, Daril A|Bowman, Natalie M|Kawai, Vivian|Cornejo del Carpio, Juan G|Cordova-Benzaquen, Eleazar|Gilman, Robert H|Bern, Caryn|Plotkin, Joshua B', 'Center for Clinical Epidemiology & Biostatistics, Department of Biostatistics & Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. mzlevy@mail.med.upenn.edu|Center for Clinical Epidemiology & Biostatistics, Department of Biostatistics & Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. mzlevy@mail.med.upenn.edu|Center for Clinical Epidemiology & Biostatistics, Department of Biostatistics & Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. mzlevy@mail.med.upenn.edu|Center for Clinical Epidemiology & Biostatistics, Department of Biostatistics & Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. mzlevy@mail.med.upenn.edu|Center for Clinical Epidemiology & Biostatistics, Department of Biostatistics & Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. mzlevy@mail.med.upenn.edu|Center for Clinical Epidemiology & Biostatistics, Department of Biostatistics & Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. mzlevy@mail.med.upenn.edu|Center for Clinical Epidemiology & Biostatistics, Department of Biostatistics & Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. mzlevy@mail.med.upenn.edu|Center for Clinical Epidemiology & Biostatistics, Department of Biostatistics & Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. mzlevy@mail.med.upenn.edu|Center for Clinical Epidemiology & Biostatistics, Department of Biostatistics & Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. mzlevy@mail.med.upenn.edu|Center for Clinical Epidemiology & Biostatistics, Department of Biostatistics & Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. mzlevy@mail.med.upenn.edu', 'United States|United States|United States|United States|United States|United States|United States|United States|United States|United States', 19, 'Chagas Disease|Cross-Sectional Studies|Epidemics|Humans|Peru|Seroepidemiologic Studies|Trypanosoma cruzi', 'Journal Article', '10.1371/journal.pcbi.1002146', '21935346', 'Vector-borne transmission of Chagas disease has become an urban problem in the city of Arequipa, Peru, yet the debilitating symptoms that can occur in the chronic stage of the disease are rarely seen in hospitals in the city. The lack of obvious clinical disease in Arequipa has led to speculation that the local strain of the etiologic agent, Trypanosoma cruzi, has low chronic pathogenicity. The long asymptomatic period of Chagas disease leads us to an alternative hypothesis for the absence of clinical cases in Arequipa: transmission in the city may be so recent that most infected individuals have yet to progress to late stage disease. Here we describe a new method, epicenter regression, that allows us to infer the spatial and temporal history of disease transmission from a snapshot of a populations infection status. We show that in a community of Arequipa, transmission of T. cruzi by the insect vector Triatoma infestans occurred as a series of focal micro-epidemics, the oldest of which began only around 20 years ago. These micro-epidemics infected nearly 5% of the community before transmission of the parasite was disrupted through insecticide application in 2004. Most extant human infections in our study community arose over a brief period of time immediately prior to vector control. According to our findings, the symptoms of chronic Chagas disease are expected to be absent, even if the strain is pathogenic in the chronic phase of disease, given the long asymptomatic period of the disease and short history of intense transmission. Traducción al español disponible en Alternative Language Text S1/A Spanish translation of this article is available in Alternative Language Text S1.'),
(85127, 2011, 'plos', 'Binding leverage as a molecular basis for allosteric regulation', 'Mitternacht, Simon|Berezovsky, Igor N', 'Computational Biology Unit/UNI Research, University of Bergen, Bergen, Norway.|Computational Biology Unit/UNI Research, University of Bergen, Bergen, Norway.', 'Norway|Norway', 0, 'Allosteric Regulation|Allosteric Site|Drug Design|Models, Molecular|Monte Carlo Method|Protein Conformation|Proteins', 'Journal Article', '10.1371/journal.pcbi.1002148', '21935347', 'Allosteric regulation involves conformational transitions or fluctuations between a few closely related states, caused by the binding of effector molecules. We introduce a quantity called binding leverage that measures the ability of a binding site to couple to the intrinsic motions of a protein. We use Monte Carlo simulations to generate potential binding sites and either normal modes or pairs of crystal structures to describe relevant motions. We analyze single catalytic domains and multimeric allosteric enzymes with complex regulation. For the majority of the analyzed proteins, we find that both catalytic and allosteric sites have high binding leverage. Furthermore, our analysis of the catabolite activator protein, which is allosteric without conformational change, shows that its regulation involves other types of motion than those modulated at sites with high binding leverage. Our results point to the importance of incorporating dynamic information when predicting functional sites. Because it is possible to calculate binding leverage from a single crystal structure it can be used for characterizing proteins of unknown function and predicting latent allosteric sites in any protein, with implications for drug design.'),
(85128, 2011, 'plos', 'A detailed history of intron-rich eukaryotic ancestors inferred from a global survey of 100 complete genomes', 'Csuros, Miklos|Rogozin, Igor B|Koonin, Eugene V', 'Department of Computer Science and Operations Research, Université de Montréal, Montréal, Québec, Canada. csuros@iro.umontreal.ca|Department of Computer Science and Operations Research, Université de Montréal, Montréal, Québec, Canada. csuros@iro.umontreal.ca|Department of Computer Science and Operations Research, Université de Montréal, Montréal, Québec, Canada. csuros@iro.umontreal.ca', 'Canada|Canada|Canada', 0, 'Alternative Splicing|Animals|Eukaryota|Evolution, Molecular|Genome|Humans|Introns|Markov Chains', 'Journal Article', '10.1371/journal.pcbi.1002150', '21935348', 'Protein-coding genes in eukaryotes are interrupted by introns, but intron densities widely differ between eukaryotic lineages. Vertebrates, some invertebrates and green plants have intron-rich genes, with 6-7 introns per kilobase of coding sequence, whereas most of the other eukaryotes have intron-poor genes. We reconstructed the history of intron gain and loss using a probabilistic Markov model (Markov Chain Monte Carlo, MCMC) on 245 orthologous genes from 99 genomes representing the three of the five supergroups of eukaryotes for which multiple genome sequences are available. Intron-rich ancestors are confidently reconstructed for each major group, with 53 to 74% of the human intron density inferred with 95% confidence for the Last Eukaryotic Common Ancestor (LECA). The results of the MCMC reconstruction are compared with the reconstructions obtained using Maximum Likelihood (ML) and Dollo parsimony methods. An excellent agreement between the MCMC and ML inferences is demonstrated whereas Dollo parsimony introduces a noticeable bias in the estimations, typically yielding lower ancestral intron densities than MCMC and ML. Evolution of eukaryotic genes was dominated by intron loss, with substantial gain only at the bases of several major branches including plants and animals. The highest intron density, 120 to 130% of the human value, is inferred for the last common ancestor of animals. The reconstruction shows that the entire line of descent from LECA to mammals was intron-rich, a state conducive to the evolution of alternative splicing.'),
(85129, 2011, 'plos', 'A switching mechanism in doxorubicin bioactivation can be exploited to control doxorubicin toxicity', 'Finn, Nnenna A|Findley, Harry W|Kemp, Melissa L', 'Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA.|Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA.|Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA.', 'Georgia|Georgia|Georgia', 0, 'Antibiotics, Antineoplastic|Cell Line, Tumor|Doxorubicin|Humans|Models, Biological|NADP|Oxidation-Reduction|Oxygen|Precursor Cell Lymphoblastic Leukemia-Lymphoma|Superoxides', 'Journal Article', '10.1371/journal.pcbi.1002151', '21935349', 'Although doxorubicin toxicity in cancer cells is multifactorial, the enzymatic bioactivation of the drug can significantly contribute to its cytotoxicity. Previous research has identified most of the components that comprise the doxorubicin bioactivation network, however, adaptation of the network to changes in doxorubicin treatment or to patient-specific changes in network components is much less understood. To investigate the properties of the coupled reduction/oxidation reactions of the doxorubicin bioactivation network, we analyzed metabolic differences between two patient-derived acute lymphoblastic leukemia (ALL) cell lines exhibiting varied doxorubicin sensitivities. We developed computational models that accurately predicted doxorubicin bioactivation in both ALL cell lines at high and low doxorubicin concentrations. Oxygen-dependent redox cycling promoted superoxide accumulation while NADPH-dependent reductive conversion promoted semiquinone doxorubicin. This fundamental switch in control is observed between doxorubicin sensitive and insensitive ALL cells and between high and low doxorubicin concentrations. We demonstrate that pharmacological intervention strategies can be employed to either enhance or impede doxorubicin cytotoxicity in ALL cells due to the switching that occurs between oxygen-dependent superoxide generation and NADPH-dependent doxorubicin semiquinone formation.'),
(85130, 2011, 'plos', 'Integrating quantitative knowledge into a qualitative gene regulatory network', 'Bourdon, Jérémie|Eveillard, Damien|Siegel, Anne', 'Computational Biology (ComBi) Group, LINA UMR 6241, Université de Nantes, Ecole des Mines de Nantes & CNRS, Nantes, France. Jeremie.Bourdon@univ-nantes.fr|Computational Biology (ComBi) Group, LINA UMR 6241, Université de Nantes, Ecole des Mines de Nantes & CNRS, Nantes, France. Jeremie.Bourdon@univ-nantes.fr|Computational Biology (ComBi) Group, LINA UMR 6241, Université de Nantes, Ecole des Mines de Nantes & CNRS, Nantes, France. Jeremie.Bourdon@univ-nantes.fr', 'France|France|France', 6, 'Algorithms|Carbon|Escherichia coli|Gene Expression Regulation|Gene Regulatory Networks|Models, Statistical', 'Journal Article', '10.1371/journal.pcbi.1002157', '21935350', 'Despite recent improvements in molecular techniques, biological knowledge remains incomplete. Any theorizing about living systems is therefore necessarily based on the use of heterogeneous and partial information. Much current research has focused successfully on the qualitative behaviors of macromolecular networks. Nonetheless, it is not capable of taking into account available quantitative information such as time-series protein concentration variations. The present work proposes a probabilistic modeling framework that integrates both kinds of information. Average case analysis methods are used in combination with Markov chains to link qualitative information about transcriptional regulations to quantitative information about protein concentrations. The approach is illustrated by modeling the carbon starvation response in Escherichia coli. It accurately predicts the quantitative time-series evolution of several protein concentrations using only knowledge of discrete gene interactions and a small number of quantitative observations on a single protein concentration. From this, the modeling technique also derives a ranking of interactions with respect to their importance during the experiment considered. Such a classification is confirmed by the literature. Therefore, our method is principally novel in that it allows (i) a hybrid model that integrates both qualitative discrete model and quantities to be built, even using a small amount of quantitative information, (ii) new quantitative predictions to be derived, (iii) the robustness and relevance of interactions with respect to phenotypic criteria to be precisely quantified, and (iv) the key features of the model to be extracted that can be used as a guidance to design future experiments.'),
(85131, 2011, 'plos', 'Filament depolymerization can explain chromosome pulling during bacterial mitosis', 'Banigan, Edward J|Gelbart, Michael A|Gitai, Zemer|Wingreen, Ned S|Liu, Andrea J', 'Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Bacterial Proteins|Caulobacter crescentus|Chromosome Segregation|Chromosomes, Bacterial|Computer Simulation|Mitosis|Models, Genetic|Molecular Dynamics Simulation|Polymerization|Protein Binding', 'Journal Article', '10.1371/journal.pcbi.1002145', '21966261', 'Chromosome segregation is fundamental to all cells, but the force-generating mechanisms underlying chromosome translocation in bacteria remain mysterious. Caulobacter crescentus utilizes a depolymerization-driven process in which a ParA protein structure elongates from the new cell pole, binds to a ParB-decorated chromosome, and then retracts via disassembly, pulling the chromosome across the cell. This poses the question of how a depolymerizing structure can robustly pull the chromosome that disassembles it. We perform Brownian dynamics simulations with a simple, physically consistent model of the ParABS system. The simulations suggest that the mechanism of translocation is self-diffusiophoretic: by disassembling ParA, ParB generates a ParA concentration gradient so that the ParA concentration is higher in front of the chromosome than behind it. Since the chromosome is attracted to ParA via ParB, it moves up the ParA gradient and across the cell. We find that translocation is most robust when ParB binds side-on to ParA filaments. In this case, robust translocation occurs over a wide parameter range and is controlled by a single dimensionless quantity: the product of the rate of ParA disassembly and a characteristic relaxation time of the chromosome. This time scale measures the time it takes for the chromosome to recover its average shape after it is has been pulled. Our results suggest explanations for observed phenomena such as segregation failure, filament-length-dependent translocation velocity, and chromosomal compaction.'),
(85132, 2011, 'plos', 'Neuromotor noise, error tolerance and velocity-dependent costs in skilled performance', 'Sternad, Dagmar|Abe, Masaki O|Hu, Xiaogang|Müller, Hermann', 'Departments of Biology, Electrical and Computer Engineering, and Physics, Northeastern University, Boston, Massachusetts, United States of America. dagmar@neu.edu|Departments of Biology, Electrical and Computer Engineering, and Physics, Northeastern University, Boston, Massachusetts, United States of America. dagmar@neu.edu|Departments of Biology, Electrical and Computer Engineering, and Physics, Northeastern University, Boston, Massachusetts, United States of America. dagmar@neu.edu|Departments of Biology, Electrical and Computer Engineering, and Physics, Northeastern University, Boston, Massachusetts, United States of America. dagmar@neu.edu', 'United States|United States|United States|United States', 0, 'Adult|Arm|Female|Humans|Learning|Linear Models|Male|Models, Biological|Motor Skills|Task Performance and Analysis|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.1002159', '21966262', 'In motor tasks with redundancy neuromotor noise can lead to variations in execution while achieving relative invariance in the result. The present study examined whether humans find solutions that are tolerant to intrinsic noise. Using a throwing task in a virtual set-up where an infinite set of angle and velocity combinations at ball release yield throwing accuracy, our computational approach permitted quantitative predictions about solution strategies that are tolerant to noise. Based on a mathematical model of the task expected results were computed and provided predictions about error-tolerant strategies (Hypothesis 1). As strategies can take on a large range of velocities, a second hypothesis was that subjects select strategies that minimize velocity at release to avoid costs associated with signal- or velocity-dependent noise or higher energy demands (Hypothesis 2). Two experiments with different target constellations tested these two hypotheses. Results of Experiment 1 showed that subjects chose solutions with high error-tolerance, although these solutions also had relatively low velocity. These two benefits seemed to outweigh that for many subjects these solutions were close to a high-penalty area, i.e. they were risky. Experiment 2 dissociated the two hypotheses. Results showed that individuals were consistent with Hypothesis 1 although their solutions were distributed over a range of velocities. Additional analyses revealed that a velocity-dependent increase in variability was absent, probably due to the presence of a solution manifold that channeled variability in a task-specific manner. Hence, the general acceptance of signal-dependent noise may need some qualification. These findings have significance for the fundamental understanding of how the central nervous system deals with its inherent neuromotor noise.'),
(85133, 2011, 'plos', 'Network-based prediction and analysis of HIV dependency factors', 'Murali, T M|Dyer, Matthew D|Badger, David|Tyler, Brett M|Katze, Michael G', 'Department of Computer Science, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America. murali@cs.vt.edu|Department of Computer Science, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America. murali@cs.vt.edu|Department of Computer Science, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America. murali@cs.vt.edu|Department of Computer Science, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America. murali@cs.vt.edu|Department of Computer Science, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America. murali@cs.vt.edu', 'United States|United States|United States|United States|United States', 30, 'Algorithms|Animals|Cercopithecus aethiops|Cluster Analysis|Databases, Protein|Disease Progression|HIV|HIV Infections|Host-Pathogen Interactions|Human Immunodeficiency Virus Proteins|Humans|Macaca nemestrina|Models, Statistical|Protein Interaction Mapping|Proteins|Proteomics|RNA Interference|Reproducibility of Results|Simian Acquired Immunodeficiency Syndrome|Simian Immunodeficiency Virus|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.1002164', '21966263', 'HIV Dependency Factors (HDFs) are a class of human proteins that are essential for HIV replication, but are not lethal to the host cell when silenced. Three previous genome-wide RNAi experiments identified HDF sets with little overlap. We combine data from these three studies with a human protein interaction network to predict new HDFs, using an intuitive algorithm called SinkSource and four other algorithms published in the literature. Our algorithm achieves high precision and recall upon cross validation, as do the other methods. A number of HDFs that we predict are known to interact with HIV proteins. They belong to multiple protein complexes and biological processes that are known to be manipulated by HIV. We also demonstrate that many predicted HDF genes show significantly different programs of expression in early response to SIV infection in two non-human primate species that differ in AIDS progression. Our results suggest that many HDFs are yet to be discovered and that they have potential value as prognostic markers to determine pathological outcome and the likelihood of AIDS development. More generally, if multiple genome-wide gene-level studies have been performed at independent labs to study the same biological system or phenomenon, our methodology is applicable to interpret these studies simultaneously in the context of molecular interaction networks and to ask if they reinforce or contradict each other.'),
(85134, 2011, 'plos', 'Network models of TEM xcexb2-lactamase mutations coevolving under antibiotic selection show modular structure and anticipate evolutionary trajectories', 'Guthrie, Violeta Beleva|Allen, Jennifer|Camps, Manel|Karchin, Rachel', 'Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.', 'United States|United States|United States|United States', 22, 'Adaptation, Biological|Anti-Bacterial Agents|Cefotaxime|Databases, Genetic|Epistasis, Genetic|Escherichia coli|Evolution, Molecular|Genes, Bacterial|Models, Genetic|Mutation|Sequence Alignment|beta-Lactam Resistance|beta-Lactamases', 'Journal Article', '10.1371/journal.pcbi.1002184', '21966264', 'Understanding how novel functions evolve (genetic adaptation) is a critical goal of evolutionary biology. Among asexual organisms, genetic adaptation involves multiple mutations that frequently interact in a non-linear fashion (epistasis). Non-linear interactions pose a formidable challenge for the computational prediction of mutation effects. Here we use the recent evolution of xcexb2-lactamase under antibiotic selection as a model for genetic adaptation. We build a network of coevolving residues (possible functional interactions), in which nodes are mutant residue positions and links represent two positions found mutated together in the same sequence. Most often these pairs occur in the setting of more complex mutants. Focusing on extended-spectrum resistant sequences, we use network-theoretical tools to identify triple mutant trajectories of likely special significance for adaptation. We extrapolate evolutionary paths (nxe2x80x8a=xe2x80x8a3) that increase resistance and that are longer than the units used to build the network (nxe2x80x8a=xe2x80x8a2). These paths consist of a limited number of residue positions and are enriched for known triple mutant combinations that increase cefotaxime resistance. We find that the pairs of residues used to build the network frequently decrease resistance compared to their corresponding singlets. This is a surprising result, given that their coevolution suggests a selective advantage. Thus, xcexb2-lactamase adaptation is highly epistatic. Our method can identify triplets that increase resistance despite the underlying rugged fitness landscape and has the unique ability to make predictions by placing each mutant residue position in its functional context. Our approach requires only sequence information, sufficient genetic diversity, and discrete selective pressures. Thus, it can be used to analyze recent evolutionary events, where coevolution analysis methods that use phylogeny or statistical coupling are not possible. Improving our ability to assess evolutionary trajectories will help predict the evolution of clinically relevant genes and aid in protein design.');
